Palliative RT has been the standard treatment for skull base malignancies providing excellent relief of pain and improvement of cranial nerve dysfunction in up to 78% of patients [4–9]. More recently, SRS has been employed as a less invasive option for the treatment of skull base metastases with the aim to deliver a high dose to the target with dose sparing of critical structures such as the optic nerves and chiasm. The efficacy of single-fraction SRS for skull base metastases has been reported in few studies that include either nasopharyngeal carcinomas or skull base metastases [14–17]. Iwai et al.  treated 21 patients with cavernous sinus cancers, including 12 patients with metastases from systemic cancer. At a median follow-up of 13 months, the 1-year and 2-year tumor control rates were 68% and 47%, respectively, with no significant differences between nasopharyngeal carcinoma and metastases. After SRS, there was a resolution or improvement of preoperative cranial nerve deficits in 47% of patients. Kano et al.  reviewed retrospectively 37 patients with cancer involving the cavernous sinus treated with gamma knife SRS at the University of Pittsburgh between 1992 and 2006. At median follow-up of 9 months the progression-free survival rates after SRS were 77.6% and 26.6% at 1 and 2 years, respectively. Lower marginal doses were associated with shorter progression-free survival, as in case of tumors in close proximity to the optic pathway or larger lesions; the progression-free survival rate was 89.7% for patients receiving a marginal dose ≥ 15 Gy as compared with 35.9% for those receiving < 15 Gy. Approximately one-third of patients had improvement in their neurologic deficits, similarly to that reported in other few series [14, 16].
Multi-fraction SRS represents an alternative to single-fraction SRS for relatively large brain metastases > 3 cm or adjacent to critical structures with a reported local control rates of 65-90% at 1 year [21–25]. In the current study we have evaluated 34 patients with a skull base metastasis compressing or in close proximity of the visual pathway who were treated with multi-fraction SRS (5 × 5 Gy). The 1-year and 2-year survival rates were 63% and 32%, and respective actuarial 1-year and 2-year local control rates were 89% and 69%, which are in the best range of results observed after single-fraction SRS [14–17] and fractionated stereotactic radiotherapy . A tumor local control of 66-76% at 1 year has been reported following multi-fraction SRS with 5 × 5–7 Gy in patients with brain metastases [21–25]. Ernst-Stecken et al.  reported the treatment results of a prospective study of multi-fraction SRS (5 x 6–7 Gy) in 51 patients with 72 brain metastases. At a median follow-up of 7 months the 1-year local control was 76% and survival 60%, respectively. Using a median prescribed dose of 25 Gy with a median of 5 fractions Kwon et al.  observed a similar actuarial local tumor control rates of 94% and 68.2% at 6 months and 1 year, respectively, in 36 patients with 66 brain metastases. While the optimal dose and fractionation for brain metastases remain to be determined, our results indicate that multi-fraction SRS with 5 × 5 Gy is an effective treatment for skull base metastases associated with good local control and improvement of cranial deficits similar to that reported after single-fraction SRS.
The main reason for using multi-fraction SRS is the advantage of fractionation with respect to radiobiology and normal brain protection. Single-fraction SRS for skull base lesions is in fact limited by the potential toxicity of high single doses to the cranial nerves. While the reported tolerance of cranial nerves in the cavernous after single-fraction SRS sinus is of 16–18 Gy , several retrospective studied have indicated that the incidence of radiation-induced optic neuropathy is about 2% for doses of 8–12 Gy, and becomes >10% for doses of 12–15 Gy [28–31]. Leavitt et al.  have recently reviewed 222 patients treated with Gamma Knife SRS for benign tumors adjacent to the anterior visual pathway. The risk of optic neuropathy was 0 for patients receiving a maximum dose of 8–12 Gy and 10% for those receiving >12 Gy, respectively, suggesting that small portions of anterior visual pathway in the range of 0.02-0.04 cm3 may receive doses up to 12 Gy. In our study no optic neuropathy were observed for doses >25 Gy to less than one-third of optic chiasm and > 27.5 Gy to a small volume of 0.01-0.06 cm3. These point doses may serve as baseline for future comparison when evaluating the risk of optic neuropathy after SRS using different schedules.
The present study has some limitations. The small number of patients and the relatively short follow-up do not allow for definitive conclusions about the risk of symptomatic optic neuropathy when using multi-fraction SRS. Further studies and larger number of patients are needed to confirm that patients receiving doses >25 Gy to the optic nerve and chiasm had a low risk of developing clinically symptomatic radiation optic neuropathy. Nevertheless, our results suggest that when single doses to the anterior optic pathway exceeds 10–12 Gy, as for large skull base metastases or for those adjacent to the optic apparatus, multi-fraction SRS may represent an alternative to single-fraction SRS with similar local control and lower risk of treatment-related complications.
The 1-year and 2-year distant failure rates were 50% and 77%, necessitating salvage treatment with SRS in ten and WBRT in seven patients, respectively. Overall, WBRT could be avoided in about 75% of patients. The main justification for omitting WBRT is that it is associated with a decline in quality of life and neurocognitive function [10–13] without conferring survival advantages [12, 13]. In a randomized study of 58 patients with 1 to 3 metastases who received WBRT plus SRS or SRS alone, Chang et al.  observed that patients treated with SRS plus WBRT showed a greater risk of a significant decline in learning and memory function at 4 months as compared with patients who received SRS alone. Sun et al.  reported similar neurocognitive impairment in patients with small cell lung carcinoma who received prophylactic WBRT. In our study the high distant failure rate was not apparently associated with increased death due to intracranial progression and neurological impairment, confirming that the omission of up-front WBRT is not detrimental for these patients. However, a close MRI follow-up is mandatory with the intent to treat early new distant brain metastases to avoid any potential neurocognitive deterioration.
In conclusion, multi-fraction SRS using 5 × 5 Gy is a feasible treatment option associated with good local control and improvement of cranial nerve symptoms in patients with a skull base metastasis involving the anterior visual pathway. A maximum dose less than 28.5 Gy delivered in 5 fractions to a small portion of the optic nerves and chiasm is associated with a very low risk of radiation-induced optic neuropathy.