Pituitary adenomas are usually benign tumors that account for 10 - 15% of primary intracranial neoplasms[¹]. Tumor growth frequently causes compression of the visual apparatus, pituitary stalk, floor of the third ventricle and enlargement of the sella turcica[²,³]. Pituitary macroadenoma (PMA) refers to tumors more than 10 mm in diameter, although this cutoff is not consensual[⁴]. Although debulking surgery is indeed beneficial in a substantial number of PMA patients, long term tumor and endocrinological control remains more often than not elusive, as a result of the tumor extension, superiorly into the suprasellar cistern and/or laterally in the cavernous sinus. Complete resection is achievable in only 44 - 84% of patients with PMA[⁵]. As such, postoperative[⁶,⁷], salvage[⁸] or radical radiation therapy (RT) is frequently administered to patients with pituitary tumors in general, and to PMA patients in particular. RT has been proven to be an effective treatment in retrospective series for controlling hormone production and tumor growth, with its consequential mass-effect on the adjacent brain structures[^9-12].

RT can be delivered by conventional 3D-conformal delivery-techniques or newer radiation techniques, allowing for better target dose-conformation, including but not limited to intensity modulated RT[¹³], proton beam therapy[¹⁴], radiosurgery[^15-17] or stereotactic fractionated RT (SFRT)[¹,¹⁸,¹⁹]. In this report, we examined the efficacy and toxicity of SFRT for PMA in 27 patients with long term follow-up treated in an academic center.

The institutional database of the departments of Radiation Oncology of Geneva University Hospital (HUG) and Lausanne University Hospital (CHUV) were queried. Eligibility criteria for this retrospective analysis were: 1) PMA; 2) SFRT with definitive intent (patients receiving palliative radiotherapy were not included in this study) and 3) complete endocrinological, radiological and ophthalmological follow-up available. Between March 2000 and March 2009, 27 such patients were identified and underwent SFRT at CHUV, using a linear accelerator dedicated to stereotactic radiation therapy (Siemens USA, New York, NY). PMA patients seen at HUG were referred to the CHUV for SFRT. This retrospective study was approved by both the CHUV's and HUG's Institutional Review Boards. The medical records of these patients, followed by the Endocrinology and Ophthalmology departments of both centers, were reviewed through the most recent follow-up visit with respect to pituitary function, visual function and radiological changes in tumor volume. The acute and late toxicity, possibly related to SFRT, was assessed during routine follow-up in the CHUV and HUG radiation oncology departments.

Prior to SFRT, all patients were evaluated by a multidisciplinary tumor board composed of endocrinologists, neurosurgeons, neuroradiologists and radiation oncologists before and after the initiation of therapy.

The baseline characteristics of the PMA 27 patients (male, n = 15; female, n = 12) are detailed in Table 1. Median age was 56.5 years (range, 20.3 - 77.4). Of the 27 patients, 26 with newly diagnosed PMA underwent transsphenoidal surgery (TSS) as initial therapy, with or without craniotomy (Table 1). Of these patients, 2 and 1 had TSS followed by craniotomy and TSS followed by a repeated TSS procedure, respectively. One patient with Cushing disease did not have surgery, as the PMA was evaluated to be invasive and thus non-resectable (Table 1) and this patient underwent radical SFRT. Ten (37%; Table 1) patients had functional (ACTH, n = 3; prolactin, n = 3; GH, n = 2; ACTH/GH, n = 1 and GH/PRL, n = 1) PMA and these patients received antisecretory medication during SFRT. Patients were considered for SFRT if they had visual function, with or without mass effect on the adjacent optic apparatus, progressive radiological and/or biological disease and definable tumor on brain MRI. SFRT was administered 4.2 to 242.6 months after the initial TSS (median, 22.4).

A thermoplastic stereotactic mask (BrainLAB, Feldkirchen, Germany) was used for SFRT. Gross tumor volume (GTV) was delineated in the Brainscan (Ver. 5.21) treatment planning system, using image fusion from the CT and MRI datasets. All GTVs and organs at risk (OARs), including but not limited to the optic apparatus, brainstem and temporal lobes, were identified and defined by the same radiation oncologist (AP). The planned target volume (PTV) was defined as the GTV + 2.5 mm. Isodose prescriptions were based on the isodose volume that most closely approximated the PTV. Two third (n = 18) of the prescription isodose were 100%. Six and 3 patients were treated at the 85% and 90% isodose line, respectively. The dose constraints to the brainstem, eyeball and temporal lobes were 54, 10 and 30 Gy, respectively. The maximum dose to the optic chiasm and optic nerve was kept below 54 Gy. All dose constraints were met during SFRT planning.

All patients were treated with 1.8 Gy dose per fraction. Median total administered dose was 50.4 Gy (range, 45.0 - 54.0). The use of stereotactic conformal technique provided appropriate coverage of the prescribed dose to the PTV with a median conformity index of 1.2 (range, 1-1.7).

All patients were able to complete SFRT. An example of a treatment is displayed in Figure 1. Mean GTV and PTV was 2.9 ± 4.6 cm³ and 8.4 ± 5.8 cm³, respectively. The median dose delivered to the optic chiasm and brainstem was 50 Gy (range, 24.5 - 54.0; mean 47.7 ± 7.3) and 41.0 Gy (range, 13.0 - 52.3; mean, 37.2 ± 12.7), respectively. Three patients had treatment interruptions (mean, 4.3 days) for technical reasons pertaining to the Linac. Ten (37%) patients had acute grade 1 - 2 toxicity: 4 patients presented with grade 1 headache, 3 patients with grade 1 - 2 asthenia (grade 2, n = 1), 2 patients with grade 1 - 2 nausea (grade 2, n = 1) and another patient presented with transient grade 1 visual compromise. No grade > 2 acute toxicity was observed. No cranial nerve dysfunction was observed.

The results of this study suggest that SFRT achieves high (> 95%) local control (Figure 2) for PMA with exceptional radiation-induced toxicity. The observed tumor control rates compares favorably with other SFRT series for smaller pituitary tumors[¹⁸,¹⁹,^22-24]. Gamma knife-radiosurgery (SRS) has also been administered to patients with PMA [¹⁵,²⁵]. Owing to the biological advantage of a single fraction of radiation, an increase in objective radiological response (i.e. 60 - 70%) is usually observed after SRS[¹⁶,²⁵] when compared to SFRT. SRS is usually limited however to smaller tumors, in vicinity (≥ 2-3 mm) of the optic apparatus but not abutting this critical structure and the radiosurgery dose constraint for the optic nerve and chiasm is usually 8 Gy. This dose constraint derives the observed 78% risk of optic neuropathy in patients receiving > 15 Gy, when compared to 27% when the radiosurgical delivered dose to the optic apparatus is the range of 10 to 15 Gy[²⁶]. Newly diagnosed pituitary dysfunction after SRS is reported in 0 - 50% of patients with normal pituitary function[⁷,^27-30]. This incidence of radiation-induced toxicity is alleged to be higher than the observed hypopituitarism rate after FSRT[²³], although data support that the SRS-SFRT toxicity profile is probably comparable[²⁴]; pituitary dysfunction is likely however to be higher when patients are followed long term, such as those treated with SRS. The indication for SRS thus depends on the target volume and distance to the optic apparatus. If a small adenoma is not located in vicinity of the chiasm, we would recommend SRS. Alternatively, a large tumor in immediate proximity to the chiasm should be treated with SFRT.

In our series, we have observed an absolute improvement of visual field defect and 5-year vision preservation rate of 50% and 93.3%, respectively. Noteworthy, approximately one patient out of two had either a tumor abutting or compressing the optic apparatus (Table 1). These results may be in keeping with other SFRT series which reported an improvement of field defect and vision preservation rate of 0 - 40%[¹,¹⁸] and 93 - 100%[¹⁸,²²,²³], respectively. Importantly, the choice of keeping the dose per fraction < 2 Gy in all patients was appropriate, on the basis of the data from Parsons et al[³¹]. The tolerance of the optic apparatus might be lower in patients with pituitary adenomas, as visual toxicity has been observed at doses as low as 46 Gy[¹³,³²,³³]. Using SFRT for dose escalation, the Thomas Jefferson group has observed two cases with visual loss at 50 Gy delivered with conventional fractionation and has consequently decreased the dose per fraction at 1.8 Gy[¹⁸].

Pituitary hormone deficiency is a frequent (30 - 50%) complication after conventional postoperative RT for PMA[⁷]. In our series, a limited number of patients presented new anterior pituitary deficits after SFRT and the estimated 5-year survival without new anterior pituitary deficits is 96% (Figure 3). These results are comparable to those reported by other SFRT series with smaller pituitary tumors[¹⁸,²²,²³,^34-36]. We have also observed a 30% hormonal response rate in the 10 patients with functional PMAs. This observed response rate is in line with other series of SFRT for pituitary tumors[¹⁹,²²,³⁶,³⁷]. Interestingly, one French prospective study reported a hormonal superior response rate when treated with SFRT only (62%), when compared to SFRT and surgery (42%)[¹⁹]. Conversely, in a retrospective comparison of radiosurgery and 3D-CRT, the 2- and 4-year hormonal complete remission rate was regardless of the treatment modality 26.2% and 76.3%, respectively[³⁸]. The median time to complete remission was however significantly (p = 0.007) longer in the non-radiosurgery group (63 months) when compared to the radiosurgery group (26 months)[³⁸]. The prolonged time to hormone normalization was also observed with SFRT (median, 18 months) when compared to radiosurgery (median, 8.5 months) in another series[²²].

With a mean follow-up period of 6 years, we have not observed any brain necrosis, cerebrovascular disease or radiation-induced tumors. During the carcinogenesis period for the latter complication, there is a latency time between exposure to radiation and cancer onset of many decades. A strong disclaimer should thus be made on the absence of any observed radiation-induced tumors in our series. The patient must always be informed of this dire complication, as the estimated 10 - 30 years cumulative actuarial risk of developing an in-field secondary cancer is 2 - 3%[¹²,³⁹,⁴⁰]. Although we did not assess specifically the cognitive function of our patients, no dementia or major cognitive impairment was observed during the follow-up period. The effect of radiation on patient's cognitive function is however controversial, as patient with pituitary adenoma have suboptimal cognition (anterograde memory[⁴¹], verbal memory and executive functioning deficits[⁴²,⁴³]) when compared to normal controls. A recent Dutch study compared the cognitive function, using validated cognitive tests, of adult patients with nonfunctioning PMA who underwent transsphenoidal surgery, with or without RT. Patients treated with radiation did not show significant cognition scores when compared to those treated with surgery only, although these results are somewhat controversial[⁴⁴].

There were several limitations of our study. First, the study was retrospective in nature and thus lacked data for certain important variables such as patient's neurocognitive function and Quality of Life. The small sample size of 27 patients limits somehow the generalizability of these results. This being said, the patient cohort studied was unselected, treated with the same physicians and the follow-up period, extending to over 10 years, is substantial.

In summary, SFRT achieves effective tumor control in patients with PMA with a low incidence of visual or endocrinological impairment. No cranial nerve dysfunction or radiation-induced tumors was observed at follow-up.

PMA: Pituitary macroadenoma; RT: radiation therapy; SFRT: stereotactic fractionated RT; HUG: Geneva University Hospital; CHUV: Lausanne University Hospital; TSS: Transsphenoidal surgery; GTV: Gross tumor volume; OAR: organ at risk; PTV: Planned target volume; MRI: magnetic resonance imagery; CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; RTOG: Radiation Therapy Oncology Group.

The authors declare that they have no competing interests.

DCW and AP were responsible for the primary concept and the design of the study; DCW, FPP, PM and AP, performed the data capture and analysis. DCW drafted the manuscript; DCW performed the statistical analysis; DCW and AP reviewed patient data; all authors revised the manuscript. All authors have read and approved the final manuscript.