There are no randomized studies comparing the outcome of surgery with surgery and radiotherapy. Nevertheless, there is considerable information on the recurrence rate of pituitary adenomas that have been incompletely excised. In retrospective comparative studies, the 10-yr progression-free survival of patients receiving radiotherapy is more than 90%, compared with less than 50% after surgery alone (15). After apparent complete excision, the 5-yr progressionfree survival is approx 90% in small patient cohorts (16,17). Radiotherapy is usually employed in patients with residual tumor after debulking surgery, where surgery is considered risky, and following failure after surgery. The long-term tumor control reported as progression-free survival is 90-95% at 10 yr and 8590% at 20 yr (18-20). The antiproliferative effect of radiotherapy is seen equally in nonfunctioning and secreting tumors.
After radiotherapy, tumors remain in situ with minimal or no decrease in the size of the tumor mass and tumor control is measured as lack of growth. This is equated with no further risk of compression of surrounding structures and no further need for surgery and its consequent morbidity.
Hormonal Control in Secretory Tumors
Primary therapy of secreting pituitary adenoma is surgical removal of the tumor, which results in biochemical cure in 40-70% of patients. Radiotherapy has been used to reduce hormone levels in patients with elevated hormones after surgical excision. After conventional radiotherapy, the majority of elevated hormones return to normal, particularly in acromegaly, with less success reported in Cushing's disease and prolactinoma. There is considerable delay in the normalization of hormones, which is largely related to the pretreatment hormone level. The time to normalization for an individual hormone level ranges from less than 1 to more than 10 yr.
Despite radical surgery, 50-70% of patients continue to have elevated growth hormone (GH) levels (21-23) (both better and worse results have been quoted recently; see Introduction), and radiotherapy has been successfully used to reduce the hormone levels. The mechanism of this phenomenon is not known but is presumed to be caused by the depletion of secreting tumor cells. Decrease in GH is slow, with considerable delay before reaching normal GH and insulin-like growth factor (IGF-1) levels. An estimate of the rate of reduction is 50% after an average of 27 (+/-5 mo) (24). This has also been measured as a drop in mean GH level in a population of patients with acromegaly and has been described as halving in approx 2 yr (25).
The rate of reduction of GH is frequently defined as the median time to normalization for a population of patients with acromegaly. The reported median time ranges from 2-7 yr (24,26,27). As the pretreatment GH level is a determinant of delay (26,28), such cohort figures are not a reflection of the rate of decline of individual GH level for a specific patient but are determined by the GH levels in the population with acromegaly studied.
In summary, patients achieve normal GH levels, with delay ranging from 6 mo to more than 10 yr, and the timing is largely dependent on the preradiotherapy GH. This, to some extent, is also related to the size of the adenoma. The current policy is to offer radiotherapy to all patients with persistent GH elevation. In the period before permanent normalization with radiation, somatostatin analogs are used to lower the effective GH level (see Chapter 3).
As in acromegaly, primary treatment for Cushing's disease (CD) is surgical, with radiotherapy reserved for patients with persistent or recurrent disease (see also Chapter 4). The results reported in retrospective studies suggest that only 5060% patients achieve normalization of plasma and urinary-free cortisol (UFC) with a delay in the normalization of hormone levels (29). However, a detailed prospective evaluation of 30 adults (30) demonstrated remission in all patients 660 mo after radiotherapy, with the majority achieving remission in the first 2 yr of treatment. The reason for the discrepancy in reported result is not clear, but low-dose radiation used in some studies may provide part of the explanation.
Nelson's syndrome as a consequence of bilateral adrenalectomy is treated by external beam radiotherapy, and the reported success rate is 30-60%, with worse results after low radiation doses. Prophylactic pituitary irradiation is associated with lower incidence of Nelson's syndrome after adrenalectomy (31).
A reasonable policy is to offer radiotherapy to all patients with residual or recurrent CD, usually in combination with medical treatment. Patients should also be offered prophylactic pituitary irradiation either before or after bilateral adrenalectomy.
Primary treatment of prolactinoma is with dopamine agonists (see Chapter 2). Radiotherapy is no longer used as initial therapy and is reserved alongside surgery for patients who are intolerant or resistant to dopamine agonists.
Initial studies of radiotherapy as primary treatment documented gradual reduction in prolactin (PRL) levels, with a delay in normalization ranging from 2 to more than 10 yr (32,33). Although radiotherapy is highly effective in preventing regrowth of the tumor mass, recurrence of PRL hypersecretion after conventional radiotherapy is more frequent than in acromegaly or Cushing's syndrome (CS) (18). The apparent difficulty in establishing complete normalization of PRL level is distinguishing the results of radiation-induced hypothalamic injury from poor response to treatment.
Patients with prolactinoma are frequently destined for long-term dopamine agonist therapy. Radiotherapy to the pituitary adenoma can be added to allow discontinuation of medical treatment, although this is not common practice. The advisability of offering treatment also depends on the perceived need to preserve normal pituitary function, and this is an important consideration particularly in women of reproductive age.
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