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Normal growth despite abnormalities of growthhormone secretion in children treated for acute leukemia
May 1979 The Journal o f P E D I A T R I C S
719
Normal growth despite abnormalities of growth hormone secretion in children treated for acute leukemia We have studied the relationship between abnormalities of the growth hormone-somatomedin axis and growth in 26 children previously treated for acute lymphatic leukemia. Each chiM had previously received cranial irradiation, was in complete clinical and hematologic remission, and off all drugs. The mean standing height SDS of the 26 children was significantly less than normal. There was no significant difference between the mean standing height SDS, height velocity SDS, somatomedin activities, and degree of bone age retardation between the 17 children who received the higher dose of cranial irradiation (Group I) and the nine who had the lower dose of cranial irradiation (Group 11). Furthermore, there was no significant reduction in mean height velocity SDS, somatomedin activity, or bone age in either group when compared to normal age-matched controls. The peak GH responses to both insulin hypoglycemia and an arginine test were significantly lowered in Groups I and 11 when compared to a control group of children. We conclude that only a minority of children, who previously received cranial irradiation for A L L were clinically GH deficient and, therefore, likely to benefit from GH therapy despite the finding that the majority of these children had reduced GH responses to pharmacologic stimuli.
Stephen M. Shalet,* David A. Price, Colin G. Beardwell, Patrieia H. Morris Jones, and Dorothy Pearson,
S IN C E the introduction of prophylactic central nervous system irradiation and combination chemotherapy there has been a major improvement in the prognosis of children treated for acute lymphatic leukemia.'. 2 Early reports had conflicted as to whether such treatment adversely affected growth? , ' Previously, we studied ~ growth hormone secretion in 25 children previously treated for ALL. Eleven, all of whom received 2,500 rads cranial irradiation over 21/2 weeks, showed impaired GH responses to both insulin hypoglycemia and Bovril. However, other groups 6, 7 have described normal GH responses to provocative stimuli in children similarly treated. In view of these discrepancies we decided to study the relationship between abnormalities of the GH-somatomedin axis and growth in children previously treated for ALL. Supported by a grant from the Leukemia Research Fund. *Reprint address: Christie Hospital and Holt Radium Institute, Withington, Manchester M20 9BX, England
0022-3476/79/500719+04500.40/0 9 1979 The C. V. Mosby Co.
Manchester, England
PATIENTS AND METHODS Twenty-six children were studied; 17 were boys. In view of the differences in GH responses to provocative stimuli previously noted 5 among children with ALL receiving different doses of cranial irradiation, the children were divided into two groups, dependent on the dose of Abbreviations used GH: growth hormone ALL: acute lymphatic leukemia SDS: standard deviation score ITT: insulin tolerance test SM: somatomedin cerebral irradiation received. Group I (17 subjects) received 2,500 rads in 10 fractions over 2~/~ weeks. Group II (9 subjects) received 2,400 rads in 20 fractions over 4 weeks. All patients had been treated for leukemia and, at the time of the study, were in complete clinical and hematologic remission. Chemotherapy had been completed at least one year before the study in all patients.
Iiol. 94, No. 5, pp. 719-722
720
Shalet et al.
The Journal of Pediatrics Mav 1979
Table I. The mean chronological and bone ages, standing height SDS, height velocity SDS, and somatomedin activities (_+ SD)
Mean age chronotogical(yr) Group I Group II
10.2 _+ 1.9 8.86 + 2.6
Mean bone age (yr)
Mean standing height SDS
9.2 + 1.9 8.22 __. 2.6
-0.76 + 1.0 -0.57 • 1.6
[
Table II. The mean basal and lowest blood glucose levels during the ITT (___SD)and the median peak GH responses to the ITT and to arginine
Group I
GroupII
Control group
Mean basal blood 4.27 _+ 0.35 4.37 _+ 0.31 3.98 _+_0.67 glucose (retool/1) Mean lowest blood 1.96 _+ 0.40 1.82 _+ 0.21 1.91 _+ 0.47 glucose during ITT (retool/l) Median peak GH re22 29 50.5 sponse to arginine (mU/1) Inter-quartile range 12-37 22-32 35-90 (rnU/l) Median peak GH re17 30 45.5 sponse to ITT (mU/1) Inter-quartile range 9-19 24-40 29-89 (mU/l)
Eleven in Group I and all nine in Group II had spinal irradiation. The chemotherapy schedules used were UKALL I, U K A L L II, CONCORD, and MEMPHIS. The drugs included in each regimen have been described elsewhere? Seventeen of the 26 children were prepubertal during the study and nine were at different stages of pubertal maturation. A control group of 16 children (mean age 7.0 years) underwent the two provocative tests of GH secretion to be described. All children in this group were prepubertal; 11 had ALL and were studied when off all drug therapy, in remission and clinically well, and before receiving cranial irradiation. The remainder were examples of constitutional short stature and delayed development. The standing height of each child in Groups I and II was measured at approximately four-month intervals for one complete year. The standing height standard deviation score was estimated by the tables of Tanner et al 9 using the most recent measurement of the child and the chronological age. For height velocity SDS, the whole-
Mean height velocity SDS -0.02 • 1.9 -0.37 -4- 1.3
Mean somatomedin activity (units/ml) 0.67 +_ 0.25 0.57 _+ 0.18
year standards of Tanner et al 9 were used, based on the child's chronological age. Bone age was assessed by the method of Greulich and Pyle. ~~ The provocative tests of GH secretion used were the insulin tolerance test and arginine stimulation test. The details of the insulin tolerance test and GH assay have been described elsewhere. 5 On a separate morning, after an overnight fast and following a 30-minute equilibration period, arginine monohydrochloride 20 g m / m 2 (20 gm/dl, buffered to pH 7~4) was infused intravenously over 30 minutes. Blood was collected at 0, 30, 60, 90, 120, and 150 minutes for GH assay. All samples for somatomedin estimation were taken between 9 and 10 AM, after an overnight fast. Serum was separated without delay and stored at - 2 0 ~ until assayed. The serum somatomedin activity was estimated by the porcine cartilage bioassay:~ using a 24-hour preincubation and a 48-hour incubation with standard and test sera. During the last 24 hours of incubation, radiolabeled (35S) sodium sulphate was added. Test sera were compared to a standard pool of serum obtained from five normal adult males, having, by definition, a potency of 1 unit/ml. Results were analyzed according to the statistical method described by Finney ~2for 6 to 8 point parallel line assays of symmetrical design. The index of precision of all assays was ~: 0.15. The statistical significance of the results was evaluated using one sample t tests, Kruskal-Wallis and the MannWhitney-u test, ~3 depending on whether or not the data were normally distributed. RESULTS The mean (___ SD) chronological age, bone age, standing height SDS, height velocity SDS, and SM activities in Groups I and II are shown in Table I. There was no significant difference in the mean chronological ages of the two groups nor was there a significant degree of bone age retardation in either group. The mean standing height SDS of all 26 children (-0.69) was significantly different ( P < 0 . 0 1 ) from nought (normal children), but there was no significant difference between the two groups.
Vohlme 94 N,mber 5
The mean height velocity SDS of each group was neither significantly different from nought nor from each other. The mean SM activities of the two groups were not significantly different from each other. The mean activity in Group I, but not in Group II, was significantly greater (P < 0.01) than the mean SM-activity of 30 normal children (0.47 ___ 0.12) between 3 and 14 years of age. The mean basal blood glucose and the mean lowest blood glucose levels observed during the ITT are shown in Table II. The peak GH responses to the two provocative stimuli were not normally distributed in Groups I and II and, therefore, nonparametric statistical analysis was carried out. The median peak GH responses to the ITT and arginine tests are shown in Table II. In agreement with the results of our previous study 5 the GH responses of Group I to hypoglycemia were significantly less than those of Group II (P < 0.002) or of the controls (P < 0.002) although the degree of hypoglycemia attained was not significantly different among the three groups. Fourteen of the 17 patients in Group I failed to reach the minimum peak concentration (20 mU/1) seen in normal children. In Group II only one child failed to attain this level but the response of the group as a whole was significantly less than that of the control group (P < 0.05). The results of the arginine stimulation test were a little different. The test was carried out in 16 of the 17 in Group I, of whom ten showed a normal response while six failed to attain the minimum peak level of 20 mU/l. Eight of the children, who had shown an impaired response to an ITT, showed a normal response to arginine while the converse situation was seen only once. The peak levels attained by Group I in this test were significantly lower than those of the control group (P < 0.002). In group II, seven children had an arginine test and six showed a normal response. The peak level of Group II, in this test, was significantly lower than that of the control group (P < 0.02). There was no significant difference between the peak levels of Groups I and II. When the responses to hypoglycemia and to arginine in the control group were compared, a significant correlation was found (Pearson correlation coefficient r = 0.7:P < 0.01). There were no significant correlations between the GH responses to an ITT and to arginine for Groups I and II. Furthermore, there was a significant difference between the peak GH responses to the ITT and to arginine in Group I (P = 0.05) but not in Group II or the controls. One girl in group 1 has been treated with exogenous GH. Her peak GH responses to both an ITT (5.0 mU/1) and to a Bovril stimulation test (9.0 mU/1) were impaired.
A b n o r m a l G H secretion in leukemia
721
She, also, had the lowest SM-activity and height velocity SDS in the study and during the pretreatment year grew 3.1 cm. During her first year of GH therapy she grew 5.8 cm. Throughout these two years she remained prepubertal, suggesting that there had been a significant growth response to the GH. DISCUSSION The findings in this study strongly confirm the original impression that many children in Group I had impaired GH responses to an ITT. 5 Comparison with the results in the control group, revealed that not only were the GH responses to arginine and to an ITT significantly lowered in Group I, but the GH responses to both stimuli in Group II, while holding an intermediate position between the values in Group I a n d the controls, were significantly lower than the latter. Despite the biochemical evidence of impaired GH secretion, it was rare to find clinical evidence of GH deficiency. The children in Groups I and II had normal or high normal SM-activities, no significant degree of bone age retardation and grew at a normal rate. It appears likely that the physiologic requirements of GH, necessary for normal growth, have been met. In agreement with this conclusion, several authors have shown that the majority of children with ALL in clinical remission and off all chemotherapy showed a normal growth pattern.6.14 However, dynamic tests of GH secretion have produced conflicting results with both normal 6.~ and abnormal GH responses reported. 5. 15 This discrepancy was almost certainly due to the variation in the dose of radiation received by the hypothalamic-pituitary axis. Despite the normal growth pattern of the children with ALL when in clinical remission and off all chemotherapy, the children were significantly smaller than normal children of the same age. This was almost certainly due to the previous three-year course of chemotherapy plus the effects of the disease itself. The site of pathologic damage in the central nervous system of these children is unknown. Samaan et al TM showed that both the hypothalamus and the pituitary gland were radiosensitive. In our study the GH responses of Group I to both an ITT and to arginine were blunted in comparison with those of the control group. However, there was a significant difference in the GH responses to these two provocative stimuli in the Group I children. The significantly greater impairment of the GH response to insulin hypoglycemia following radiation to the hypothalamic-pituitary axis in Group I suggested that the hypothalamus rather than the pituitary gland was likely to be the site of damage in the children. The practical conclusion from our study is that only a
722
Shalet et al.
1-he Journal of Pediatrics May 1979
minority of children, who previously received cranial irradiation for ALL, were clinically GH deficient and, therefore, likely to benefit from GH therapy, despite the finding that the majority of these children had reduced GH responses to pharmacologic stimuli. Therefore, our present policy with such children is the same as that for any child with a potential growth disorder. We measure the growth rate at regular intervals and only if this has declined significantly do we test GH secretion. We thank M. Goode, M. P. Astin, and M. Barker for technical assistance, R. Swindell for statistical advice, and Mrs J. Franks for typing the manuscript.
REFERENCES
7.
8.
9.
10.
11.
1. Hustu HO, Aur RJA, Verzosa MS, Simone JV, and Pinkel D: Prevention of central nervous system leukemia by irradiation, Cancer 32:585, 1973. 2. Aur RJA, Simone JV, Hustu HO, and Verzosa MS: A comparative study of central .nervous system irradiation and intensive chemotherapy early in remission of childhood acute lymphocytic leukemia, Cancer 29:381, 1972. 3. Sunderman CR, and Pearson HA: Growth effects of longterm antileukemic therapy. J Pediatr 75:1058, 1969. 4. Pinkel D: Five-year follow-up of 'total therapy' of childhood lymphocytic leukemia, JAMA 216:648, 1971. 5. Shalet SM, Beardwell CG, Twomey JA, Morris Jones PH, and Pearson D: Endocrine function following the treatment of acute leukemia in childhood, J PEDIATR90:920, 1977. 6. Swift PGF, Kearney PJ, Dalton RG, Bullimore JA, Mott MG, and Savage DCL: Growth and hormonal status of
12. 13. 14.
15.
16.
children treated for acute lymphoblastic leukemia, Arch Dis Child 53:890, 1978. Muhlendahl KEV, Gadner H, Riehm H, Helge H, Weber B, and Muller-Hess R: Endocrine function after antineoplastic therapy in 22 children with acute lymphoblastic leukemia, Helv Paediatr Acta 31:463, 1976. Shalet SM, Beardwell CG, Morris Jones PH, and Pearson D: Growth hormone deficiency after treatment of acute leukemia in children. Arch Dis Child 51:489, 1976. Tanner JM, Whitehouse RH, and Takaishi M: Standards from birth to maturity for height, weight, height velocity and weight velocity. British children (1965), Arch Dis Child 41:454, 1966. Greulich WW, and Pyle SI: Radiographic atlas of skeletal development of the hand and wrist, Stanford, 1959, Stanford University Press. Van der Brande JL, and du Caju MVL: An improved technique for measuring somatomedin activity in vitro, Acta Endocrinol (Kbh) 75:233, 1974. Finney DJ: Statistical method in biological assay, ed 2, London, 1967, Griffin. Siegel S: Nonparametric studies, New York, 1956, McGraw-Hill Book Company, Inc. Verzosa MS, Aur RJA, Simone JV, Hustu HO, and Pinkel D: Five years after central nervous system irradiation of children with leukemia, Int J Radiat Oncol Biol Phys 1:209, 1976. Schiliro G, Russo A, Sciotto A, Distefano G, and Vigo R: Radiotherapy, chemotherapy and growth hormone deficiency, Lancet 2:1031, 1976. Samaan NA, Bakdash MM, Caderao JB, Cangir A, Jesse RH, and Ballantyne AJ: Hypopituitarism after external irradiation, Ann Intern Med 83:771, 1975.
Copyright information The appearance of a code at the bottom of the first page of an original article in this JOURNALindicates the copyright owner's consent that copies of the article may be made for personal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., P.O. Box 765, Schenectady, N.Y. 12301, (518) 374-4430, for copying beyond that permitted by Sections 107 or 108 of the U.S. Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale.
719
Normal growth despite abnormalities of growth hormone secretion in children treated for acute leukemia We have studied the relationship between abnormalities of the growth hormone-somatomedin axis and growth in 26 children previously treated for acute lymphatic leukemia. Each chiM had previously received cranial irradiation, was in complete clinical and hematologic remission, and off all drugs. The mean standing height SDS of the 26 children was significantly less than normal. There was no significant difference between the mean standing height SDS, height velocity SDS, somatomedin activities, and degree of bone age retardation between the 17 children who received the higher dose of cranial irradiation (Group I) and the nine who had the lower dose of cranial irradiation (Group 11). Furthermore, there was no significant reduction in mean height velocity SDS, somatomedin activity, or bone age in either group when compared to normal age-matched controls. The peak GH responses to both insulin hypoglycemia and an arginine test were significantly lowered in Groups I and 11 when compared to a control group of children. We conclude that only a minority of children, who previously received cranial irradiation for A L L were clinically GH deficient and, therefore, likely to benefit from GH therapy despite the finding that the majority of these children had reduced GH responses to pharmacologic stimuli.
Stephen M. Shalet,* David A. Price, Colin G. Beardwell, Patrieia H. Morris Jones, and Dorothy Pearson,
S IN C E the introduction of prophylactic central nervous system irradiation and combination chemotherapy there has been a major improvement in the prognosis of children treated for acute lymphatic leukemia.'. 2 Early reports had conflicted as to whether such treatment adversely affected growth? , ' Previously, we studied ~ growth hormone secretion in 25 children previously treated for ALL. Eleven, all of whom received 2,500 rads cranial irradiation over 21/2 weeks, showed impaired GH responses to both insulin hypoglycemia and Bovril. However, other groups 6, 7 have described normal GH responses to provocative stimuli in children similarly treated. In view of these discrepancies we decided to study the relationship between abnormalities of the GH-somatomedin axis and growth in children previously treated for ALL. Supported by a grant from the Leukemia Research Fund. *Reprint address: Christie Hospital and Holt Radium Institute, Withington, Manchester M20 9BX, England
0022-3476/79/500719+04500.40/0 9 1979 The C. V. Mosby Co.
Manchester, England
PATIENTS AND METHODS Twenty-six children were studied; 17 were boys. In view of the differences in GH responses to provocative stimuli previously noted 5 among children with ALL receiving different doses of cranial irradiation, the children were divided into two groups, dependent on the dose of Abbreviations used GH: growth hormone ALL: acute lymphatic leukemia SDS: standard deviation score ITT: insulin tolerance test SM: somatomedin cerebral irradiation received. Group I (17 subjects) received 2,500 rads in 10 fractions over 2~/~ weeks. Group II (9 subjects) received 2,400 rads in 20 fractions over 4 weeks. All patients had been treated for leukemia and, at the time of the study, were in complete clinical and hematologic remission. Chemotherapy had been completed at least one year before the study in all patients.
Iiol. 94, No. 5, pp. 719-722
720
Shalet et al.
The Journal of Pediatrics Mav 1979
Table I. The mean chronological and bone ages, standing height SDS, height velocity SDS, and somatomedin activities (_+ SD)
Mean age chronotogical(yr) Group I Group II
10.2 _+ 1.9 8.86 + 2.6
Mean bone age (yr)
Mean standing height SDS
9.2 + 1.9 8.22 __. 2.6
-0.76 + 1.0 -0.57 • 1.6
[
Table II. The mean basal and lowest blood glucose levels during the ITT (___SD)and the median peak GH responses to the ITT and to arginine
Group I
GroupII
Control group
Mean basal blood 4.27 _+ 0.35 4.37 _+ 0.31 3.98 _+_0.67 glucose (retool/1) Mean lowest blood 1.96 _+ 0.40 1.82 _+ 0.21 1.91 _+ 0.47 glucose during ITT (retool/l) Median peak GH re22 29 50.5 sponse to arginine (mU/1) Inter-quartile range 12-37 22-32 35-90 (rnU/l) Median peak GH re17 30 45.5 sponse to ITT (mU/1) Inter-quartile range 9-19 24-40 29-89 (mU/l)
Eleven in Group I and all nine in Group II had spinal irradiation. The chemotherapy schedules used were UKALL I, U K A L L II, CONCORD, and MEMPHIS. The drugs included in each regimen have been described elsewhere? Seventeen of the 26 children were prepubertal during the study and nine were at different stages of pubertal maturation. A control group of 16 children (mean age 7.0 years) underwent the two provocative tests of GH secretion to be described. All children in this group were prepubertal; 11 had ALL and were studied when off all drug therapy, in remission and clinically well, and before receiving cranial irradiation. The remainder were examples of constitutional short stature and delayed development. The standing height of each child in Groups I and II was measured at approximately four-month intervals for one complete year. The standing height standard deviation score was estimated by the tables of Tanner et al 9 using the most recent measurement of the child and the chronological age. For height velocity SDS, the whole-
Mean height velocity SDS -0.02 • 1.9 -0.37 -4- 1.3
Mean somatomedin activity (units/ml) 0.67 +_ 0.25 0.57 _+ 0.18
year standards of Tanner et al 9 were used, based on the child's chronological age. Bone age was assessed by the method of Greulich and Pyle. ~~ The provocative tests of GH secretion used were the insulin tolerance test and arginine stimulation test. The details of the insulin tolerance test and GH assay have been described elsewhere. 5 On a separate morning, after an overnight fast and following a 30-minute equilibration period, arginine monohydrochloride 20 g m / m 2 (20 gm/dl, buffered to pH 7~4) was infused intravenously over 30 minutes. Blood was collected at 0, 30, 60, 90, 120, and 150 minutes for GH assay. All samples for somatomedin estimation were taken between 9 and 10 AM, after an overnight fast. Serum was separated without delay and stored at - 2 0 ~ until assayed. The serum somatomedin activity was estimated by the porcine cartilage bioassay:~ using a 24-hour preincubation and a 48-hour incubation with standard and test sera. During the last 24 hours of incubation, radiolabeled (35S) sodium sulphate was added. Test sera were compared to a standard pool of serum obtained from five normal adult males, having, by definition, a potency of 1 unit/ml. Results were analyzed according to the statistical method described by Finney ~2for 6 to 8 point parallel line assays of symmetrical design. The index of precision of all assays was ~: 0.15. The statistical significance of the results was evaluated using one sample t tests, Kruskal-Wallis and the MannWhitney-u test, ~3 depending on whether or not the data were normally distributed. RESULTS The mean (___ SD) chronological age, bone age, standing height SDS, height velocity SDS, and SM activities in Groups I and II are shown in Table I. There was no significant difference in the mean chronological ages of the two groups nor was there a significant degree of bone age retardation in either group. The mean standing height SDS of all 26 children (-0.69) was significantly different ( P < 0 . 0 1 ) from nought (normal children), but there was no significant difference between the two groups.
Vohlme 94 N,mber 5
The mean height velocity SDS of each group was neither significantly different from nought nor from each other. The mean SM activities of the two groups were not significantly different from each other. The mean activity in Group I, but not in Group II, was significantly greater (P < 0.01) than the mean SM-activity of 30 normal children (0.47 ___ 0.12) between 3 and 14 years of age. The mean basal blood glucose and the mean lowest blood glucose levels observed during the ITT are shown in Table II. The peak GH responses to the two provocative stimuli were not normally distributed in Groups I and II and, therefore, nonparametric statistical analysis was carried out. The median peak GH responses to the ITT and arginine tests are shown in Table II. In agreement with the results of our previous study 5 the GH responses of Group I to hypoglycemia were significantly less than those of Group II (P < 0.002) or of the controls (P < 0.002) although the degree of hypoglycemia attained was not significantly different among the three groups. Fourteen of the 17 patients in Group I failed to reach the minimum peak concentration (20 mU/1) seen in normal children. In Group II only one child failed to attain this level but the response of the group as a whole was significantly less than that of the control group (P < 0.05). The results of the arginine stimulation test were a little different. The test was carried out in 16 of the 17 in Group I, of whom ten showed a normal response while six failed to attain the minimum peak level of 20 mU/l. Eight of the children, who had shown an impaired response to an ITT, showed a normal response to arginine while the converse situation was seen only once. The peak levels attained by Group I in this test were significantly lower than those of the control group (P < 0.002). In group II, seven children had an arginine test and six showed a normal response. The peak level of Group II, in this test, was significantly lower than that of the control group (P < 0.02). There was no significant difference between the peak levels of Groups I and II. When the responses to hypoglycemia and to arginine in the control group were compared, a significant correlation was found (Pearson correlation coefficient r = 0.7:P < 0.01). There were no significant correlations between the GH responses to an ITT and to arginine for Groups I and II. Furthermore, there was a significant difference between the peak GH responses to the ITT and to arginine in Group I (P = 0.05) but not in Group II or the controls. One girl in group 1 has been treated with exogenous GH. Her peak GH responses to both an ITT (5.0 mU/1) and to a Bovril stimulation test (9.0 mU/1) were impaired.
A b n o r m a l G H secretion in leukemia
721
She, also, had the lowest SM-activity and height velocity SDS in the study and during the pretreatment year grew 3.1 cm. During her first year of GH therapy she grew 5.8 cm. Throughout these two years she remained prepubertal, suggesting that there had been a significant growth response to the GH. DISCUSSION The findings in this study strongly confirm the original impression that many children in Group I had impaired GH responses to an ITT. 5 Comparison with the results in the control group, revealed that not only were the GH responses to arginine and to an ITT significantly lowered in Group I, but the GH responses to both stimuli in Group II, while holding an intermediate position between the values in Group I a n d the controls, were significantly lower than the latter. Despite the biochemical evidence of impaired GH secretion, it was rare to find clinical evidence of GH deficiency. The children in Groups I and II had normal or high normal SM-activities, no significant degree of bone age retardation and grew at a normal rate. It appears likely that the physiologic requirements of GH, necessary for normal growth, have been met. In agreement with this conclusion, several authors have shown that the majority of children with ALL in clinical remission and off all chemotherapy showed a normal growth pattern.6.14 However, dynamic tests of GH secretion have produced conflicting results with both normal 6.~ and abnormal GH responses reported. 5. 15 This discrepancy was almost certainly due to the variation in the dose of radiation received by the hypothalamic-pituitary axis. Despite the normal growth pattern of the children with ALL when in clinical remission and off all chemotherapy, the children were significantly smaller than normal children of the same age. This was almost certainly due to the previous three-year course of chemotherapy plus the effects of the disease itself. The site of pathologic damage in the central nervous system of these children is unknown. Samaan et al TM showed that both the hypothalamus and the pituitary gland were radiosensitive. In our study the GH responses of Group I to both an ITT and to arginine were blunted in comparison with those of the control group. However, there was a significant difference in the GH responses to these two provocative stimuli in the Group I children. The significantly greater impairment of the GH response to insulin hypoglycemia following radiation to the hypothalamic-pituitary axis in Group I suggested that the hypothalamus rather than the pituitary gland was likely to be the site of damage in the children. The practical conclusion from our study is that only a
722
Shalet et al.
1-he Journal of Pediatrics May 1979
minority of children, who previously received cranial irradiation for ALL, were clinically GH deficient and, therefore, likely to benefit from GH therapy, despite the finding that the majority of these children had reduced GH responses to pharmacologic stimuli. Therefore, our present policy with such children is the same as that for any child with a potential growth disorder. We measure the growth rate at regular intervals and only if this has declined significantly do we test GH secretion. We thank M. Goode, M. P. Astin, and M. Barker for technical assistance, R. Swindell for statistical advice, and Mrs J. Franks for typing the manuscript.
REFERENCES
7.
8.
9.
10.
11.
1. Hustu HO, Aur RJA, Verzosa MS, Simone JV, and Pinkel D: Prevention of central nervous system leukemia by irradiation, Cancer 32:585, 1973. 2. Aur RJA, Simone JV, Hustu HO, and Verzosa MS: A comparative study of central .nervous system irradiation and intensive chemotherapy early in remission of childhood acute lymphocytic leukemia, Cancer 29:381, 1972. 3. Sunderman CR, and Pearson HA: Growth effects of longterm antileukemic therapy. J Pediatr 75:1058, 1969. 4. Pinkel D: Five-year follow-up of 'total therapy' of childhood lymphocytic leukemia, JAMA 216:648, 1971. 5. Shalet SM, Beardwell CG, Twomey JA, Morris Jones PH, and Pearson D: Endocrine function following the treatment of acute leukemia in childhood, J PEDIATR90:920, 1977. 6. Swift PGF, Kearney PJ, Dalton RG, Bullimore JA, Mott MG, and Savage DCL: Growth and hormonal status of
12. 13. 14.
15.
16.
children treated for acute lymphoblastic leukemia, Arch Dis Child 53:890, 1978. Muhlendahl KEV, Gadner H, Riehm H, Helge H, Weber B, and Muller-Hess R: Endocrine function after antineoplastic therapy in 22 children with acute lymphoblastic leukemia, Helv Paediatr Acta 31:463, 1976. Shalet SM, Beardwell CG, Morris Jones PH, and Pearson D: Growth hormone deficiency after treatment of acute leukemia in children. Arch Dis Child 51:489, 1976. Tanner JM, Whitehouse RH, and Takaishi M: Standards from birth to maturity for height, weight, height velocity and weight velocity. British children (1965), Arch Dis Child 41:454, 1966. Greulich WW, and Pyle SI: Radiographic atlas of skeletal development of the hand and wrist, Stanford, 1959, Stanford University Press. Van der Brande JL, and du Caju MVL: An improved technique for measuring somatomedin activity in vitro, Acta Endocrinol (Kbh) 75:233, 1974. Finney DJ: Statistical method in biological assay, ed 2, London, 1967, Griffin. Siegel S: Nonparametric studies, New York, 1956, McGraw-Hill Book Company, Inc. Verzosa MS, Aur RJA, Simone JV, Hustu HO, and Pinkel D: Five years after central nervous system irradiation of children with leukemia, Int J Radiat Oncol Biol Phys 1:209, 1976. Schiliro G, Russo A, Sciotto A, Distefano G, and Vigo R: Radiotherapy, chemotherapy and growth hormone deficiency, Lancet 2:1031, 1976. Samaan NA, Bakdash MM, Caderao JB, Cangir A, Jesse RH, and Ballantyne AJ: Hypopituitarism after external irradiation, Ann Intern Med 83:771, 1975.
Copyright information The appearance of a code at the bottom of the first page of an original article in this JOURNALindicates the copyright owner's consent that copies of the article may be made for personal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., P.O. Box 765, Schenectady, N.Y. 12301, (518) 374-4430, for copying beyond that permitted by Sections 107 or 108 of the U.S. Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale.