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

Background

 

  • 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

Methods

 

  • 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

Patient Population

 

  • 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)

Radiation Treatment Details

 

  • 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

Progression-Free Survival

 

  • 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)

Local Control

 

  • Only 3 local failures identified during follow-up
  • 10-year actuarial LC rate: 98.3%
  • No significant differences between secretory and nonsecretory tumors
  • No association with type of radiotherapy (SRS vs fractionated)
  • Equivalent high rates of LC with both modalities

Secondary outcome: Factors associated with PFS

 

  • 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)

Hormonal Control

 

  • 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)

Secondary outcome: Toxicity and side effects

Factors associated with increased hormonal deficiency:

  • Increasing number of surgeries (HR 0.41, 95% CI 0.13-0.69, P < 0.01)
  • No significant association with:
    • Secretory status of tumor
    • Size of planning target volume
    • Age at diagnosis

Other Toxicities

 

  • 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

Conclusions

 

  • Modern LINAC-based RT provided excellent long-term outcomes:
    • 5-year local control: >94% for both secretory and nonsecretory tumors
    • No significant difference in LC between functional and nonfunctional tumors
    • 50% hormonal control at 5 years for secretory tumors
  • Contrary to prior reports, no difference in LC between secretory and nonsecretory tumors
  • Likely due to:
    • Higher total doses
    • More conformal radiation (IMRT, VMAT)
    • Daily image guidance
  • Primary toxicity was hypopituitarism, but many deficits present before RT

Strengths

 

  • Large single-institution cohort (140 patients)
  • Long follow-up (median 5.35 years)
  • Includes modern RT techniques:
    • Intensity-modulated RT (51.4%)
    • Volumetric modulated arc therapy (39.3%)
    • Dynamic conformal arcs (9.3%)
  • Both secretory and nonsecretory tumors included
  • Consistent use of daily image guidance
  • Detailed assessment of both local control and hormonal control
  • Analysis of hypopituitarism before and after RT

Limitations

 

  • Retrospective study design
  • Heterogeneous patient population
  • Selection bias for treatment modality (not randomized)
  • Limited number of progression events (only 3 local failures)
  • MIB-1 proliferation index not available for many patients (65%)
  • No standardized protocols for::
    • Timing of surgery and radiation
    • Type of RT (SRS vs fractionated)
    • Medical management of secretory tumors
  • No data on newer hypofractionated approaches (e.g., 5 fraction SRS)