To investigate treatment outcome and long term complication after surgery and radiotherapy (RT) for pituitary adenoma.
From 1990 to 2009, 73 patients with surgery and RT for pituitary adenoma were analyzed in this study. Median age was 51 years (range, 25 to 71 years). Median tumor size was 3 cm (range, 1 to 5 cm) with suprasellar (n = 21), cavernous sinus extension (n = 14) or both (n = 5). Hormone secreting tumor was diagnosed in 29 patients; 16 patients with prolactin, 12 patients with growth hormone, and 1 patient with adrenocorticotrophic hormone. Impairment of visual acuity or visual field was presented in 33 patients at first diagnosis. Most patients (n = 64) received RT as postoperative adjuvant setting. Median RT dose was 45 Gy (range, 45 to 59.4 Gy).
Median follow-up duration was 8 years (range, 3 to 22 years). In secreting tumors, hormone normalization rate was 55% (16 of 29 patients). For 25 patients with evaluable visual field and visual acuity test, 21 patients (84%) showed improvement of visual disturbance after treatment. The 10-year tumor control rate for non-secreting and secreting adenoma was 100% and 58%, respectively (p < 0.001). Progression free survival rate at 10 years was 98%. Only 1 patient experienced endocrinological recurrence. Following surgery, 60% (n = 44) suffered from pituitary function deficit. Late complication associated with RT was only 1 patient, who developed cataract.
Surgery and RT are very effective and safe in hormonal and tumor growth control for secreting and non-secreting pituitary adenoma.
Pituitary adenoma is a benign tumor representing 10% to 15% of primary intracranial tumors. This tumor may cause nonspecific headache, diminished vision, diplopia, hypopituitarism, and other neurologic symptoms as a result of mass effect on adjacent intracranial structures. Functioning adenoma may cause various metabolic symptoms due to hypersecretion of pituitary hormone, such as prolactin (PRL), growth hormone (GH), thyroid-stimulating hormone, adrenocorticotropic hormone (ACTH), and gonadotropins. In patients with non-secreting macroadenoma or non-prolactin-secreting adenoma, surgery (usually the transsphenoidal approach) is considered the treatment of choice. In prolactin-secreting adenoma, medical treatment is the treatment of choice. Radiotherapy (RT) usually is applied to patients with residual or recurrent disease after surgical resection, patients who are not operative candidates, and patients with secreting adenoma that do not respond to surgery or medication. RT can achieve excellent long term tumor control, with reported rates of 80%–95% at 10 years after 45–50 Gy [
Nevertheless, RT has been associated with possible long-term complications, such as hypopituitarism, cerebrovascular accident, damage to the visual apparatus, and secondary brain neoplasm. The incidence of hypopituitarism has been reported to be 20%–60% at 5–10 years after RT [
Pituitary adenoma is a benign tumor that has a long natural history, and complication can occur even more than 10 years after RT, so proper evaluation of treatment requires a long-term follow-up [
From 1999 to 2009, 101 patients who had diagnosed pituitary adenoma received RT in Dongsan Medical Center, Keimyung University School of Medicine. Of these patients, 21 patients without regular follow-up, 4 patients without medical records, 3 patients with incomplete RT were excluded, and 73 patients were analyzed in this study. Patient characteristics are summarized in
In this analysis, all patients received surgery before RT. Sixty four patients had RT in the postoperative adjuvant setting. In the remaining 9 patients, RT was performed as a salvage treatment for recurrent or persistent disease after the first operation. Most patients (n = 70) had surgery with transsphenoidal approach. Surgical extent was determined by imaging methods like computed tomography (CT) or magnetic resonance imaging (MRI), operation record, or surgeon’s opinion. Based on brain CT or MRI after operation, gross total resection was defined as no residual tumor, and subtotal resection was defined as residual tumor enhancement. Of total 73 patients, 64 patients who had subtotal resection of tumor received RT as postoperative adjuvant setting. For RT, CT simulation was performed in patients immobilized using a thermoplastic mask. Before three-dimensional (3D) conformal therapy, simulation film was used to shield and shape the radiation field, and treated with the 3-field technique (1 antero-superior oblique and 2 lateral fields). In 3D conformal therapy, gross tumor volume (GTV) was defined as gross disease, which was seen in the contrast-enhanced CT or MRI. Median tumor dose was 45 Gy (range, 45 to 59.4 Gy) with 1.8 Gy per fraction, once a day, 5 times a week.
Two patients with PRL secreting adenoma, 1 patient with ACTH secreting, and 1 patient with GH secreting treated with medication, such as bromocriptine, ketoconazole, and octreotide either before or after surgery.
The follow-up period was calculated from the last date of RT to time of last follow-up or death. Treatment outcomes was evaluated by ophthalmological (visual acuity and visual field test), endocrinological (thyroid stimulating hormone, thyroxine, triiodothyronine, ACTH, PRL, GH, luteinizing hormone, and follicle-stimulating hormone) and radiological (brain MRI) studies after completion of RT at 6 months, 1 year and then once a year.
The primary outcome of this study were tumor control, disease-specific survival (DSS), overall survival (OS), progression-free survival (PFS) and hormone normalization rate of secreting adenomas. In non-secreting adenoma, tumor control was defined as lack of radiological progression on follow-up brain imaging studies and lack of mass-related symptom. Regardless of conservative management, if there was an improvement of mass-related symptom, such as headache, it was defined as resolution of symptom. In secreting adenoma, tumor control was defined as normalization of hypersecreted hormones, maintenance of normalized status, and lack of radiological progression. Secreting adenomas was considered to have had a hormone normalization to RT if there hypersecreted hormone decreased to the normal range without suppressive medication after surgery and RT. Progression free interval was defined as duration from the date of end of RT to the date of radiological or endocrinological relapse after control of tumor. The tumor control rate DSS, OS, and PFS rate was calculated using Kaplan-Meier method. For patients who never achieved hormone normalization during the follow-up period, we considered that patients did not have tumor control at the time of last follow-up time.
The secondary outcome of interest in this study was treatment-related chronic complication, including hypopituitarism, radiation-induced optic neuropathy, cataract, cerebrovascular accident, and so on.
Median follow-up duration was 8 years (range, 3 to 22 years) and 26 patients (36%) had 10 year or more follow-up duration. RT was well tolerated by all patients. No acute toxicities during RT was observed except headache reported by 16 patients (all grade 1), and nausea reported by 3 patients (all grade 1 or 2).
Of the 29 patients with all type of secreting adenomas, with a median follow-up duration of 8 years, 16 patients (55%) showed complete hormone normalization without suppressive medication. The 10-year tumor control rate for secreting adenoma was 58% (
Of the 23 patients with headache, all patients showed resolution of symptoms after surgery and RT. Of the 33 patients with initial visual field defect or visual acuity impairment, 8 patients did not have ophthalmologic test during the follow-up period. For 25 patients with evaluable visual field and visual acuity test, 21 patients (84%) showed improvement of visual disturbance after treatment (17 patients after surgery and 4 patients after RT).
The 10-year tumor control rate for non-secreting and secreting adenoma was 100% and 58%, respectively (p < 0.001). Whether the adenoma was secreting or non-secreting was the significant prognostic factor for local control in multivariate analysis (p = 0.015) (
The DSS and OS rate at 10 years was 100% and 92.8%, respectively. Of the 5 patients who died during the follow-up period, none had a cause of death that was attributable to the pituitary adenoma, and RT; traffic accident, gastric cancer, chronic renal failure, pontine infarction, and unknown cause. Patients who died due to pontine infarction had uncontrolled diabetes mellitus. Thus, the pituitary adenoma itself or treatment might be not associated with death (see below “treatment-related late complication”). The PFS rate at 10 years was 98%. There was no tumor regrowth of non-secreting adenoma on follow-up brain image. However, 1 patient experienced endocrinological recurrence of disease 4.5 years after RT leading to hormone suppressive medication. This patient required octreotide to inhibit secretion and action from GH until last follow-up.
After surgery, 44 patients (60%) suffered from pituitary function deficit, and had hormone replacement with levothyroxine, and/or hydrocortisone. After RT, none had newly diagnosed as treatment-related hypopituitarism.
Headache was the most common acute complication during RT (n = 13), and all was the grade I (Common Terminology Criteria for Adverse Events [CTCAE] ver. 4). Of 13 patients, 10 patients had headache before surgery. These 10 patients with preoperative headache were defined as tumor control, not progression of tumor, because preoperative headache was disappeared after surgery, and grade I headache during RT was also disappeared after RT despite of no conservative management.
Six patients (8.2%) experienced ischemic stroke after a median 5.3 years (range, 2.3 to 8.5 years) (
One patient who had received RT at 66 years experienced cataract after 7 years. No patient experienced radiation-induced optic neuropathy, brain necrosis, and secondary malignancy as a result of RT.
This study is a retrospective analysis with long-term follow-up results of surgery and RT for pituitary adenoma. Our study confirms that surgery and RT are very effective and safe in hormonal and tumor growth control, similarly, in other studies. Numerous studies demonstrated that surgery followed by RT or RT alone achieved excellent long-term outcome of both secreting and non-secreting pituitary adenoma. Brada et al. [
For all type of secreting adenomas, 55% presently showed complete hormone normalization. Rate of hormone normalization of PRL and GH secreting adenoma was 44% and 75%, respectively, which is comparable to previous reports. In previous reports, rates of normalization of serum PRL levels in prolactinoma ranged from 12% to 60%, and rates of normalization serum of GH levels in patients with GH-secreting adenoma ranged from 61% to 77% [
In the present study, the median time to hormone normalization after RT was 3.1 years (range, 0.1 to 10.1 years). Some authors have suggested that SRS achieved faster control of hypersecreted hormones than does conventional fractionated RT [
Hypopituitarism is most common late complication after RT for pituitary adenoma. Its incidence is varies from 20% to 60%, depending on the duration of follow-up [
Stroke is also important late complication after RT. Some investigators reported on increased incidence of stroke in patients treated with RT compared with normal population. Brada et al. [
There was no second brain malignancy during the follow-up period. This is very important because some physicians may be hesitant to conduct RT for benign neoplasm in critical locations. Minniti et al. [
In conclusion, with median 8 years follow-up, surgery and RT are very effective and safe in hormonal and tumor growth control for secreting and non-secreting pituitary adenoma. However, efforts are needed to improve hormonal control for secreting adenoma.
Hormone normalization rate after treatment. Sixteen patients (55%) showed complete hormone normalization with median follow-up duration of 8 years.
Patients and tumor characteristics
Variable | No. of patients (%) |
---|---|
Age (yr), median (range) | 51 (25–71) |
Gender | |
Male | 33 (45) |
Female | 40 (55) |
Tumor size (cm), median (range) | 3 (1–5) |
Tumor extension | |
Sella only (no extension) | 18 (25) |
Suprasellar | 26 |
Cavernous sinus | 19 |
Sphenoid sinus | 2 (3) |
Unknown | 13 (18) |
Hormone secreting | |
Non-secreting | 44 (60) |
Secreting | 29 (40) |
Prolactin | 16 |
Growth hormone | 12 |
Adrenocorticotrophic hormone | 1 |
5 patients had both suprasella and cavernous sinus extension.
Multivariate analysis of factors related to tumor control
Variable | HR (95% CI) | p-value |
---|---|---|
Secreting status | 2.491 (1.195–5.193) | 0.015 |
Radiation dose | - | 0.299 |
Tumor extension | - | 0.339 |
Tumor size | - | 0.345 |
HR, hazard ratio; CI, confidence interval.
p < 0.05.
Cerebrovascular accident after treatment
Patient | Age (yr) |
Sex | Tumor type | RT dose (cGy) | Time since RT (yr) | Hormone normalization | Stroke lesion | Stroke risk factors |
---|---|---|---|---|---|---|---|---|
1 | 53 | M | Secreting (GH) | 5,400 | 5.2 | Yes | Pons | DM |
2 | 29 | F | Secreting (PRL) | 5,400 | 3.8 | Yes | Pons | DM |
3 | 68 | F | Non-secreting | 5,400 | 8.5 | - | Midbrain | - |
4 | 59 | M | Non-secreting | 5,220 | 2.3 | - | Unknown | HTN |
5 | 66 | M | Non-secreting | 4,500 | 6.0 | - | Right inferior cerebellum | Arrhythmia |
6 | 48 | F | Non-secreting | 5,400 | 5.5 | - | Left frontal lobe (subcortical area) | Arrhythmia |
RT, radiotherapy; M, male; F, female; GH, growth hormone; DM, diabetes mellitus; PRL, prolactin; HTN, hypertension; Arrhythmia, atrial fibrillation.
Age at radiotherapy treatment.