Stereotactic Radiosurgery and Stereotactic Radiotherapy for Malignant Skull Base Tumors

The role of stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) for malignant skull base tumors was summarized and discussed. The treatment of skull base tumors remains challenging. Their total resection is often difficult. SRS/SRT is one useful treatment option for residual or recurrent tumors after surgical resection in cases of primary skull base tumors. If skull base metastasis and skull base invasion are relatively localized, they can be candidates for SRS/SRT. Low rates of cervical lymph node involvement in early-stage (N0M0, no lymph node involvement or distant metastasis) nasal and paranasal carcinomas (NpNCa) and external auditory canal carcinomas (EACCa) have been reported in the literature. Such cases might be good candidates for SRS/SRT as the initial therapy. We previously reported the results of SRS/SRT for various malignant extra-axial skull base tumors. In addition, treatment results of early-stage head and neck carcinomas were summarized. Those of our data and those of other reported series were reviewed here to clarify the usefulness of SRS/SRT for malignant extra-axial skull base tumors.


Introduction And Background
Treatment of skull base tumors is challenging. Their total resection is often difficult, as they involve or are located adjacent to various important structures including cranial nerves, major vessels, and the brainstem [1]. Stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) is one treatment option for residual or recurrent tumors after surgical resection in cases of primary skull base tumors such as chordoma, paraganglioma, and non-benign meningioma [2]. If skull base metastasis and skull base invasion are relatively localized, they are good candidates of SRS/SRT.

Review
Various kinds of malignant tumors arise in the skull base ( Table 1)

1: Intracranial extra-axial malignant tumors including skull base tumors
In primary tumors, SRS/SRT is a treatment option after surgical resection with histological diagnosis. Localized distant metastases to the skull base could be treated on the basis of clinical diagnosis. Skull base invasion of head and neck cancers, most commonly recurrent after 1st line treatment including radiation therapy, can be treated by SRS/SRT, if the lesion is relatively localized. Furthermore, of various head and neck cancers, low rates of cervical lymph node involvement in early-stage nasal and paranasal carcinomas (NpNCa) and external auditory canal carcinomas (EACCa) have been reported in the literature [14-16, 17,18]. This might make them good candidates for SRS/SRT, instead of surgical extirpation.

Chordoma
Chordoma has a clinically malignant nature invading skull base structures. Total resection is always difficult, and marginal recurrence often develops. In such cases, SRS/SRT can be expected to control the recurrent or residual tumor instead of repeat surgery.
Mori et al. reported the treatment results of Gamma Knife SRS (GK-SRS) for chordoma in seven patients ( Table 2) [3][4][5][6]. Although the sample size was small, the follow-up period was relatively long. Five-year local control rates (LCRs) of treated tumors, residual and recurrent after surgical resection, were 67%. With additional treatment for marginal and distant relapse, the five-year disease specific survival rate (DSSR) was 100%. They used mainly SRS by Gamma Knife (GK) (Elekta, Tokyo). In addition, SRT using Novalis (BrainLAB, Tokyo) was done for recurrence in one case, as the recurrent tumors were relatively large and fractionated SRT was deemed better to avoid adverse radiation effects. They delivered a single marginal dose of 15 to 20 Gy (median, 16 Gy) to the target tumors of 0.6 to 24 ml in volume. Temporary adverse effects were limited to only a single case in which right trigeminal nerve deficits, hypesthesia in the right cheek and right masseter muscle weakness were reported.   A number of papers have been published on chordoma SRS/SRT both with particle-beam and photon-beam [3,[19][20][21][22][23][24][25][26][27][28]. However, in early-reported series the treatment results of both chordoma and chondrosarcoma were mixed [29]. Reported series dealing with only chordoma were summarized in Table 3 for particle-beams and in Table 4 for photon-beams [3,[19][20][21][22][23][24][25][26][27][28]. Relatively larger volume cases were treated effectively by particle beam series with a more frequent fraction schedule.   Photon beam seemed to be effective if the target tumors were not large and when large a single fraction dose was used.
After surgery or SRS/SRT timely assessment in cases developing local or marginal relapse with repeat SRS/SRT or surgical resection is indispensable to control chordoma, which shows a proclivity to develop repeat recurrence.
SRS/SRT is effective also in skull base chondrosarcoma residual and recurrent after surgical resection [30]. The prognosis was reported to be a little better for chondrosarcoma [31]. Murakami et al. reported a case of skull base mesenchymal chondrosarcoma, surviving more than 10 years after the initial surgery, with repeated SRS/SRT in addition to surgical resection 10 times [32]. They concluded that the extent of the initial resection is important for treatment outcome.

Paraganglioma (Glomus tumor)
Paraganglioma located at the skull base is also difficult to manage. Paraganglioma often arises around the jugular bulb system and involves cranial nerves such as the lower cranial nerves. It often exists over intracranial and infracranial spaces in a dumbbell shape. In addition, it is vascular-rich.   Tripathi et al. used a hypofractionated schedule using GK [36]. Gigliotti et al. reported the results of Linac-based SRT [37]. Recently, we treated two cases of large recurrent paraganglioma by two-volume staged GK-SRT (unpublished data).

Non-benign meningioma
Histologically 4-7% of meningiomas are considered atypical meningioma (AM) and 1-2% are malignant meningioma (MM) [5]. Non-benign meningiomas tend to recur within a relatively short term even after radical surgical resection.  [38]. Single-fraction SRS in the range of 15-18 Gy, or SRT of 21-24 Gy in three fractions, or 20-25 Gy in 4-5 fractions was delivered. The LCRs were 97%, 77%, and 67% at one, two, and five years, respectively, in AM and 66% each at one and two years in MM. The regional progression-free survival (PFS) was 93%, 73%, and 59% at one, three, and five years, respectively, in AM and 93% and 46% at one and two years in MM. The estimated distant tumor PFS in AM was 80%, 44%, and 44% at one, three, and five years, respectively, and 49% and 24% at one and two years, respectively, in MM. They treated the median planning target volume of 1.71 ml (range, 0.06 to 22.5) mostly by single-session SRS.
Recently Wu et al. published a review of the results of particle radiotherapy for WHO grade II (AM) and grade III meningiomas (MM) in 11 articles including 240 patients [39]. LCR at five years or at the end of the follow-up (median 145 months) ranged from 46.7 to 86%. Radiation necrosis was reported in 3.9% (3/77 patients) across the three studies available. Of them only one patient, who had had previous radiotherapy to the pituitary region, showed serious radiation necrosis (Common Terminology Criteria for Adverse Events (CTCAE) Grade 3).
Kaur et al. also published a review article on adjuvant radiotherapy for AM and MM [40]. The median five-year PFS and overall survival (OS) were 54.2% and 67.5%, respectively, for AM and 48% and 55.6% for MM. The complication rates were 11.1% for AM and 5.1% for MM. They described that incomplete resection and radiation dose < 50 Gy conferred significantly poorer five-year PFS. Adjuvant radiotherapy improved local control especially in patients with subtotally resected AM and MM, while inducing modest treatment toxicity. However, in patients with completely excised AM adjuvant radiotherapy did not confer any prognostic advantage, though in those with MM an advantage for adjuvant radiotherapy was indicated.

Hemangiopericytoma (Solitary fibrous tumor)
The clinical behavior of hemangiopericytoma is more aggressive than that of meningioma. This tumor is notable not only for its local aggressiveness and high rate of recurrence but also for its proclivity to develop extracranial metastases [6]. Spina et al. published a systematic review of 18 studies including 208 patients (366 tumors) [41]. Radiotherapy modality was GK in 14 series and CyberKnife (CK) or linear accelerator-based (LINAC) system in four. In the review of the literature, they described that the median time for recurrence was about five years, with PFSs of 96%, 49%, and 28% at one, five, and 10 years, respectively. In addition, the incidence of metastasis increased over time, amounting to 13%, 33%, and 64% at five, 10, and 15 years, respectively.
Tsugawa et al. reported the treatment results of GK-SRS for hemangiopericytoma in seven cases (

Distant metastasis and direct invasion of malignancies
Metastases to the skull base are challenging situations because they often involve critical structures including cranial nerves and induce progressive ipsilateral neurological deficits. Skull base infiltrations by direct invasion of a regional primary malignant tumor of head and neck cancers, for example along the cranial nerve routes, often occur. Both metastasis and invasion by carcinomas, when localized, can be treated effectively by SRS/SRT. A number of reported series have documented the effectiveness of SRS/SRT for both situations, which were mixed [43]. However, the respective results differed somewhat. Improvement of local cranial nerve impairment is more expected in cases of isolated distant metastases. Improvement of neurological symptoms was obtained in 91% (10/11) of cases of distant metastases in contrast to 40% (4/10) of direct skull base invasions by head and neck carcinomas ( Table 6) [8,9]. Mori   Minniti et al. also reported the effectiveness of SRT, good local control and neurological improvement, in cases of skull base metastases involving the anterior visual pathway [44]. They delivered 25 Gy in five fractions. In 51% of their patients clinical improvement of preexisting cranial nerve deficits was achieved.
Indications and treatment planning, including optimal prescription dose, fraction schedule and field decision, will have to be established in future studies.

SRS and SRT
GK and cone collimated CK have similar dose distributions, steep dose fall-off around the target and relatively high doses inside the target. Gamma Knife procedures previously needed rigid head frame fixation with skull screws and were only suitable for single-session SRS. However, Icon (Elekta, Tokyo) with a relocatable thermoplastic facial mask system, good for fractionated SRT, has recently become available. We have used GK-SRS for relatively localized small tumors, especially postoperative residual and recurrent, in primary skull base tumors of chordoma, paraganglioma, meningioma, and hemangiopericytoma. If a relatively broad target with prophylactic surrounding area, i.e. the operative field of tumor bed, has to be included as the target, we have used Novalis or CK. Metastatic carcinomas with a highly invasive nature were targeted by LINAC, such as Novalis or TomoTherapy.
Considering chordoma, non-benign meningioma, and hemangiopericytoma, the feasibility of postoperative adjuvant therapy has to be established, even if the tumor is resected totally. The optimal treatment protocols for early-stage nasal and paranasal carcinomas and external ear canal carcinomas have to be established.

Conclusions
SRS/SRT has been clinically applied for various malignant skull base tumors successfully. However, further investigation of larger populations with longer follow-up periods will be necessary to establish optimal indications and treatment planning considering the histological diagnosis, location, and individual circumstances, including whether it is to be the initial radiotherapy or retreatment of the tumors.