2 Irradiation-induced growth failure S. M. S H A L E T E. C. C R O W N E
M. A. DIDI A . L. O G I L V Y - S T U A R T W. H . B. W A L L A C E
Therapeutic irradiation in childhood may affect final height adversely for a number of reasons, which include growth hormone (GH) deficiency, impaired spinal growth and precocious or early puberty. The risk of radiation-induced GH deficiency is related to the dose of radiation received by the hypothalamic-pituitary axis. Thus, although the risk is readily estimated in those receiving whole head irradiation, it is often extremely difficult to calculate the dose received by the hypothalamicpituitary axis in those receiving focal cranial irradiation, e.g. posterior fossa. Children at particular risk include those irradiated for brain tumours, such as medulloblastoma, ependymoma and glioma, or extracranial turnouts, including nasopharyngeal carcinoma and retinoblastoma, and those who have received prophylactic whole head irradiation for acute lymphoblastic leukaemia (ALL) or other leukaemias. In addition, GH deficiency may occur in those children with leukaemia or other malignant disorders who receive total body irradiation (TBI) as part of the preparative treatment to suppress the immune system and eradicate the underlying malignant disorder prior to bone marrow transplantation. Impaired growth of the whole spine has been reported in those children receiving craniospinal irradiation for a brain tumour or TBI for leukaemia, and impaired growth of part of the spine may occur in children in whom the spine is contained within the abdominal or thoracic field of irradiation. Early or precocious puberty may occur in either sex following cranial irradiation for a brain tumour but only appears to occur in girls following prophylactic cranial irradiation for ALL. The variation in sex-incidence for this complication may be dose-related in that the children treated for brain tumours tend to receive higher doses of cranial irradiation than those receiving prophylactic cranial irradiation for ALL. BailliOre's Clinical Endocrinology and Metabolism-513 Vol. 6, No. 3, July 1992 Copyright © 1992, by Bailli6re Tindall ISBN 0-7020--1620-9 All rights of reproduction in any form reserved
514
S.M.
SHALET ET AL
FACTORS INFLUENCING GH DEFICIENCY Radiation schedule
The radiobiological impact of an irradiation schedule is dependent on the total dose, number of fractions and duration. The same total given in fewer fractions over a shorter period is likely to cause a greater incidence of G H deficiency than if the schedule were spread over a longer time with a greater number of fractions. Thus, Shalet et al (1979) observed G H deficiency in 14 out of 17 ALL children who received cranial irradiation in a schedule of 2500 cGy in ten fractions over 21/2weeks but only in one out of nine children who received 2400 cGy in 20 fractions over 4 weeks. The radiation schedule for TBI consists of a dose of approximately 750-1300cGy administered either as a single dose or multiple fractions. Either schedule may induce G H deficiency (Leiper et al, 1987a; Borgstrom and Bolme, 1988; Sanders et al, 1988; Clark et al, 1991) but it is unclear if the single dose schedule does so more frequently.
Dose
The degree of pituitary hormonal deficit is related to the radiation dose received by the hypothalamic-pituitary axis. Thus after lower radiation doses, isolated GH deficiency ensues, whilst higher doses may produce panhypopituitarism. In the vast majority of children considered in this review the G H deficiency is isolated; however, in certain centres, children with brain tumours or nasopharyngeal carcinoma may receive a higher dose of irradiation to the hypothalamic-pituitary axis, leading to other pituitary hormone deficits. In addition, children irradiated for brain tumours show a high prevalence of primary thyroid dysfunction (Livesey and Brook, 1989; Ogilvy-Stuart et al, 1991), which is greater after craniospinal irradiation but is still significantly in excess of that seen in the normal population in those receiving cranial irradiation. In a number of children the thyroid dysfunction proves reversible with time but a significant number of children will require thyroxine replacement therapy (Ogilvy-Stuart et al, 1991). Similarly, after TBI there is a high incidence of primary thyroid dysfunction (Leiper et al, 1987a; Sanders et al, 1988; Katsanis et al, 1990; Clark et al, 1991). The greater the radiation dose the earlier GH deficiency will occur after treatment, so that between 2 and 5 years after irradiation 100% of children receiving :> 3000cGy (over 3 weeks) to the hypothalamic-pituitary axis showed subnormal GH responses to an insulin tolerance test (ITT), whilst 35% of those receiving < 3000 cGy (over 3 weeks) still show a normal G H response (Clayton and Shalet, 1991a). The prospective studies, however, have concentrated on G H responses to provocative tests: the speed of onset of G H deficiency detected by measurement of spontaneous GH secretion following radiation-induced damage and the natural history of G H deficiency after TBI remain unknown.
515
IRRADIATION-INDUCEDGROWTH FAILURE
AGE AND PUBERTAL STATUS In the human, investigations of G H secretion after cranial irradiation support the experimental animal data, which show the central nervous system (CNS) of young animals to be more radiosensitive than that of older animals. After a mean time of 2.8 years following TBI (1000-1320 cGy in 5-6 fractions over 3 days), all 18 adults showed a normal G H response to an ITT (Littley et at, 1991), whilst after a mean time of 2.2 years after a similar TBI schedule (1100-1520 cGy in 3-8 fractions over 2-5 days) 13 out of 29 children showed subnormal G H responses to an ITT (Clark et al, 1991). Three of the 13 children had also received cranial irradiation previously, which might have explained the GH deficiency, but no other irradiation had been administered to the remaining 10 children. Thus the CNS of children appears more radiosensitive than that of adults. Furthermore, there is some evidence in children receiving prophylactic cranial irradiation for ALL that the younger the child then the greater the susceptibility to radiation-induced GH deficiency (Brauner et al, 1986). GROWTH HORMONE TESTS
A further factor influencing the prevalence of radiation-induced GH deficiency will be the type of investigation used to assess G H secretion. Chrousos et al (1982) showed in the irradiated primate model that physiological GH secretion could be severely reduced in quantity in an animal which showed a normal G H response to arginine or L-dopa stimulation. Similarly Blatt et al (1984) reported normal GH responses to a pharmacological stimulus but subnormal spontaneous GH secretion in a group of children who received prophylactic cranial irradiation for ALL. This phenomenon has been described as radiation-induced GH neurosecretory dysfunction. RADIATION-INDUCED GH DEFICIENCY
RADIATION DOSE
PHYSIOLOGICAL GH DEFICIENCY
M. A. DIDI A . L. O G I L V Y - S T U A R T W. H . B. W A L L A C E
Therapeutic irradiation in childhood may affect final height adversely for a number of reasons, which include growth hormone (GH) deficiency, impaired spinal growth and precocious or early puberty. The risk of radiation-induced GH deficiency is related to the dose of radiation received by the hypothalamic-pituitary axis. Thus, although the risk is readily estimated in those receiving whole head irradiation, it is often extremely difficult to calculate the dose received by the hypothalamicpituitary axis in those receiving focal cranial irradiation, e.g. posterior fossa. Children at particular risk include those irradiated for brain tumours, such as medulloblastoma, ependymoma and glioma, or extracranial turnouts, including nasopharyngeal carcinoma and retinoblastoma, and those who have received prophylactic whole head irradiation for acute lymphoblastic leukaemia (ALL) or other leukaemias. In addition, GH deficiency may occur in those children with leukaemia or other malignant disorders who receive total body irradiation (TBI) as part of the preparative treatment to suppress the immune system and eradicate the underlying malignant disorder prior to bone marrow transplantation. Impaired growth of the whole spine has been reported in those children receiving craniospinal irradiation for a brain tumour or TBI for leukaemia, and impaired growth of part of the spine may occur in children in whom the spine is contained within the abdominal or thoracic field of irradiation. Early or precocious puberty may occur in either sex following cranial irradiation for a brain tumour but only appears to occur in girls following prophylactic cranial irradiation for ALL. The variation in sex-incidence for this complication may be dose-related in that the children treated for brain tumours tend to receive higher doses of cranial irradiation than those receiving prophylactic cranial irradiation for ALL. BailliOre's Clinical Endocrinology and Metabolism-513 Vol. 6, No. 3, July 1992 Copyright © 1992, by Bailli6re Tindall ISBN 0-7020--1620-9 All rights of reproduction in any form reserved
514
S.M.
SHALET ET AL
FACTORS INFLUENCING GH DEFICIENCY Radiation schedule
The radiobiological impact of an irradiation schedule is dependent on the total dose, number of fractions and duration. The same total given in fewer fractions over a shorter period is likely to cause a greater incidence of G H deficiency than if the schedule were spread over a longer time with a greater number of fractions. Thus, Shalet et al (1979) observed G H deficiency in 14 out of 17 ALL children who received cranial irradiation in a schedule of 2500 cGy in ten fractions over 21/2weeks but only in one out of nine children who received 2400 cGy in 20 fractions over 4 weeks. The radiation schedule for TBI consists of a dose of approximately 750-1300cGy administered either as a single dose or multiple fractions. Either schedule may induce G H deficiency (Leiper et al, 1987a; Borgstrom and Bolme, 1988; Sanders et al, 1988; Clark et al, 1991) but it is unclear if the single dose schedule does so more frequently.
Dose
The degree of pituitary hormonal deficit is related to the radiation dose received by the hypothalamic-pituitary axis. Thus after lower radiation doses, isolated GH deficiency ensues, whilst higher doses may produce panhypopituitarism. In the vast majority of children considered in this review the G H deficiency is isolated; however, in certain centres, children with brain tumours or nasopharyngeal carcinoma may receive a higher dose of irradiation to the hypothalamic-pituitary axis, leading to other pituitary hormone deficits. In addition, children irradiated for brain tumours show a high prevalence of primary thyroid dysfunction (Livesey and Brook, 1989; Ogilvy-Stuart et al, 1991), which is greater after craniospinal irradiation but is still significantly in excess of that seen in the normal population in those receiving cranial irradiation. In a number of children the thyroid dysfunction proves reversible with time but a significant number of children will require thyroxine replacement therapy (Ogilvy-Stuart et al, 1991). Similarly, after TBI there is a high incidence of primary thyroid dysfunction (Leiper et al, 1987a; Sanders et al, 1988; Katsanis et al, 1990; Clark et al, 1991). The greater the radiation dose the earlier GH deficiency will occur after treatment, so that between 2 and 5 years after irradiation 100% of children receiving :> 3000cGy (over 3 weeks) to the hypothalamic-pituitary axis showed subnormal GH responses to an insulin tolerance test (ITT), whilst 35% of those receiving < 3000 cGy (over 3 weeks) still show a normal G H response (Clayton and Shalet, 1991a). The prospective studies, however, have concentrated on G H responses to provocative tests: the speed of onset of G H deficiency detected by measurement of spontaneous GH secretion following radiation-induced damage and the natural history of G H deficiency after TBI remain unknown.
515
IRRADIATION-INDUCEDGROWTH FAILURE
AGE AND PUBERTAL STATUS In the human, investigations of G H secretion after cranial irradiation support the experimental animal data, which show the central nervous system (CNS) of young animals to be more radiosensitive than that of older animals. After a mean time of 2.8 years following TBI (1000-1320 cGy in 5-6 fractions over 3 days), all 18 adults showed a normal G H response to an ITT (Littley et at, 1991), whilst after a mean time of 2.2 years after a similar TBI schedule (1100-1520 cGy in 3-8 fractions over 2-5 days) 13 out of 29 children showed subnormal G H responses to an ITT (Clark et al, 1991). Three of the 13 children had also received cranial irradiation previously, which might have explained the GH deficiency, but no other irradiation had been administered to the remaining 10 children. Thus the CNS of children appears more radiosensitive than that of adults. Furthermore, there is some evidence in children receiving prophylactic cranial irradiation for ALL that the younger the child then the greater the susceptibility to radiation-induced GH deficiency (Brauner et al, 1986). GROWTH HORMONE TESTS
A further factor influencing the prevalence of radiation-induced GH deficiency will be the type of investigation used to assess G H secretion. Chrousos et al (1982) showed in the irradiated primate model that physiological GH secretion could be severely reduced in quantity in an animal which showed a normal G H response to arginine or L-dopa stimulation. Similarly Blatt et al (1984) reported normal GH responses to a pharmacological stimulus but subnormal spontaneous GH secretion in a group of children who received prophylactic cranial irradiation for ALL. This phenomenon has been described as radiation-induced GH neurosecretory dysfunction. RADIATION-INDUCED GH DEFICIENCY
RADIATION DOSE
PHYSIOLOGICAL GH DEFICIENCY
