Use of radiotherapy after pituitary surgery for non-functioning pituitary adenomas

Abstract

Surgery is the treatment of choice for non-functioning pituitary macroadenomas (NFPAs). In cases of postoperative remnant growth or tumor recurrence, radiotherapy (RT) can be considered. The role of RT in the postoperative management of NFPAs is still debated. The main arguments against routine use of RT are the lack of randomized controlled trials, the use of clinically irrelevant endpoints in most studies on RT, the benign character of the condition, the potential for side effects of RT, and the option to apply RT at a later stage. However, because of its excellent efficacy in inhibiting tumor growth, reducing tumor volume and improving any existing visual defects, and as its side effects seem to be limited compared to the benefits provided, RT keeps a place in the management of NFPAs when a tumor remnant persists, particularly if it is invasive and displays high proliferation markers, if surveillance shows a relevant increase in tumor volume or if the tumor is close to the optic chiasm. The size of the remnant, its vicinity with the optic pathways, and the potential risk to healthy surrounding tissues need to be considered when deciding on an RT procedure.

The epidemiology of aggressive pituitary tumors (and its challenges)

“…If we consider regrowth after treatment as the first hallmark of aggressiveness, several studies show that approximately 20-50% of patients with a nonfunctioning adenoma display signs of regrowth five years after initial surgery [9,20]; this number is lower if additional radiotherapy is applied [20]. After ten years, the percentage of patients with a regrowth of the adenoma is >50% [20].…”

“…If we consider regrowth after treatment as the first hallmark of aggressiveness, several studies show that approximately 20-50% of patients with a nonfunctioning adenoma display signs of regrowth five years after initial surgery [9,20]; this number is lower if additional radiotherapy is applied [20]. After ten years, the percentage of patients with a regrowth of the adenoma is >50% [20]. In series on hormone secreting adenomas, the recurrence risk is lower after medical treatment or surgery, but it needs to be acknowledged that in prolactinomas [21], acromegaly [22] and Cushing's disease [23][24][25] the tumor size at detection and treatment is smaller compared to nonfunctioning adenomas.…”

The natural history and treatment of non-functioning pituitary adenomas (non-functioning PitNETs)

“…At 15 years post-operatively, mean PFS was calculated as 93% after RT compared to 33% if no RT was administered (Gittoes et al 1998). However, there are no randomised controlled trials indicating the superiority of adjuvant post-operative RT compared to active surveillance, while the potential side-effects of RT render the indication for RT debatable (Chanson et al 2019). Furthermore, a recent meta-analysis reported that residual tumour growth occurs slowly as the tumour doubling time is only 3.4 years with no growth observed during follow-up in 50-60% of patients (Chen et al 2012).…”

“…Certainly, unless the tumour exhibits especial aggressiveness radiologically and/or histopathologically, we believe RT should be reserved for the time of disease progression during follow-up, while immediate post-operative treatment should be reserved for cases with significant tumour remnant and high risk of progression (Lucas et al 2016). Furthermore, adjuvant RT should be considered for patients presenting with aggressive NFpitNENs, large tumours with suprasellar extension or cavernous sinus invasion or displaying aggressive histopathological characteristics such as a LI Ki-67 >3% or extensive immunostaining for p53 (Chanson et al 2019). RT may also be used as primary treatment in cases where surgery is not feasible.…”

“…Follow-up with assessment of anterior pituitary function is recommended every 6 months post-treatment with RT. Rare side effects of RT include optic neuropathy, neurocognitive dysfunction, a probably increased risk of secondary malignancies of the CNS, and an increased risk of cerebrovascular events (Brada et al 1993, Chanson et al 2019. Visual problems are exceptionally rare for fractionated RT as long as the daily dose is <1.80 Gy and the total dose does not exceed 45 Gy, and for single-dose radiosurgery, the dose to the optic apparatus is <8 Gy, although it may still occur.…”