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Departments of Endocrinology (H.K.G., L.S., S.M.S.), Clinical Oncology (H.R.G.), and Paediatric Oncology (B.M.B.), Christie Hospital, Manchester, M20 4BX, United Kingdom
Address all correspondence and requests for reprints to: Professor S. M. Shalet, Department of Endocrinology, Christie Hospital, Wilmslow Road, Withington, Manchester, M20 4BX, United Kingdom. E-mail: Helena.Gleeson{at}christie-tr.nwest.nhs.uk.
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Abstract |
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To investigate whether patients diagnosed in childhood as GHD secondary to irradiation require retesting after FH, GH status has been reassessed in a large cohort of irradiated children treated with GH during childhood.
Seventy-three children underwent biochemical assessment of GH status after irradiation and again at FH after GH therapy had been discontinued; 66 and 67 of the 73 patients underwent two provocative tests at the two time points, respectively. The characteristics of the cohort include a median age at irradiation of 5 yr (range, 1–11 yr), a median biological effective dose (BED) of irradiation to the hypothalamic pituitary axis of 54 Gy (range, 23–82 Gy), and a median time of GH status reassessment after FH of 0.4 yr (range, 0–8.4 yr).
During childhood, patients with all degrees of GHD (peak GH responses to provocative test < 6.7 ng/ml) are treated, whereas in adulthood, only patients with severe GHD (peak GH responses to provocative test < 3 ng/ml) are considered for GH replacement. GH status has been grouped as follows: group 1, peak GH less than 3 ng/ml to both tests (severe GHD); group 2, one test with a peak GH less than 3 ng/ml and the other test with a peak of 3 ng/ml or greater; group 3, peak GH of 3–6.7 ng/ml to both tests; group 4, one test with a peak GH of 3–6.7 ng/ml and the other test with a peak of more than 6.7 ng/ml; and group 5, peak GH more than 6.7 ng/ml to both tests (normal GH status). In childhood, the number of patients in groups 1, 2, 3, and 4 were 33, 22, 17, and one, respectively. At retesting, severe GHD was diagnosed in 21 (64%) of 33 patients who were diagnosed in childhood with severe GHD (group 1) and 17 (44%) of 39 patients who were diagnosed in childhood with moderate GHD (groups 2 and 3). In total, 35 (48%) of 73 patients in the whole cohort and 12 (36%) of 33 patients with severe GHD in childhood did not fulfill the severe GHD biochemical criteria for GH replacement in adulthood. Using multiple linear regression, GH status at retesting is predicted by BED, age at irradiation, and use of chemotherapy.
In conclusion, the diagnosis of severe GHD in childhood secondary to irradiation should not be taken as irrefutable evidence of permanent severe organic GHD, and our recommendation is that retesting of GH status at FH should be mandatory.
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Introduction |
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There are several reasons why retesting at FH should be mandatory in patients who are replaced with GH during childhood. The biochemical criteria for diagnosing GHD in childhood differ from those used in adulthood. There are few data on peak GH responses during provocative tests in normal children (6, 7, 8), but patients with all degrees of GHD from severe to mild are considered for GH replacement in childhood; thus, the threshold cutoff (i.e. GH < 6.7 ng/ml; 1 ng/ml = 3 mU/liter) for diagnosis is both arbitrary and probably generous (9). In contrast in adulthood, only those patients who are severely GHD (i.e. GH < 3 ng/ml) on provocative testing are considered for GH replacement (10). Therefore, patients fulfilling the criteria for GH replacement in childhood will not necessarily do so in adulthood. Pharmacological tests of GH status also have low reproducibility in childhood (7, 11) and adulthood (12, 13, 14, 15), and therefore, an individual testing GHD on one occasion may not do so on a subsequent occasion.
GHD after radiation damage to the hypothalamic pituitary axis is well recognized. It is one of the few evolving forms of GHD, i.e. with time there is a decline in GH secretion (16). Therefore, patients who are partially GHD in childhood may become severely GHD in adulthood. However, radiation-induced GHD is also dose dependent (17), and therefore, not all cranial irradiation (CI) schedules will result in GHD.
Recently the Growth Hormone Research Society (GRS) drew up consensus guidelines for the management of GHD in childhood and adolescence and recommended that, in childhood, for "those with ... history of irradiation, multiple pituitary hormone deficits (MPHD) or a genetic defect, one test will suffice," and then, after FH, it recommends that "patients with severe long-standing MPHD, those with genetic defects, and those with severe organic GHD can be excluded from GH retesting." This statement suggests that patients testing severely GHD in childhood with a history of irradiation constitute a cohort of patients affected by severe organic GHD, and therefore retesting of such individuals is unnecessary (9).
To clarify whether teenagers require retesting at FH if they have been treated with GH for radiation-induced GHD during childhood, data on GH status before and after childhood GH replacement therapy have been analyzed.
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Subjects and Methods |
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Information was collected on age at irradiation, irradiation schedule, use of chemotherapy (CT), time lapsed between irradiation and retesting for GHD, time lapsed between cessation of GH and retesting for GHD, body mass index (BMI) at retesting, and other pituitary hormone deficits.
Characteristics of the cohort as a whole and patients with brain tumors and hematological malignancies are presented in Table 1
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The physical radiation dose affecting the hypothalamic pituitary axis was transformed to the biological effective dose (BED) using the following linear quadratic model: BED = D x [1 + d/(
/ß)], where D is the total dose, d is the fraction size, represents the linear nonreparable component of cell killing, and ß represents the reparable quadratic component of cell killing. /ß equals 3, which is the value taken for late responding tissue (18).
The brain tumor group received the following CI schedules. Fifteen children with the histological diagnosis of a locally invasive tumor received a fractionated course of radiotherapy (median total dose, 42.5 Gy in 16 fractions over 21 d). One patient received local irradiation to the posterior fossa only, and two patients received radiation to the orbit or optic nerve, whereas the remaining 12 patients received radiation to the hemispheres.
Thirty-one children who had tumors with the propensity to disseminate throughout the central nervous system received an initial fractionated course of radiotherapy to the tumor site (median dose, 15 Gy in 10 fractions over 11 d), followed by a course of radiotherapy to the whole head and spine (median dose, 30 Gy in 20 fractions over 27 d). Twenty-seven patients received local radiation to the posterior fossa, two received radiation to the pineal gland, and the remaining two patients received radiation to the hemispheres.
Three children treated before 1972 received multiple-field irradiation (two field), including the spine, without a separate dose to the tumor site (median dose, 27 Gy in 17 fractions over 22 d).
The patients with hematological malignancies received the following CI schedules. Three patients received total body irradiation (TBI) alone (12 Gy in 3 fractions, n = 1; 14 Gy in 8 fractions, n = 2; BED, 23–25 Gy); nine patients received 18 Gy in 10 fractions (BED, 29–30 Gy) and five received 24 Gy in 12 fractions (BED, 40–46 Gy) of CI; three patients received CI (18 Gy in 10 fractions) plus TBI (14 Gy in 8 fractions; BED, 52–54 Gy); and four patients received both 18 Gy in 10 fractions and 24 Gy in 12 fractions of CI (BED, 69–72 Gy).
CT
Of the brain tumor group, 18 patients received 12–18 months of CT in the treatment of the original disease, which consisted of vincristine alone (1.5 mg/m2, n = 3) or in combination with carmustine (100 mg/m2, n = 3) given every 6 wk for a period of 12 months (Manchester protocol before 1975); vincristine (1.5 mg/m2) in combination with lomustine alone (40 mg/m2, n = 2) or also with procarbazine (100 mg/m2, n = 10) given for a period of 18 months (United Kingdom Children’s Cancer Study Group protocol after 1979). Three additional children received other CT for a shorter time interval as follows: two courses of mustine, vincristine, prednisolone, and procarbazine (n = 1); cisplatinum (n = 1); and actinomycin (n = 1).
All children with hematological malignancies received CT. The regimens used for ALL patients and the patient with non-Hodgkin’s lymphoma were the Manchester Protocol (n = 1), and Medical Research Council Acute Lymphoblastic Leukemia Trials (UKALL) IV (n = 1), VI (n = 1), VIII (n = 6), and X (n = 11). A further two patients also went on to receive UKALL XI at relapse. UKALL IV and VI and the Manchester Protocol contain the drugs vincristine, prednisolone, L-asparaginase, methotrexate, and 6-mercaptopurine, but they were administered in a pulse manner. UKALL VIII used the same drugs but administered in a sustained manner, and UKALL X and X1 were similar to the standard regimens with the addition of intensification blocks of treatment in some but not all patients. Five patients went on to receive preparative CT for bone marrow transplantation, which consisted of high-dose cyclophosphamide. In the treatment of the four patients with acute myeloblastic leukemia, the subjects received intensive blocks of treatment consisting of courses of cytarabine, daunorubicin, and etoposide; cytarabine, daunorubicin, and thioguanine; mitoxantrone, cytarabine, and etoposide; and amsacrine, cytarabine, and etoposide.
Biochemical testing of GH status
GH status was assessed in childhood before starting GH therapy and in adulthood when FH had been achieved and after GH had been discontinued. Conventional GH stimulation tests were used to diagnose GHD [insulin tolerance test (ITT), arginine stimulation test (AST), and glucagon stimulation test (GST)] (19). Details of tests used to diagnose GHD were recorded.
The results of the GH tests in childhood and adulthood were grouped as follows: group 1, peak GH less than 3 ng/ml to both tests (severe GHD); group 2, one test with a peak GH less than 3 ng/ml and the other test with a peak of 3 ng/ml or more (discordant GH results); group 3, peak GH of 3–6.7 ng/ml to both tests; group 4, one test with a peak GH of 3–6.7 ng/ml and the other test with a peak greater than 6.7 ng/ml; and group 5, peak GH greater than 6.7 ng/ml to both tests (normal GH status). Those patients who underwent only one test were placed into group 1, 3, or 5 depending on the result.
Assays
Serum GH levels were measured by a two-site immunoradiometric assay, with a limit of sensitivity of 0.4 ng/ml. The reference preparation used was National Institute for Biological Standards and Control (NIBSC) 66/217 until March 1990, when the results were reported using NIBSC 80/505, which produced results 1.2 times those obtained with the previous preparation. GH levels from the patients who were assessed before January 2, 1990, have been multiplied by a factor of 1.2 to allow comparison with the GH levels obtained after this date. Within- and between-batch coefficients of variation were less than 15% at all measurable analyte concentrations.
Statistics
Data are presented as median (range). The rank sum test was used to look for differences between GH status groups. Data for age at irradiation and GH response to ITT and AST were not normally distributed and were thus transformed using natural log (ln). Multiple linear regression analyses were then used to examine whether the independent factors [age at irradiation (ln), BED, use of CT, time lapsed between irradiation and retesting of GH status and BMI] were predictive of GH status at FH [GH status group and GH response to ITT and AST (ln)].
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Results |
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The numbers of patients taking other hormone replacement therapy at last review were as follows: three patients were on hydrocortisone replacement, 17 were on thyroxine replacement (15 due to direct radiation damage to the thyroid), and 16 were on sex steroid replacement (10 due to primary gonadal failure). In total, nine patients had evidence of pituitary hormone deficits other than GH. The median BED in these patients was 68 Gy (range, 43–77 Gy). Eight of the nine patients had severe GHD in adulthood.
Diagnosis of GHD
The tests performed to diagnose GHD were as follows. Before GH replacement, 66 patients had two tests (53 and 13 had ITT + AST and GST + AST, respectively), six patients had a single test (ITT, n = 5; and AST, n = 1), and one patient had a GH profile. After GH replacement was discontinued at FH, 67 patients had two tests (53, 13, and one had ITT + AST, GST + AST, and ITT + GST, respectively), and six patients had a single test (ITT, n = 4; AST, n = 1; and GST, n = 1). Ninety-one percent of patients at both time points had two diagnostic tests. Seventy-one percent (52 of 73 patients) had the same two biochemical tests at both time points (44 and eight patients had an ITT + AST and GST + AST, respectively). Similarly, 61, 53, and nine patients had an AST, ITT, and GST, respectively, at both time points.
The tests at FH were performed at a median time of 0.4 yr (range, 0–8.4 yr) after GH replacement was discontinued.
Factors affecting GH status at FH
Overall, the percentage of patients fulfilling the biochemical criteria for severe GHD increased from 45% in childhood to 52% in adulthood (Table 2). In 48% of patients, however, the criteria of severe GHD in adulthood were not met. Forty percent of patients did not alter their GH status category, whereas 30% showed improved and 30% showed reduced GH status defined by provocative testing. Fourteen percent of the whole group had a normal GH response to at least one provocative test on retesting.
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). A similar percentage remained severely GHD when only data from the same two (Table 3) or same single biochemical tests at both time points in an individual patient were assessed. In total, 17 (43%) of 40 children diagnosed with partial GHD in childhood became severely GHD in adulthood (Table 2).
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50%) to be severely GHD on retesting at FH were patients treated either for brain tumors or those patients with hematological malignancies who had received a BED of more than 40 Gy (Table 4). Patients who received TBI or 18 Gy of CI in the treatment of hematological malignancies were much less likely (<20%) to be severely GHD on retesting.
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). GH response to ITT and to AST at FH was predicted by BED and by BED and age at irradiation (ln), respectively (Table 5). Although a younger age at irradiation was an independent factor in developing a more marked degree of GHD, age at irradiation itself was closely correlated with the timing after irradiation at which retesting occurred (r = -0.8, P < 0.001); therefore, the effect of age at irradiation on GH status at FH may in part simply reflect the postirradiation time interval.
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), revealed that only BED (higher in the former) but not age at irradiation, use of CT, time of retesting after irradiation, or BMI was a significant influence.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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There is a more than 50% likelihood of GHD if the BED is greater than 40 Gy. Consequently, none of the patients who underwent fractionated TBI in preparation for bone marrow transplantation alone, despite receiving GH during childhood, were severely GHD on retesting at FH (23). Similarly, in the treatment of ALL, patients receiving 18 Gy of CI rather than 24 Gy were less likely to test severely GHD (21).
Age at radiotherapy was an independent predictor of GH status at FH, which is an observation that may be explained by evolving GHD, i.e. the younger the patient is at irradiation, the longer period of time is after irradiation before retesting during which severe GHD may develop. Higher doses of CI result in a more rapid decline in GH secretion than lower doses (22); therefore, a more prolonged period of follow-up after irradiation may result in severe GHD being diagnosed after lower doses of irradiation.
Use of CT was also a confounding variable for developing GHD. There are limited data that suggest that CT may increase the chance of developing radiation-induced GHD (24). The mechanism by which this effect may occur is unclear.
Transition from childhood to adulthood is a key time in GH replacement strategy as the indication for replacement changes from all degrees of GHD in childhood, i.e. GH < 6.7 ng/ml (9), to severe GHD in adults, i.e. GH < 3 ng/ml to provocative testing (10). At the same time, spontaneous GH secretion is much higher in a teenager compared with an adult. Therefore, because the criteria defining severe GHD in adults were derived from studies in middle-aged adults (25), it may be inappropriate to use the same threshold for diagnosing severe GHD in teenagers. Nonetheless, consensus guidelines (9) from the leading authority on GH issues in the world, GRS, advise that GH replacement during the transition period from childhood to adulthood should be considered in patients fulfilling the adult GHD diagnostic criteria (10). The consensus guidelines (9) also suggest that children with a history of CI do not need retesting at FH, a recommendation which encompasses an understanding of the evolution of GHD after irradiation but totally fails to take into consideration the dose dependency of this process. Consequently, the finding that 36% of patients treated with GH for severe radiation-induced GHD during childhood are not severely GHD at retesting implies that the same 36% would have been misclassified if no test had been performed.
Therefore, we must conclude that the advice from the GRS on retesting at FH for children with radiation-induced GHD is erroneous. To establish which patients should be considered for continued GH during the transition period from childhood to adulthood among the patients that have received childhood GH replacement for radiation-induced GHD, retesting should be considered mandatory. Our data suggest that only one of every two children treated with GH for radiation-induced GHD will qualify for GH replacement in adult life and emphasize that the likelihood of developing severe GHD is dose dependent. Finally, those patients retesting as partially GHD at FH require continued follow-up and retesting because they may become severely GHD in the future.
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Footnotes |
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Received July 15, 2003.
Accepted October 17, 2003.
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