Authors
Type of irradiation
Type of adenoma
Patients (no)
Follow-up median (years)
Local control (%)
Late toxicity (%)
Visual
Hypopituitarism
Grigsby et al. (1989) [1]
CRT
NFA, SA
121
11.7
89.9 at 10 years
1.7
NA
McCollough et al. (1991) [2]
CRT
NFA, SA
105
7.8
95 at 10 years
NA
NA
Brada et al. (1993) [3]
CRT
NFA, SA
411
10.8
94 and 88 at 10 and 20 years
1.5
30 at 10 years
Tsang et al. (1994) [4]
CRT
NFA, SA
160
8.7
87 at 10 years
0
23
Zierhut et al. (1995) [5]
CRT
NFA, SA
138
6.5
95 at 5 years
1.5
27
Estrada et al. (1997) [17]
CRT
ACTH
30
3.5
73 at 2 yearsa
0
57
Breen et al. (1998) [7]
CRT
NFA
120
9
87.5 at 10 years
1
NA
Gittoes et al. (1998) [8]
CRT
NFA
126
7.5
93 at 10 and 15 years
NA
NA
Barrande et al. (2000) [9]
CRT
GH
128
11
53 at 10 yearsa
0
50 at 10 years
Biermasz et al. (2000) [10]
CRT
GH
36
10
60 at 10 yearsa
0
54 at 10 years
Epaminonda et al. (2001) [11]
CRT
GH
67
10
65 at 15 yearsa
0
NA
Minniti et al. (2005) [12]
CRT
GH
45
12
52 at 10 yearsa
0
45 at 10 years
Minniti et al. (2007) [13]
CRT
ACTH
40
9
78 and 84 at 5 and 10 yearsa
0
62 at 10 years
Milker-Zabel et al. (2001) [23]
FSRT
NFA, SA
68
38
93 at 5 years
7.5
5
Milker-Zabel et al. (2004) [24]
FSRT
GH
20
26
92a
0
3
Paek et al. (2005) [25]
FSRT
NFA
68
30
98 at 5 years
3
6
Colin et al. (2005) [26]
FSRT
NFA, SA
110
48
99 at 5 years
1.8
29 at 4 years
Minniti et al. (2006) [27]
FSRT
NFA, SA
92
32
98 at 5 years
1
22
Kong et al. (2007) [28]
FSRT
NFA, SA
64
36.7
97
0
27.3 at 5 years
Wilson et al. (2012) [30]
FSRT
NFA
67
60.1
93 at 5 years
1.5
7
Kim et al. (2013) [31]
FSRT
NFA, SA
76
80
97.1 at 7 years
0
48
Ronson et al. (2006) [62]
Protons
NFS,SA
47
>6 months
94
6
23
The reported tumor control is similar for doses ranging from 45 to 55 Gy at ≤ 2 Gy per fraction. The recommended dose for pituitary adenomas is generally 45–50 Gy at <2 Gy per fraction. There is no clear evidence that long-term control is influenced by timing of radiotherapy. Although some authors suggest that surgery followed by radiotherapy may provide the best therapeutic option for patients with residual tumor without major risks [14, 15], most of published series reported no difference in tumor growth control for patients who received immediate postoperative radiotherapy and those who received radiotherapy at the time of recurrence or progression [16]. In practice this means that deferring radiotherapy for patients with complete or near-complete resection seems to be a safe and reasonable approach. Tumor progression may be detected early with a close postoperative imaging follow-up and patients may be treated effectively with radiotherapy at time of tumor regrowth. Immediate postoperative RT as a potentially effective treatment modality can be reserved for patients with large and invasive pituitary adenomas after incomplete surgical removal. However, only prospective randomized trials can determine whether radiotherapy and its timing alter survival and quality of life in patients with subtotally resected pituitary adenomas.
In patients with secreting pituitary adenomas, the main goal of treatment is normalization of excess hormone production. Radiotherapy is effective in normalizing growth hormone (GH) and insulin-like growth factor I (IGF-1) levels in a consistent proportion of acromegalic patients, with a progressive rate of GH and IGF-1 declining. Most studies report the biochemical remission of disease in 30–50 % of acromegalic patients at 5–10 years and 75 % of patients at 15 years after treatment [9–12]. GH levels fall to around 50 % by 2 years with IGF-1 taking longer. Lower initial levels are associated with faster biochemical control of the disease.
Pituitary irradiation in patients with Cushing’s disease in whom transsphenoidal surgery is unsuccessful achieves a biochemical remission of disease, measured as normalization of urinary and plasma cortisol concentration, in up to 80 % of patients at 5 years. After radiotherapy, the rate of reduction of urinary free cortisol is a 50 % drop in 6–12 months and the rate of decline of plasma cortisol is 50 % in 12 months [6, 13]. In a series of 42 patients with Cushing’s disease treated with postoperative radiotherapy, the 10-year actuarial progression-free survivals were 93 % and 95 %. Biochemical remission of disease occurred in 80 % of patients with remission rates of 73, 78, and 83 % after 3.5 and 10 years [13]. Estrada et al. [6] reported a similar remission rate of 83 % in 30 patients with Cushing’s disease after postoperative radiotherapy, with the majority of remissions that occurred within the first 2 years after the treatment.
Radiotherapy is less frequently used in the treatment of prolactinomas since medical treatment with dopamine agonists can achieve tumor shrinkage and normalize prolactin levels in more than 80 % of patients. It is employed in occasional patients who fail surgery and medical therapy with a reported hormone normalization rate of 30–50 % [17].
4.4 Toxicity
The risk of late normal CNS toxicity of external beam radiotherapy to doses <50 Gy at <2 Gy per fraction is low, with a reported incidence of optic neuropathy resulting in visual deficit of 1–3 % and risk of necrosis of normal brain structures of 0–2 % (Table 4.1). Hypopituitarism represents the most commonly reported late complication of radiotherapy, occurring in 30–60 % of irradiated patients 10 years after treatment, and the proportion is likely to increase with time. An increased incidence of cerebrovascular accidents and excess cerebrovascular mortality has been reported in patients with pituitary adenoma treated with conventional radiotherapy, although the risk has not been defined and the influence of radiation on its frequency is also not clear [18]. Radiation is associated with the development of a second, radiation-induced brain tumor. The reported frequency of development of gliomas and meningiomas following treatment of pituitary adenoma is 2 % at 20 years [19]. Although radiotherapy to large volumes of normal brain, particularly in children, is a recognized consequence of large-volume cranial irradiation [20, 21], there is little evidence that fractionated irradiation for pituitary adenomas may significantly alter cognitive function beyond the effect of other interventions and the tumor itself.
4.5 Fractionated Stereotactic Radiotherapy
The reported 5-year control for pituitary adenomas following FSRT is 85–100 % [22–30] (Table 4.1). In a series of 92 patients with either nonfunctioning or secreting pituitary adenomas treated with FSRT at a dose of 45 Gy delivered in 25 fractions at the Royal Marsden Hospital, the 5-year tumor control was 97 % and the 5-year survival 98 % [26]. Colin et al. [26] reported the clinical outcomes in 110 patients with pituitary adenomas who received FSRT at a mean dose of 50.4 Gy in 28 fractions. After a minimum follow-up of 48 months, the 5-year tumor control was 99 % and hormone hypersecretion normalization was 42 % out of 47 patients with a secreting tumor. Similar results have been reported by others using a dose of 45–54 Gy, with an overall median 5-year control of 95 % [27–30]. A reduction in size of the tumor after FSRT is reported in 15–45 % of patients. An improvement of visual deficits has been reported in up to 20–50 % of patients after FSRT.
Milker-Zabel et al. [23] reported normalization of elevated growth hormone level in 70 % of acromegalic patients at a median of 26 months. In another series of 34 acromegalic patients treated with FSRT, Roug et al. [29] reported the normalization of GH and IGF-1 levels in 30 % of patients at a median follow-up of 30 months, being 24 %, 38 %, and 64 % after 1, 3, and 5 years, respectively, similar to that seen following conventional radiotherapy. There is limited data on FSRT in patients with Cushing’s disease or prolactinomas. In a small series of 12 patients, control of elevated cortisol concentration was reported in nine out of 12 patients (75 %) at a median time of 29 months [32].
Hypopituitarism is reported in 20–40 %% of patients at 5 years (Table 4.1). Even if FSRT may reduce radiation doses to the hypothalamus, theoretically reducing the incidence of hypopituitarism after the treatment, damage to the pituitary gland cannot be avoided when irradiating the pituitary fossa. So far, the incidence of hypopituitarism is likely to represent the major complication of radiation treatment even with the further optimization of techniques. Other late complications are rarely recorded; however, the relatively short follow-up requires caution in interpretation until more mature and reliable results are available both in terms of efficacy and late radiation-induced toxicity.
4.6 Stereotactic Radiosurgery
SRS is frequently used in patients with residual or recurrent pituitary adenomas. The reported 5-year tumor growth control with the use of SRS in patients with nonfunctioning pituitary adenomas is between 87 and 100 % (Table 4.2) [33–58]. In a large retrospective multicenter study of 512 patients with nonfunctioning pituitary adenomas treated with SRS, the reported actuarial tumor control was 95 and 85 % at 5 and 10 years [38], respectively, and similar results have been documented in few other large series using doses of 16–25 Gy [34–37].
Table 4.2
Summary of recent published of SRS for pituitary adenomas
Authors | Patients (no) | Type of adenoma | Follow-up (months) | Tumor control (%) | Late toxicity (%) | |
|---|---|---|---|---|---|---|
Visual | Hypopituitarism | |||||
Losa et al. (2004) [33] | 56 | NFA | 41 | 88 at 5 years | 0 | 24 |
Mingione et al. (2006) [34] | 100 | NFA | 45 | 92.2 | 0 | 25 |
Liscak et al. (2007) [35] | 140 | NFA | 60 | 100 | 0 | 2 |
Park et al. (2011) [36] | 125 | NFA | 62 | 94 at 5 years | 0.8 | 24 |
Starke et al. (2012) [37] | 140 | NFA | 50 | 97 at 5 years | 12.8 | 30.3 |
Sheehan et al. (2013) [38] | 512 | NFA | 36 | 95 at 5 years | 6.6 | 21 |
Jezkova et al. (2006) [39] | 96 | GH | 53.7 | 44 at 5 years | 0 | 27.1 |
Voges et al. (2006) [40]
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