BSPED CONSENSUS
GUIDELINES: USE OF GROWTH HORMONE IN NON-LICENSED INDICATIONS
Jeremy Kirk Consultant Paediatric Endocrinologist, Birmingham
Children’s Hospital
INTRODUCTION
Growth hormone (GH) is currently licensed in the United Kingdom
for treatment of children with short stature due to 1.) Growth hormone-insufficiency
(GHI) 2.) Turner syndrome (TS) 3.) Chronic renal failure (CRI),
and now 4.) Prader-Willi syndrome (PWS).
With the current availability of biosynthetic GH (albeit at a cost), increasing numbers of patients with short stature secondary to a number of (unlicensed) conditions have been treated with GH in order to try and improve both short-term growth and final height. It is estimated that approximately 25% of the ~4000 paediatric patients currently treated with GH in the United Kingdom are outside licensed indications. As with other groups of patients without GH-insufficiency, the doses of GH used are usually higher at 0.33mg/kg/week (9-10mg/m2/week), although (especially in small for gestational age (SGA)) even higher doses have be used (DeZegher et al., 1999). However, side-effects of treatment with GH, which include an increased incidence of diabetes (Cutfield et al., 2000) must be weighed against any potential benefits of therapy.
Whilst this paper reviews the current status of information regarding GH use in unlicensed indications, unfortunately, much of the data is scanty. Many of the studies to date involve small numbers of patients, treated in an uncontrolled manner for short periods of time, with few followed to final height. In addition, few have included a control group, and fewer still a placebo arm. Investigation of other potential benefits of GH therapy to the patient; physical, social and psychological are rarely included.
IDIOPATHIC SHORT STATURE (ISS)
This group is a heterogeneous one, made up of patients with familial short stature (FSS) and constitutional delay of growth and puberty (CDGP). The demonstration of a spectrum of GH secretion (Hindmarsh et al., 1987), with arbitrary cut-offs of GH-insufficiency would appear to indicate that almost all short children will respond to GH therapy, but require larger doses to produce lesser growth responses than that seen in GH-insufficiency (Hindmarsh et al., 1988). There have been a number of studies which indicate that short but otherwise normal children will improve short-term height velocity with GH therapy. One study with a degree of randomisation showed an overall improvement in growth rate, although, as expected, less than that seen in GH-insufficiency (McGaughey et al., 1994). This study also indicated a potential improvement in final height, based on bone age.
Long-term final height data has been summarised in 413 patients from 11 studies with ISS (Guyda, 1999). Most patients were male, and the mean duration of GH therapy exceeded five years. The overall mean final height gain over predicted adult height was only +0.4SD or 2.7cm, although another, more recent study has indicated improved results (5.9cm in girls and 5.0cm for boys) (Hintz et al., 1999), possibly due to earlier institution of GH therapy.
SMALL FOR GESTATIONAL AGE (SGA)
In approximately 15% to 20% of short children, post-natal growth failure appears to be related to reduction in pre-natal growth velocity (intra-uterine growth retardation (IUGR), resulting in children who are small for gestational age (SGA). The precise definition has, however, varied between different investigators, making comparison difficult, and these are also a heterogeneous group, often including specific dysmorphic syndromes such as Silver-Russell syndrome (SRS). A number of studies have reported that GH increases height velocity in short children with SGA, and pooled data from five separate European trials has shown that GH can normalise height in short prepubertal children with SGA when given at doses of 7,14 or 21mg/m2/week (0.23, 0.47, 0.7mg/kg/week) over 2 years (Hokken-Kolega, 1999). Meta-analysis of the combined data from three randomised GH trials in short pre-pubertal children with SGA has demonstrated a GH dose-dependent response during the first 2 years of therapy (DeZegher et al., 1996). In addition, it appears evident that younger children receiving higher doses appear to benefit most over the short term (DeZegher et al., 1999). High-dose (14mg/m2/week) discontinuous GH therapy (two years-on, two years-off) has been shown to be equivalent to four years continuous low-dose GH (7mg/m2/week) in terms of overall height increment.
There is, however, a paucity of final height data on substantial numbers of patients from these randomised trials. Ranke et al. (1996) assessed 720 SGA patients treated with GH in the KIGS database, of whom 50% were considered to be GH-insufficient using their criteria. Of this cohort, sixteen patients who have received GH at a median dose of 0.25mg/kg/week have gained 1.0 SD score in final height. Lower doses (0.13mg/kg/week) had a limited effect on final height in patients with SGA and GH-insufficiency compared to an untreated group (Coutant et al., 1998).
NOONAN SYNDROME
Phenotypic similarities between Noonan and Turner syndrome have lead to the assumption that treatment with GH might have the same effect on short-term growth and final height. Prospective trials have only treated for short periods (Cotterill et al., 1996), and consequently much of the longer-term data is based on only small numbers, or from retrospective analyses using databases. These show short-term improvements in height velocity during initial GH therapy, which slows with continuing treatment, and few patients followed to final height (Romano et al., 1996). Recent analysis of United Kingdom patients treated with GH on the KIGS database (N = 66) has shown them to be short both compared to normal and Noonan children (Kirk et al., in press). During the first year of GH therapy (mean dose 0.23mg/kg/ week) height velocity increased from a pre-treatment mean(SD) of 4.8 (1.1) to 7.2 (1.7) cm a year. As with other studies, there was a waning of the effect of GH over ensuing years, and if assessed by a change in Noonan reference standards, final height (N=10) was increased by a mean of 3.1 cm, with only 2 patients increasing their predicted final height by 5 cm or more.
SKELETAL DYSPLASIAS
Although individuals with skeletal dysplasias show a GH-resistant pattern, therapy with GH (either on its own or in combination with surgical limb lengthening) has been attempted to try and improve their height. There are a number of published trials in achondroplasia and hypochondroplasia, although patient numbers once again are limited, with no control groups. A review of these studies (Bridges, 1999) indicated that in both of these conditions GH therapy for 1 or 2 years appears to increase height velocity over pre-treatment values, with no evidence (at least in achondroplasia) that disproportion is worsened. Final height data (both from trials and databases) is currently unavailable.
CONCLUSIONS & RECOMMENDATIONS
In all these patient groups, short-term GH therapy has resulted in an improvement in height velocity, although (as predicted), not as great as that seen in patients with GH-insufficiency. There is usually a waning of effect with continued use of GH, but despite this many studies have indicated that final height (as assessed using surrogate markers such as bone age and target height) may be increased. Final height data is either very limited or restricted by trial design (often from retrospective databases), but rarely shows very substantial gains in final height. Although the role of GH therapy in these patients is to improve both short-term height velocity, and also final height, there is currently little data to indicate that these patients are disadvantaged as a result of their short stature (Downie et al., 1997), or gain any psychological benefit from treatment (Downie et al., 1996). As a result, some have considered it is inappropriate to treat these children with GH outside of controlled clinical trials (Lawson Wilkins, 1995).
When considering the use of GH for non-conventional purposes, Kodesh & Cuttler (1996) have suggested a number of questions should be considered:
- When is it ethical to use a treatment if the scientific data about its efficacy are not clear?
- What are the goals of treatment? How can we determine if the goals are being met?
- What is the risk-benefit ratio?
- What should be the role of parents in treatment decisions?
- What are the implications of our treatment decisions for child healthcare in general?
Some of these questions may be answered as further data becomes available from existing trials. At present, however, the data is either scanty or non-existent. It must be remembered, however, that absence of evidence does not necessarily mean evidence of absent (effect), and further large-scale prospective trials to answer these questions are urgently required. These should be performed on a national or international basis, looking at a number of outcomes, not only auxological, but also physical, emotional, psychological and social. On the basis of these, evidence based guidelines for treatment should be produced.
In addition, and whatever the outcome of these trials, there almost certainly still remain a small number of children with either other dysmorphic syndromes (diagnosed or undiagnosed), and/or those with extreme short stature, where GH might be currently considered outwith licensed indications. In these children the following guidelines might be appropriate:
- That treatment should only be undertaken in specialist centres that regularly participate in national audit of their clinical activities.
- That any potential benefits and adverse medical events of therapy are discussed fully with the parents and child prior to treatment.
- That the response to treatment is carefully monitored, and the need for ongoing treatment re-evaluated annually.
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