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Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom
Address all correspondence and requests for reprints to: Dr. S. M. Shalet, Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: stephen.m.shalet{at}man.ac.uk.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Therapeutic external irradiation for malignant brain and other head and neck tumors predisposes to the development of deficiencies of one or more pituitary hormones when the hypothalamic-pituitary (HP) axis falls within the radiation field (4, 5, 6). GH secretion is the most vulnerable of the pituitary hormones to radiation-induced damage, with doses as low as 18 Gy shown to result in GH insufficiency many years later (7). Collectively, survivors of childhood and adult malignant brain and other head and neck tumors represent an emerging cohort achieving long-term survival, but often at the expense of untreated endocrine deficits.
The quality of life (QOL) in adults with severe GH deficiency (GHD) has been studied extensively over the last decade or so, and specific characteristics of the QOL impairment have been identified. GHD is associated with impairment in many aspects of QOL, as defined by validated general health and psychological well-being instruments (8, 9, 10, 11, 12, 13). In particular, the QOL domain most affected by GHD is vitality (9).
Since the recognition of the adult GH deficiency syndrome in the late 1980s, GH replacement has increasingly been instituted in subsets of severely GHD patients deemed to benefit from this therapy, such as adults with severe impairment in QOL, provided that a trial of GH replacement results in objective improvement in the latter, and more recently, transitional GHD adults, for its beneficial effects on skeletal and somatic maturation. Studies assessing QOL in severely GHD adults have generally been limited to adults with primary pituitary pathologies and have excluded patients with underlying cancer diagnoses. In only one study has QOL been investigated in adult GHD cancer survivors (14). This study demonstrated significant improvements in QOL for up to 12 months after commencement of GH replacement in adult GHD cancer survivors with severe impairment in QOL at baseline. However, the specific characteristics of the QOL impairment in these individuals may be different from those observed in GHD adults with primary pituitary pathologies. Adverse health status in cancer survivors is well recognized (15, 16, 17, 18), and other factors, in addition to GHD, associated with the cancer diagnosis and/or its treatment may contribute significantly to overall QOL in these subjects.
The aim of this study was to identify the characteristics of QOL impairment in adult GHD survivors of cancer compared with those observed in GHD adults with primary pituitary pathologies and to compare the early and long-term QOL responses to GH replacement in these two groups.
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Subjects and Methods |
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Cancer survivors cohort.
Fifty (27 females) patients with a previous diagnosis of cancer, who were in established long-term remission based on clinical and radiological grounds and in whom severe GHD had been confirmed by standard provocation tests (see below) and a subjectively poor QOL had been noted at clinical interview, were included. The primary underlying cancer diagnoses of these patients are listed in Table 1
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Thirty-two patients had either isolated GHD or only one additional anterior pituitary hormone deficit, 18 patients had multiple additional anterior pituitary hormone deficits, and four patients had vasopressin deficiency. The median age at cancer diagnosis was 13 yr (range, 1–64 yr), and that at study entry was 26 yr (range, 15–72 yr).
Pituitary pathologies cohort. The control group consisted of 47 patients (24 women and 23 men) with severe GHD due to either nonsecreting pituitary adenoma (n = 38) or macroprolactinoma (n = 9). Severe GHD was confirmed by standard provocation tests (see below). A subjectively poor QOL, noted at clinical interview was a requirement for inclusion in the study. Patients with Cushing’s disease, acromegaly, and craniopharyngioma were excluded because of the possible confounding QOL effects of the comorbidities specifically associated with these tumors. Of the 47 patients in this group, only one had childhood-onset GHD, and childhood treatment with GH was discontinued in this individual 13 yr before the current study. Forty-two patients received HP radiotherapy, and 43 patients underwent surgery (25 transsphenoidal, 16 transcranial, one both transsphenoidal and transcranial, and one transethmoidal). Fourteen patients had either isolated GHD or only one additional anterior pituitary hormone deficit, 33 patients had multiple additional anterior pituitary hormone deficits, and four patients had vasopressin deficiency. The median age at primary diagnosis was 46 yr (age range, 15–72), and that at study entry was 56 yr (age range, 30–76).
Study protocol
The study was approved by South Manchester local research ethics committee and the Christie Hospital Clinical Trials Resource Group. All patients gave informed consent for demographic and QOL data to be used in the study. In this study all patients with severe GHD and QOL impairment were managed similarly by a protocol-driven pathway regardless of the etiology of their GHD. Furthermore, the same protocol was used, by the same physicians and in the same clinics, to recruit patients for adult GH replacement from both the patient cohorts studied. QOL was assessed in all severely GHD adults by an in-depth interview about the patients’ day to day physical, psychosocial, and emotional functioning, and an additional consultation detailing adult GH replacement was offered to all individuals in whom severe impairment in QOL was perceived to be present by the endocrinologist and the patient. A trial of GH replacement was then offered if it was believed to be mutually appropriate. Long-term adult GH replacement was instituted in all patients in whom a trial of GH replacement led to a subjective improvement in overall QOL. Moreover, with these selection criteria, a bias toward individuals with the most severe QOL impairment would be expected to occur. Before entering the study, in all patients replacement therapy with sex steroids, T4, hydrocortisone, and desmopressin was optimized and stable for at least 12 months; each patient underwent a general physical examination.
Patients were trained in the use of an automated pen device (Genotropin pen, Pfizer, New York, NY) for sc self-injection of GH. The patients were commenced on GH replacement using the low dose titration method, with the usual starting dose being 0.27 mg/d. The GH dose was subsequently adjusted at intervals of 6–8 wk to normalize the IGF-I to within the range of 2 to –2 SD of the age-adjusted population mean.
The study was of open treatment design. GH replacement was only offered to those patients with severe impairment in QOL, resulting in an active selection bias. QOL was assessed objectively by two self-rating questionnaires: the psychological general well-being schedule (PGWB), which is a generic QOL instrument, and the assessment of GH deficiency in adults (AGHDA), which is a disease-orientated QOL instrument (see below). All patients were questioned specifically about potential side-effects of treatment at each visit to determine the occurrence of adverse events.
Demographic and QOL data relating to the two patient groups were studied at baseline, early follow-up (EFU; range, 6–13 months), and long-term follow-up (LTFU; range, 24–77 months). The mean EFU interval time for the cancer survivors was 9.88 ± 2.23 months (n = 43), and that for the pituitary pathologies group was 9.31 ± 2.65 months (n = 35). The mean LTFU interval for the cancer survivors group was 45.3 ± 13 months (n = 28), and that for the pituitary pathologies group was 47.1 ± 14.6 months (n = 21).
QOL measures
PGWB. This is a generic self-assessment inventory designed to measure intrapersonal affective or emotional state (19). It contains 22 items that are scored on a scale of 0–5; a value of 0 is the most negative, and 5 is the most positive. The score range for the PGWB is 0–110.
AGHDA. This is a self-assessment questionnaire designed for use in adults with GHD (20). The format consists of 25 statements to which a "yes" or "no" response is requested. The score range for the AGHDA is 0–25; a score of 25 represents the greatest morbidity.
Diagnosis of severe GHD
All patients were required to undergo two tests of GH reserve to confirm their GH secretory status, except in the setting of panhypopituitarism and a peak GH response to the insulin tolerance test of less than 3 µg/liter (21). GH status was assessed using the insulin tolerance test (soluble insulin, 0.2 IU/kg, iv), glutathione-S-transferase (glucagon, 1 mg, im), or aspartate aminotransferase (20 g/m2 arginine, iv, as a 20% solution infused over 30 min). In patients with childhood-onset GHD, retesting of GH reserve was repeated after discontinuation of childhood GH replacement. Severe GHD was defined as a peak GH response of less than 3 µg/liter to all stimulation tests undertaken.
Assays
GH was measured by a two-site immunoradiometric assay. Assays were measured against the reference preparation NIBSC 80/505.
IGF-I assays were performed by a hydrochloric acid-ethanol extraction RIA method using synthetic IGF-I for labeling. The assay was performed by Sahlgrenska Hospital, Gothenburg (Nichols Institute Diagnostics, San Juan Capistrano, CA). The reference range of the assay was calculated using normative data from 400 healthy individuals.
Statistical methods
Simple comparisons between groups were made using unpaired t tests.
The structure of the dataset is longitudinal, with three visits per patient and four covariates measured at the level of the individual: body mass index (BMI), age, gender, and group membership. The primary outcome measures were the overall scoring of the QOL instruments, PGWB and AGHDA. Of secondary interest were the six domains of the PGWB.
The statistical modeling framework used for each outcome was the same, namely, mixed effects linear modeling (22); the fact that there are repeated assessments for individuals means that we must allow for correlations between observations made on the same subject. The chosen modeling framework permits this and, after a suitable model has been selected, allows the concentration to be placed on the mean structure, the primary focus here. For simplicity we elected to group the responses at the three visits (baseline, EFU, and LTFU) rather than use the actual times between the visits. Such an approach means that there are only three correlations to model, i.e. those between visits 1 and 2, 1 and 3, and 2 and 3, respectively. It transpired that these correlations were approximately equal, so models with a simple random intercept term were adequate.
Having selected models with an appropriate random structure, models for the mean structure were considered; these are analogous to the familiar multiple regression models. Primary interest lay in assessing whether the response to treatment differed between the two patient groups: in statistical terms, an assessment of the group x visit interaction terms. It was noted that the groups differed with respect to some measured covariates thought likely to affect baseline QOL, namely, age, sex, and BMI; therefore, these variables were included in all of the fitted models. For each outcome measure, four models were fitted for the mean structure: 1) gender, age, BMI, and group x visit; 2) gender, age, BMI, group, and visit; 3) gender, age, BMI, and visit; and 4) gender, age, BMI, group, and pre-post. Comparisons between models were made with likelihood ratio tests and address the following questions. 1 vs. 2 assesses whether treatment has a differential effect on the mean outcomes between the two groups; a significant result implies that the impact is differential. 2 vs. 3 is used after a nonsignificant result from 1 vs. 2. This assesses whether there is any difference between the two patient groups after adjustment for the included covariates. 2 vs. 4, pre-post, is a contrast on the visit means grouping posttreatment visits (EFU and LTFU). A significant result for this comparison implies that the early and long-term effects differ. All model fitting was performed using S-PLUS 2000 software (23).
As with most longitudinal datasets it soon became apparent that quite a lot of response data were missing for one reason or another. This needed to be addressed before the formal model fitting and we adopted the following strategy. Occasionally the PGWB response was incomplete, in that less than 22 questions had been answered. Often it was the last four questions that had been omitted, and these appear together on the back page of the instrument. We elected to impute the missing question(s) using the average result from the completed questions in the same subscale, provided that more than half the questions in that subscale had been completed. Overall PGWB scores were only counted provided that every subscale satisfied these same criteria.
For clinical and ethical reasons some patients stopped treatment due to a lack of response. The subsequent missing responses on such a patient are clearly informative rather than missing at random, so we elected to impute the remaining missing responses by carrying forward the data from the last observed visit.
Finally, many responses were missing simply because the patient had not had sufficient time to have an early and/or long-term visit at the time the data were collected. On odd occasions, responses were missing due to missed visits. On the assumption that these remaining missing responses are missing at random, the linear mixed effects models may be legitimately fitted with the caveat that the estimated regression coefficients will pertain to the marginal mean profiles, i.e. the hypothetical ones for the notional complete dataset. This is exactly the structure about which we wish to make inferences, i.e. the mean structure if everybody had remained on treatment. The threshold of significance was set at 0.05. Results are expressed as the mean ± SD or as the estimated mean (confidence limit).
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Results |
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A significant difference in the age at primary diagnosis (cancer survivors, 17.7 ± 2.12 yr; pituitary pathologies, 45.3 ± 1.95 yr) and age at commencement of GH replacement (cancer survivors, 30.3 ± 1.83 yr; pituitary pathologies, 55.0 ± 1.86 yr) was evident, with the patients in group 2 being significantly older (P < 0.0001). Moreover, childhood-onset GHD was present significantly more frequently in the cancer survivors group (P < 0.0001). At study entry, BMI was significantly greater in the pituitary pathologies group (31.1 ± 1.1) than in the cancer survivors (27.1 ± 0.81; P = 0.004). The prevalence of multiple anterior pituitary hormone deficits was also greater in the pituitary pathologies group (P = 0.0015). Mean baseline age-adjusted IGF-I SD score (SDS) was –1.95 ± 0.30 in the cancer survivors and –2.00 ± 0.44 in the pituitary pathologies group (not significant).
The mean baseline PGWB total score before accounting for covariates was 60.7 ± 2.57 for the cancer survivors and 62.6 ± 3.31 for the pituitary pathologies group (not significant). The mean baseline AGHDA score was 16.4 ± 0.63 for the cancer survivors and 14.5 ± 1.08 for the pituitary pathologies group (not significant). After adjustments to take account of covariates, the groups remained similar, although the parameter estimates indicated a trend toward lower mean values in the cancer survivors group (Table 2, column 2 vs. 3; Tables 3 and 4, group data). Transformed percentage scores for the PGWB total score and ranking for each of the PGWB subscales at baseline are shown in Fig. 1. The vitality domain has the lowest score in both patient groups.
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). The pattern of change in mean scores for all outcome measures from baseline did not differ between the two groups (P = 0.86; Table 2
, column 1 vs. 2). There was no evidence of a difference in the EFU and LTFU means for any of the outcomes (Table 2, column 2 vs. 4; PGWB domain data not shown). The estimated effects of the covariates on baseline PGWB and AGHDA scores are summarized in Tables 3 and 4, respectively. AGHDA scores for all completed visits for all patients are presented graphically in Fig. 3.
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The mean IGF-I SDS increased significantly between baseline and EFU from –1.95 ± 0.30 to 0.01 ± 0.24 in the cancer survivors group (P < 0.0001) and from –1.99 ± 0.44 to 0.88 ± 0.24 in the pituitary pathologies group (P < 0.0001). These levels were achieved at a median GH dose of 0.4 mg (0.3–0.5) in the cancer survivors group and 0.3 mg (0.27–0.4) in the pituitary pathologies group (P = 0.03).
The mean IGF-I SDS at LTFU was 0.26 ± 0.30 in the cancer survivors group and 0.74 ± 0.19 in the pituitary pathologies group (not significant). These levels were achieved at a median GH dose of 0.4 mg (0.4–0.5) in the cancer survivors and 0.2 mg (0.17–0.36) in the pituitary pathologies group (P = 0.002). These values were significantly higher than baseline IGF-I SDS values for both groups, but were not significantly different from IGF-I SDS scores achieved at EFU.
In the cancer survivors group, one patient discontinued GH replacement 20 months after starting GH replacement due to tumor recurrence, 14 yr after the original cancer diagnosis (glioma). In the pituitary pathologies group, one patient discontinued GH replacement due to tumor recurrence, 10 yr after original diagnosis (nonsecreting pituitary adenoma), and one patient died, of an unrelated cause, 17 months after commencing GH replacement. Neither of the two patients with tumor recurrence exhibited supraphysiological age-adjusted IGF-I values during GH replacement.
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Discussion |
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This study was carried out in the United Kingdom (UK) and was of open treatment design. A selection bias toward GHD individuals with the most severe QOL impairment was inevitable, reflecting standard UK practice (24, 25). Although this specific QOL license for GH, used in the UK, does not represent an international consensus approach, it has serendipitously resulted in an opportunity to compare QOL in two very different GHD populations and, in particular, assess the QOL benefits and short- to medium-term safety of GH replacement in a novel group, namely adult GHD cancer survivors, for whom there has historically been very little GH replacement data available. This study cannot address or quantify placebo effect, and a double-blind, placebo-controlled study remains desirable in this context.
It is well recognized that severely GHD adults show heterogeneity of QOL response, with approximately 30–40% of individuals demonstrating severe QOL impairment on subjective or objective testing. Furthermore, several studies have demonstrated that patients with GHD who have a QOL objectively demonstrated to be within a range expected for normal healthy individuals would not be expected to show an improvement above normal after a trial of GH replacement (25, 26). The mechanism for QOL impairment in a proportion of severely GHD adults remains unknown (27), but is likely to be multifactorial in origin because of the widespread physiological actions of GH. The mechanisms involved appear to have a rapid onset of action, because most of the QOL improvement is observed to occur rapidly in affected GHD adults, within the first 3 months of physiological GH replacement (24, 28).
The PGWB is a generic QOL instrument (19). As such, it has the disadvantage of not being specifically designed to address particular issues of concern to individuals with GHD or hypopituitarism. Conversely, this instrument has been used extensively to study QOL in GHD adults over the last 15 yr, and therefore, large amounts of reference data exist with which to compare results. It also has the advantage of subdividing QOL into specific subscales or domains, so that characteristic patterns of QOL deficit can be identified. The AGHDA is a QOL questionnaire that was designed for use in adults with GHD (20). This questionnaire does not, however, allow subdivision of QOL into domains. We therefore used both the latter questionnaires to study QOL in our two patient cohorts with severe GHD and found good conformity of results of overall QOL scoring at baseline and at follow-up as measured by the two questionnaires.
A number of differences were evident between the patients in the two cohorts in this study, the most pertinent being the differences between age at primary diagnosis and age at starting GH replacement; the cancer survivors group was considerably younger. There is some controversy as to whether overall QOL is influenced by age. When present, the extent of age dependence of QOL appears to vary among different countries. Only a weak trend of age influence on QOL had been observed in U.S. and UK (29). Conflicting results have been found in studies of GHD adults from other countries (30, 31). In our study the effect of age on outcome variables was not significant.
Patients in the cancer survivors group had a lower BMI, in keeping with the greater proportion of childhood-onset GHD patients in this group (32), and BMI contributed significantly to baseline overall QOL in this study. Fewer additional pituitary hormone deficits were also present in the patients in this group. Nonetheless, most previous data suggest that QOL in untreated GHD adults is not influenced by the number of additional pituitary hormone deficits (28, 33).
Irradiation to the cranium may affect QOL and therefore may act as a confounder to the effects of severe GHD on QOL. However, this study focuses on the QOL response to GH replacement, and radiation effects on QOL would not be expected to change with GH replacement. Moreover, the cancer survivors group would be expected to show a more blunted or absent QOL response to GH replacement due to their greater radiation exposure, which was not observed in this study.
Adult GHD cancer survivors represent an emerging cohort of patients achieving long-term survival. Such cohorts comprise a large proportion of individuals with childhood-onset GHD, some of whom may have been treated with GH during childhood to optimize linear growth. Historically, patients with childhood-onset GHD have discontinued GH replacement at the completion of statural growth. Regardless of QOL, a number of other advantages of continuing GH replacement after this milestone have become evident in recent years. These benefits may also apply to transitional GHD cancer survivors, including the beneficial effects of GH on skeletal and somatic maturation, which continue through the second and third decades of life and are impaired in the absence of GH. Recent discontinuation studies and placebo-controlled randomized therapeutic trials are beginning to provide guidance about the need for continuation of GH replacement for GHD and the choice of GH dose throughout this transition phase (34, 35, 36, 37, 38).
Few centers have instituted GH replacement in adult GHD cancer survivors because of the malignant nature of the underlying pathologies, the mitogenic nature of GH, and a lack of long-term safety data for this therapy in such cohorts. In our study, one patient in each group developed a recurrence of their original tumor during GH replacement, but causality is unproven. Neither patient exhibited supraphysiological age-adjusted IGF-I values during GH replacement. The safety profile of our study in terms of tumor development or recurrence is in keeping with that of a previous multicenter study of childhood GHD cancer survivors treated with GH (39). The latter study demonstrated that children receiving GH were not found to be at increased risk of recurrence (relative risk, 0.6) after a mean follow-up of 6.4 yr after the first GH injection was administered. Our study, although containing small numbers, has a relatively long duration of treatment follow-up and provides new safety data relating to GH replacement in adult GHD cancer survivors in the context of aggressive, malignant diagnoses.
In summary, GH replacement has been given safely and without adverse sequelae to a cohort of 50 adult GHD cancer survivors with QOL impairment for a mean of 45.3 months. Dramatic and sustained improvements in QOL during this treatment were observed. The sustained nature of the improvements in QOL and the similarity of the QOL deficits between the two patient groups studied, both at baseline and during treatment follow-up, strongly support the hypothesis that GHD is the primary cause of adverse psychological health and well-being in both groups. Moreover, GHD, rather than factors relating to cancer diagnosis and treatment, appears responsible for the reduced QOL in adult GHD cancer survivors.
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Footnotes |
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Abbreviations: AGHDA, Assessment of GH deficiency in adults; BMI, body mass index; EFU, early follow-up; GHD, GH-deficient; HP, hypothalamic-pituitary; LTFU, long-term follow-up; PGWB, psychological general well-being schedule; QOL, quality of life; SDS, SD score.
Received June 24, 2004.
Accepted December 1, 2004.
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). •, Informative missing data where treatment was stopped due to lack of benefit and therefore where the last value has been carried forward. 1:01–50 represent the cancer survivors group; 2:01–47 represent pituitary pathologies group.