**2.2.3 Clinical impact and treatment**

GH deficiency is an important cause for impaired linear growth in irradiated children cured from cancer. Ample evidence from studies in brain tumour survivors suggests that GH therapy in those patients prevent further height loss and maintain their initial height centile to adulthood (Clayton et al., 1988; Sulmont et al., 1990) while those who do not receive treatment show further deterioration in their height centiles with a tendency for extreme short stature (Brauner et al., 1989; Clarson & Del Maestro, 1999). In addition, those patients may also need GH replacement therapy in the transition to adulthood to maximize bone density and prevent osteoporosis, which is a frequent finding in the irradiated cancer survivors (Brennan et al., 2005; Murray et al., 1999; Shalet & Rosenfeld, 1998).

In adults, GH deficiency may be associated with symptoms and signs of the well described adult GH deficiency syndrome (Table 1), in particular impaired quality of life (QoL) (de Boer et al., 1995).

GH replacement therapy in the irradiated adult cancer survivors may improve QoL, as in those with GH deficiency due to pituitary tumours (Murray et al., 2002). Thus, it is important that a robust diagnosis of radiation-induced GH deficiency is made so that appropriate GH replacement therapy can be introduced at the right time. Despite the numerous and proven benefits of GH replacement therapy in adults (Table 2), this is currently only recommended to primarily improve QoL. It is given on a trial basis with


Table 1. Features of the adult growth hormone deficiency syndrome.

Endocrine Complications Following Radiotherapy

**2.3 Gonadotrophin deficiency** 

and Chemotherapy for Nasopharyngeal Carcinoma 141

The gonadotrophin axis is the second most vulnerable to radiation damage. Gonadotrophin deficiency is frequently seen after intensive h-p axis irradiation (Chen et al., 1989; Constine

Gonadotrophin deficiency varies from subtle (subclinical) abnormalities in secretion detected only by GnRH testing to severe impairment associated with diminished circulating sex hormone levels. Although abnormalities in LH/FSH secretion can be demonstrated on dynamic testing, sometimes as early as one month following high dose irradiation (Chen et al., 1989), clinically-significant gonadotrophin deficiency is usually a late complication with a cumulative incidence in excess of 20% after long term follow up whether radiation was administered in childhood or adult life (Agha et al., 2005; Constine et al., 1993; Lam et al., 1991; Rappaport et al., 1982; Samaan et al., 1987). For example, Lam et al (Lam et al., 1991) reported a cumulative incidence of 30.7% 5 years after radiation treatment of NPC, while Samaan et al (Samaan et al., 1987) reported LH and FSH deficiency in 20% and 35% of NCP

The diagnosis of gonadotrophin deficiency is confirmed by normal or low normal basal LH/FSH with diminished circulating sex hormone concentrations. In children, gonadotrophin deficiency may retard pubertal development and linear growth, especially in the context of GH deficiency, which almost always occurs following radiation doses that causes gonadotrophin deficiency. Those children will typically have a delayed bone age as assessed by a wrist radiograph. Treatment with sex steroids is needed to induce and support development of secondary sex characteristics as well as linear growth. It is extremely important that GH deficiency is recognised and treated for some time before introducing sex

In adults, secondary hypogonadism is associated with sexual dysfunction and reduced fertility. In the long term sex steroid deficiency may have adverse impact on metabolic, cardiovascular, muscular, and skeletal health and quality of life (QoL). Patients should be tested at regular intervals and whenever the diagnosis is suspected clinically. Women may present with oligomenorrhoea, amenorrhoea, sweating, and/or hot flushes. Men may complain from reduced libido, erectile dysfunction, reduced shaving frequency, fatigue and tiredness, mood changes and weight increase with central adiposity. Treatment with sex steroid replacement therapy improves QoL and prevent decline in physical and mental health. Gonadotrophin therapy is needed to restore fertility, unless gonadal damage from

GnRH testing may help to differentiate between hypothalamic and pituitary cause for gonadotrophin deficiency. A delayed peak gonadotrophin response and/or a delayed decline indicate hypothalamic damage; a blunted response indicates pituitary damage or secondary pituitary atrophy; a mixed pattern of responses indicates possible damage at both sites. Repeated intermittent infusion of GnRH may restore pituitary responsiveness and therefore differentiate between primary and secondary pituitary atrophy (Yoshimoto et al., 1975) and with prolonged treatment there is the potential for restoring gonadal function and

et al., 1993; Lam et al., 1991; Rappaport et al., 1982; Samaan et al., 1987).

patients 1-4 years and more than 15 years after radiotherapy, respectively.

steroids to maximise the chances of attaining normal height.

chemotherapy coexists.

fertility (Hall et al., 1994).

gradual dose titration to achieve an IGF-I level in the upper quartile of the normal range (Bengtsson et al., 2000). The treatment is administered as a daily subcutaneous injection. Treatment is withdrawn if there is no improvement in QoL after 9 months of treatment. GH therapy for severe osteoporosis, but not QoL issuers, remains controversial.

#### **2.2.4 Timing of testing**

Testing for GH deficiency should be initiated at the time when GH therapy is considered safe. It is generally agreed that GH therapy should be avoided in the first 2-3 years after completion of cancer treatment, when the chance of cancer recurrence is greatest. GH therapy offered within this time period may be associated with a number of tumour recurrences and deaths that many families and doctors would associate with GH therapy despite a lack of proof of a causal relationship between GH therapy and tumour recurrence (Shalet et al., 1997; Sklar, 2004; Wilton, 1994).

Given the very high chance of developing severe GH deficiency 2-3 years after intensive radiotherapy in children, offering GH therapy without recourse to GH tests or evidence of impaired growth is an acceptable approach in certain centres. Alternatively, others would consider GH therapy when GH deficiency is established biochemically irrespective of growth rate. These approaches assume, given the epidemiological evidence, that it is highly likely that growth will soon decline in those patients or that an "apparently" normal growth rate is perhaps subnormal. A more selective approach, however, is still adopted by some endocrinologists who would insist on biochemical evidence of GH deficiency and a subnormal growth rate before initiating GH treatment. If GH status appears to be normal and the growth rate is appropriate for pubertal status, then growth is observed closely and the GH stimulation tests are repeated annually.

Testing in adults is only indicated if GH replacement therapy is to be considered in those who manifest symptoms and signs suggestive of severe GH deficiency (de Boeret al., 1995) (Table 1). A normal test 15 years after radiotherapy usually eliminates the need for further annual testing, as further decline in GH secretion is unlikely to occur after that time from radiotherapy.

Radiation-induced GH deficiency is irreversible. However, retesting in adulthood of those who were diagnosed with GH deficiency in childhood is mandatory before adult GH therapy is initiated or continued to address quality of life (QoL) issues. This is because the diagnostic threshold to treat GH deficiency is much lower in adults compared with children.


Table 2. Benefits of growth hormone replacement therapy in adults.

## **2.3 Gonadotrophin deficiency**

140 Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma

gradual dose titration to achieve an IGF-I level in the upper quartile of the normal range (Bengtsson et al., 2000). The treatment is administered as a daily subcutaneous injection. Treatment is withdrawn if there is no improvement in QoL after 9 months of treatment. GH

Testing for GH deficiency should be initiated at the time when GH therapy is considered safe. It is generally agreed that GH therapy should be avoided in the first 2-3 years after completion of cancer treatment, when the chance of cancer recurrence is greatest. GH therapy offered within this time period may be associated with a number of tumour recurrences and deaths that many families and doctors would associate with GH therapy despite a lack of proof of a causal relationship between GH therapy and tumour recurrence

Given the very high chance of developing severe GH deficiency 2-3 years after intensive radiotherapy in children, offering GH therapy without recourse to GH tests or evidence of impaired growth is an acceptable approach in certain centres. Alternatively, others would consider GH therapy when GH deficiency is established biochemically irrespective of growth rate. These approaches assume, given the epidemiological evidence, that it is highly likely that growth will soon decline in those patients or that an "apparently" normal growth rate is perhaps subnormal. A more selective approach, however, is still adopted by some endocrinologists who would insist on biochemical evidence of GH deficiency and a subnormal growth rate before initiating GH treatment. If GH status appears to be normal and the growth rate is appropriate for pubertal status, then growth is observed closely and

Testing in adults is only indicated if GH replacement therapy is to be considered in those who manifest symptoms and signs suggestive of severe GH deficiency (de Boeret al., 1995) (Table 1). A normal test 15 years after radiotherapy usually eliminates the need for further annual testing, as further decline in GH secretion is unlikely to occur after that time from

Radiation-induced GH deficiency is irreversible. However, retesting in adulthood of those who were diagnosed with GH deficiency in childhood is mandatory before adult GH therapy is initiated or continued to address quality of life (QoL) issues. This is because the diagnostic threshold to treat GH deficiency is much lower in adults compared with

2- Normalisation of body composition (reduced fat mass and increased lean body mass)

therapy for severe osteoporosis, but not QoL issuers, remains controversial.

**2.2.4 Timing of testing** 

radiotherapy.

children.

(Shalet et al., 1997; Sklar, 2004; Wilton, 1994).

the GH stimulation tests are repeated annually.

1- Improved psychological well-being and quality of life

3- Increased bone mineral content

5- Improved cardiac function 6- Improved exercise capacity

4- Increased ECF volume and renal function

7- May reduce mortality in hypopituitary patients

Table 2. Benefits of growth hormone replacement therapy in adults.

The gonadotrophin axis is the second most vulnerable to radiation damage. Gonadotrophin deficiency is frequently seen after intensive h-p axis irradiation (Chen et al., 1989; Constine et al., 1993; Lam et al., 1991; Rappaport et al., 1982; Samaan et al., 1987).

Gonadotrophin deficiency varies from subtle (subclinical) abnormalities in secretion detected only by GnRH testing to severe impairment associated with diminished circulating sex hormone levels. Although abnormalities in LH/FSH secretion can be demonstrated on dynamic testing, sometimes as early as one month following high dose irradiation (Chen et al., 1989), clinically-significant gonadotrophin deficiency is usually a late complication with a cumulative incidence in excess of 20% after long term follow up whether radiation was administered in childhood or adult life (Agha et al., 2005; Constine et al., 1993; Lam et al., 1991; Rappaport et al., 1982; Samaan et al., 1987). For example, Lam et al (Lam et al., 1991) reported a cumulative incidence of 30.7% 5 years after radiation treatment of NPC, while Samaan et al (Samaan et al., 1987) reported LH and FSH deficiency in 20% and 35% of NCP patients 1-4 years and more than 15 years after radiotherapy, respectively.

The diagnosis of gonadotrophin deficiency is confirmed by normal or low normal basal LH/FSH with diminished circulating sex hormone concentrations. In children, gonadotrophin deficiency may retard pubertal development and linear growth, especially in the context of GH deficiency, which almost always occurs following radiation doses that causes gonadotrophin deficiency. Those children will typically have a delayed bone age as assessed by a wrist radiograph. Treatment with sex steroids is needed to induce and support development of secondary sex characteristics as well as linear growth. It is extremely important that GH deficiency is recognised and treated for some time before introducing sex steroids to maximise the chances of attaining normal height.

In adults, secondary hypogonadism is associated with sexual dysfunction and reduced fertility. In the long term sex steroid deficiency may have adverse impact on metabolic, cardiovascular, muscular, and skeletal health and quality of life (QoL). Patients should be tested at regular intervals and whenever the diagnosis is suspected clinically. Women may present with oligomenorrhoea, amenorrhoea, sweating, and/or hot flushes. Men may complain from reduced libido, erectile dysfunction, reduced shaving frequency, fatigue and tiredness, mood changes and weight increase with central adiposity. Treatment with sex steroid replacement therapy improves QoL and prevent decline in physical and mental health. Gonadotrophin therapy is needed to restore fertility, unless gonadal damage from chemotherapy coexists.

GnRH testing may help to differentiate between hypothalamic and pituitary cause for gonadotrophin deficiency. A delayed peak gonadotrophin response and/or a delayed decline indicate hypothalamic damage; a blunted response indicates pituitary damage or secondary pituitary atrophy; a mixed pattern of responses indicates possible damage at both sites. Repeated intermittent infusion of GnRH may restore pituitary responsiveness and therefore differentiate between primary and secondary pituitary atrophy (Yoshimoto et al., 1975) and with prolonged treatment there is the potential for restoring gonadal function and fertility (Hall et al., 1994).

Endocrine Complications Following Radiotherapy

therapy is strongly recommended in those patients.

existing primary thyroid dysfunction causing TSH elevation.

after commencing thyroxine replacement therapy.

**2.5 TSH deficiency** 

picture.

and Chemotherapy for Nasopharyngeal Carcinoma 143

Patients with clinically significant ACTH deficiency may experience symptoms of adrenal insufficiency including poor appetite, nausea, vomiting, tiredness, easy fatigability, muscle weakness, and breathlessness on exertion. Weight loss may not occur due to coexisting GH deficiency and/or hypothyroidism, which cause central obesity. Regular replacement

Like the ACTH axis, the hypothalamic-pituitary-thyroid axis appears to be the least vulnerable to radiation damage and the latter is highly dose-dependent (Constine et al., 1993; Lam et al., 1991; Littley et al., 1989a). With radiation doses of less than 50 Gy, the frequency of TSH deficiency remains as low as 3-6%, such as that found in survivors of non-pituitary brain tumours (Livesey et al., 1990; Oberfield et al., 1992). Patients irradiated during adulthood for non-pituitary brain tumours were reported to have 9% rate of secondary hypothyroidism (Agha et al., 2005). A higher incidence of overt secondary hypothyroidism is noted in patients with pituitary tumours (Littley et al., 1989a), but more frequently following intensive irradiation schedules utilizing doses in excess of 50 Gy, typically used for head and neck tumours including NPC (Chen et al., 1989; Constine et al., 1993; Lam et al., 1991; Pai et al., 2001; Samaan et al., 1987). For example Lam et al (Lam et al., 1991) reported a cumulative incidence of secondary hypothyroidism of 14.9% after 5 years of follow up. The exact incidence of TSH deficiency may be under-estimated in NPC patients due to the high frequency of co-

Annual testing of thyroid function is indicated in patients irradiated for NPC who are particularly at much greater risk of primary hypothyroidism due to radiation-induced damage of the thyroid gland. The diagnosis of frank central hypothyroidism is straightforward - subnormal T4 level with normal or low basal TSH concentration. Given the wide range of normal free T4 levels, a significant decline in free T4 levels over time with normal or low normal TSH levels may signify a diagnosis of evolving central hypothyroidism or a mixed (primary and secondary) hypothyroidism even before free T4 levels drop below the lower normal limit. This should be highly suspected in the presence of gonadotrophin and/or ACTH deficiency or if there is history of thyroidal irradiation and it may warrant a therapeutic trial with thyroxin in the presence of a supportive clinical

Thyroxine replacement therapy may precipitate symptomatic acute adrenal insufficiency in an otherwise asymptomatic individual with unrecognised ACTH deficiency. It is mandatory that reduced cortisol production be ruled out with certainty before starting thyroxine therapy. If cortisol deficiency coexists, it should be treated first before intruding thyroxine therapy. It is also important to continue to assess the ACTH-adrenal axis at regular intervals

With the difficulty in diagnosing evolving central hypothyroidism by a single test, it has been claimed that the presence of a hypothalamic TSH response to a TRH test and/or diminished nocturnal TSH surge despite a normal free T4 level may imply a diagnosis of socalled "hidden" central hypothyroidism in a substantial proportion of irradiated children (Rose et al., 1999). In a recent study by the author et al (Darzy & Shalet, 2005), however, it was demonstrated that, like in some normal individuals, the loss of nocturnal TSH surge

#### **2.4 ACTH deficiency**

The hypothalamic-pituitary-adrenal axis appears to be the most radioresistant in patients irradiated for non-pituitary disorders. Clinically apparent ACTH deficiency occurs in only about 3% of patients receiving a total radiation dose to the h-p axis of 40-50 Gy (Constine et al., 1993; Livesey et al., 1990). In contrast, the frequency of ACTH deficiency in patients treated with intensive irradiation for NPC is significantly higher. Samman et al (Samaan et al., 1987) reported a frequency of 4% in the first 4 years after irradiation and a cumulative frequency of 20% after 15 years, while Lam et al (Lam et al., 1991) reported a cumulative frequency of 30.7% after 5 years. Differences in radiation schedules and diagnostic criteria may explain the higher frequency in the latter study (Lam et al., 1991). In most reported cases, however, ACTH deficiency was partial and only a few patients needed regular hydrocortisone replacement because of symptoms of hypocortisolism (Lam et al., 1991; Samaan et al., 1987; Samaan et al., 1982).

From a clinical perspective, significant as opposed to subtle abnormalities in ACTH secretion, are unlikely to be missed by the ITT, which remains the "gold standard". If the ITT is contraindicated, alternative tests like Glucagon and Synacthen may be considered. Measurements of 9 am cortisol may be adequate; a level in excess of 300 nmol/l almost always excludes significant ACTH deficiency. However, during periods of acute stress or acute illness, a level in excess of 500 nmol/l is required to confirm normality of the ACTHadrenal axis. Patients with lower levels or those who are symptomatic should be considered for a stimulation test. As ACTH deficiency is a slowly evolving abnormality, it is very unusual to have a normal synacthen test in the context of a clinically significant ACTH deficiency that normally results in secondary adrenal atrophy.

It is to be noted that increased oestrogen levels due to HRT, use of contraceptive pill (OCP) or pregnancy may raise cortisol binding globulin (CBG) resulting in spurious elevation of circulating total cortisol levels by as much as 3 folds or more. Under these circumstances, an apparently normal random cortisol level may occur in the presence of a significant cortisol deficiency. Any assessment of cortisol levels should only be done after withdrawing any oestrogen containing medications for at least 4 weeks. If the patient was on the oral contraceptive pill (OCP) appropriate advice about mechanical contraception should be provided. If the patient is not willing to stop oestrogen replacement therapy or if pregnant, a stimulation test may be needed. The normality of the ACTH-adrenal axis is then determined by a normal cortisol increment rather than by the normality of the absolute basal or stimulated cortisol levels.

Adrenal dysfunction with reduction in spontaneous and/or stimulated cortisol secretion is an important diagnosis to make. Missing a diagnosis of this nature may put patients at risk of acute adrenal crisis during periods of acute stress. Although regular hydrocortisone replacement therapy may not be necessary in asymptomatic patients with partial ACTH deficiency, oral or intravenous hydrocortisone replacement therapy may become necessary during situations that can lead to acute adrenal crisis due to failure of the ACTH-adrenal axis to meet the increased demands for cortisol. Such patients should be properly informed about the emergency use of hydrocortisone during severe stress, acute illness, surgery, and trauma. Patients should also be advised to have a steroid medi-alert bracelet for emergency situations.

Patients with clinically significant ACTH deficiency may experience symptoms of adrenal insufficiency including poor appetite, nausea, vomiting, tiredness, easy fatigability, muscle weakness, and breathlessness on exertion. Weight loss may not occur due to coexisting GH deficiency and/or hypothyroidism, which cause central obesity. Regular replacement therapy is strongly recommended in those patients.
