Modern Linear Accelerator–Based Radiotherapy Is Safe and Effective in the Treatment of
Secretory and Nonsecretory Pituitary Adenomas

Janopaul-Naylor JR, Rupji M, Zhong J, Eaton BR, Ali N, Ioachimescu AG, Oyesiku NM, Shu HKG
World Neurosurg. 2022;160:e33-e39

Pituitary adenomas (PAs) can cause symptoms from:
- Compression of adjacent structures (optic apparatus, cranial nerves)
- Hypersecretion syndromes (hormonal excess)
Previous studies mostly on Gamma Knife radiosurgery (GKRS)
Limited modern data on LINAC-based approaches:
- LINAC fractionated RT
- LINAC stereotactic radiosurgery (SRS)
Prior reports suggested functional tumors had worse local control
Study aimed to report long-term outcomes with modern LINAC RT

Single institution retrospective review (2003-2017)
Inclusion: LINAC-based RT for histologically/clinically confirmed PA
Minimum 3 years of MRI follow-up required
Endpoints:
- Local control (LC): RECIST criteria on surveillance MRI
- Hormonal control: biochemical remission without medications
- Progression-free survival (PFS): time alive with LC without hormonal recurrence
- Pituitary hormone deficiencies before and after RT
Statistical analysis:
- Kaplan-Meier method for PFS and LC
- Cox proportional hazards models for associations with outcomes

140 patients with pituitary adenomas:
- 94 nonsecretory (67.1%)
- 46 secretory (32.9%): 23 GH-secreting, 13 ACTH-secreting, 9 prolactin-secreting, 1 TSH-secreting
Median age: 46.5 years
Gender: 51.4% female, 48.6% male
Most had prior surgery (135/140 patients)
Median number of surgeries: 1.4
Surgical details:
- Transsphenoidal approach: 94.8%
- Gross total resection: 17.9%
- Subtotal resection: 77.9%
Median follow-up: 5.35 years (IQR 4.0-8.5 years)

RT technique:
- Fixed gantry intensity-modulated RT: 51.4%
- Dynamic conformal arcs: 9.3%
- Volumetric modulated arc therapy: 39.3%
Type of radiotherapy:
- Fractionated RT: 75.0% (105 patients)
- SRS: 25.0% (35 patients)
Target delineation:
- Co-registration of planning CT with diagnostic MRI
- SRS offered if minimum distance from tumor to optic apparatus >4mm
- PTV margins: 1-3mm for fractionated RT, 0-1mm for SRS
Dose specifications:
- Nonsecretory tumors: median 50.4 Gy fractionated / 15 Gy SRS
- Secretory tumors: median 50.4-54 Gy fractionated / 15.5 Gy SRS
Daily image guidance for setup accuracy

No difference in PFS between secretory and nonsecretory groups (log rank p=0.70)
5-year PFS rates:
- Secretory tumors: 95.3%
- Nonsecretory tumors: 94.8%
10-year PFS rates:
- Secretory tumors: 95.3%
- Nonsecretory tumors: 81.3%
On multivariable analysis, only larger PTV was associated with worse PFS (HR 2.60, 95% CI 1.08-6.28, p=0.03)

Factors associated with worse PFS on univariate analysis:
- Larger planning target volume (HR 2.41, p=0.036)
- Pituitary apoplexy (HR 0.11, p=0.03)
On multivariable analysis, only larger PTV remained significant:
- HR 2.60, 95% CI 1.08-6.28, p=0.033
Factors associated with better hormonal control:
- Higher dose to tumor (HR 1.05, 95% CI 1.02-1.09, p=0.005)
- More surgeries (HR 1.74, 95% CI 1.05-2.89, p=0.032)

For secretory tumors, hormonal control at 5 years: 50.0%
Factors associated with improved hormonal control:
- Higher 2-Gy equivalent dose to tumor (HR 1.05, 95% CI 1.02-1.09, p<0.01)
- Number of surgeries (HR 1.74, 95% CI 1.05-2.89, p=0.03)
No association with:
- Age, sex, gross tumor volume
- MIB-1 index, Knosp grade
- Use of SRS vs fractionated RT
Similar time to hormonal control with SRS (mean 3.23 years) vs fractionated RT (mean 3.82 years, p=0.55)

Low rates of non-endocrine toxicities:
- Transient diabetes insipidus: 16 patients (postoperative)
- Unilateral muffled hearing: 3 patients (lasting 2-5 months)
No reported cases of:
- Radiation necrosis
- Optic neuropathy
- Other significant neurological complications
No reported grade 3-4 acute toxicities