23.2.1 Brainstem

The brainstem is considered an eloquent area as it possesses highly condensed and critical neurologic functionality. Brainstem radiation injury can clinically manifest as cranial nerve palsies, focal motor or sensory deficits, or possibly death, most commonly when damage to the medulla oblongata occurs. QUANTEC recommends a maximal dose tolerance of 12.5 Gy to limit the toxicity risk to less than 5% for single-session stereotactic radiosurgery (SRS) ^{2 ,​ 3} and 54 to 59 Gy, depending on if a partial or total volume of brainstem is irradiated, with conventional fractionated radiotherapy. Some researchers suggest that the brainstem surface has a higher radiation tolerance than the brainstem “core,” although data on this topic are generally limited.

Distinct anatomical regions of the brainstem have shown different radiosensitivity. Uh et al observed nonhomogeneous changes in substructures within the brainstem of pediatric patients ⁴ ; in particular, the pontine transverse fibers were more susceptible to radiation when DTI parameters were analyzed. However, this has not yet translated into clinical practice and the same treatment is considered for any part of the brainstem.

23.2.2 Optic Pathway

In order to decrease the risk of radiation-induced optic neuropathy (RON), most studies and guidelines suggest a maximum point dose threshold of 8 Gy per single fraction to the optic nerves and optic chiasm. QUANTEC guidelines have recommended a maximum dose of 10 to 12 Gy for a single-fraction treatment, while Stafford et al from Mayo Clinic ⁵ reported the safety of 10 Gy as median point maximum dose and less than 2% of RON with ≤12 Gy based on DVH-toxicity analysis. This is in concordance with the most recent data from Milano et al that showed that there was a <1% RON risk for 12, 20, and 25 Gy as maximum point doses for single-fraction, three-fraction, and five-fraction SRSs, respectively, where 10 Gy was their recommended dose for single-fraction SRS. ⁶ During conventionally fractionated radiation therapy, a maximum dose limit of 54 to 55 Gy is utilized, with a low risk of RON (<2%), especially when the fractional dose is kept below 2 Gy. ⁶

Patient-specific characteristics are associated with increased risk of RON. For instance, patients with pituitary neoplasms have increased radiosensitivity and a dose limit of 46 to 48 Gy at 1.8 Gy per day has been recommended in one series. ⁷

23.2.3 Skull Base Structures

The majority of the patients who undergo SRS for skull base–located tumors usually carry benign neoplasms as meningioma, schwannomas, and pituitary adenomas (PA). Consequently, long-term tumor control in addition to a low-morbidity profile is the treatment goal.

Minimizing the radiation doses reaching tumor surroundings is particularly important as cranial nerves, pituitary, brainstem, blood vessels, venous sinuses, and the cochlea portray the organs at risk (OAR) in this anatomical region.

SRSs to lesions within the cavernous sinus (CS) and parasellar region have been focused on optic apparatus (OA) safety, and the previously described criteria apply in this regard. As new technologies such as Gamma Knife (GK) Perfexion and Icon allow for steep gradients that keep optic pathway doses way below 8 Gy, DVH of the others cranial nerves, sometimes even encased by the tumor, will guide therapy. Within the CS, the trigeminal nerve has been proven more sensitive to RON than oculomotor nerves, ⁸ which obtained safe and effective clinical alleviation and tumor control with upfront SRS delivering marginal doses of 12 to 14 Gy for small to medium size schwannomas. ⁹ For bigger tumors, surgical resection and adjuvant SRS can be offered. The same tumor margin dose ranges applied to vagal, glossopharyngeal, or hypoglossal nerves rarely lead to neurological deficits.

Dose tolerance of the cochlea should be considered in head and neck cancers as well as in vestibular schwannomas radiation planning. Mean dose tolerance of the cochlea to conventional radiotherapy is estimated from less than 35 to 45 Gy with different risk and severity of sensory neural hearing loss. ¹⁰ For SRS, marginal or maximum dose of 12 to 14 Gy to the cochlea and a mean dose of 4 to 6 Gy should be considered.

23.2.4 Spine

Advances in radiation delivery, including three-dimensional localization and intensity modulation, have resulted in high accuracy in achieving dose conformality, increasing the ability to deliver cytotoxic tumor doses while sparing normal tissue ¹¹ and improving the response rate of radioresistant primary and metastatic spine tumors to external beam radiation.

Complications from spinal radiotherapy are usually mild and self-limited. These common toxicities include esophagitis, dysphagia, transient laryngitis, mucositis, diarrhea, paresthesia, and transient radiculitis. ^{12 ,​ 13 ,​ 14} However, radiating the spinal cord, a more compact continuation of the brainstem, with either fractionated radiation or SRS, can cause radiation myelopathy, a rare but feared complication. Careful planning is needed to prevent focal or segmental motor or sensory abnormalities, bowel or urinary incontinence, or Brown-Séquard syndrome, when high dose is delivered. If spinal cord injury occurs due to radiation, typical electromyography findings of myokymia and characteristic T2 abnormalities and gadolinium enhancement on magnetic resonance imaging (MRI) correspond to the level of injury. Symptoms of radiation myelopathy typically appear between 6 months and 3 years. Although there are no data supporting different radiosensitivity of various spinal cord segments, it is well known that the cauda equina is more tolerant to radiation injury, while the thoracic cord is the most sensitive.

Prior radiation increases the risk of myelopathy and cumulative dose limits have been proposed. Sahgal et al reported on the probability of developing radiation myelopathy for unirradiated and previously irradiated patients after a multicenter DVH-based analysis. For the unirradiated patients, a maximal single-fraction point dose of 12.4 Gy was recommended to the thecal sac or spinal cord planning organ-at-risk volume. For the second group, dose limits were based on the amount of prior conventional irradiation and at least a 5- to 6-month interval between prior conventional radiotherapy and spine SRS was suggested. For conventional fractionated radiation to the full circumference of the spinal cord in unirradiated patients, doses below 50 Gy are associated with a very low risk of radiation myelopathy (<1%).

23.3.1 Brain Metastases

Today, the most common indication for radiation therapy is brain metastases. In general, patients eligible for microsurgery should also be considered for radiosurgery, weighing the risks and benefits of these two approaches. ^{15 ,​ 16} Moreover, even after gross total microsurgical resection, tumor progression within the tumor cavity occurs in over 50% of patients, and postoperative radiosurgery dramatically reduces this risk. ¹⁷ Additional data exist supporting favorable local control and survival ^{18 ,​ 19} even in patients harboring up to 10 lesions. ²⁰

The utilization of radiosurgery for metastases located in eloquent regions of the brain has been studied by several researchers. Dea et al published a retrospective analysis of 164 metastases located in eloquent areas (primary motor, somatosensory, speech, and visual cortex; basal ganglia; thalamus; and brainstem) in 95 patients treated with Gamma Knife stereotactic radiosurgery (GKSR) in a single session. The median dose to the tumor margin was 18 Gy (range: 14–24 Gy) and the median maximal dose was 36 Gy (range: 22.5–48 Gy). This series showed radiosurgery to be safe and effective with a median time to tumor progression of 16 months and a median survival of 8.2 months. New neurological deficits occurred in a transient fashion resolving with steroids use in 5.7% of patients, seizures occurred in 5.7%, and biopsy-proven radiation necrosis in 1.4%. ²¹

Hsu et al also reported on the use of GKRS for lesions located in eloquent areas in 24 patients: 11 in brainstem, 9 in thalamus, and 5 in basal ganglia. The median dose prescription to thalamus and basal ganglia was 18 Gy (range: 15–24 Gy) and 12 Gy to the brainstem (range: 12–18 Gy). In general, there was no difference in the overall survival when compared to the cohort harboring noneloquent lesions receiving a median prescription dose of 24 Gy. ²² The only symptomatic complication was grade 2 headaches, and asymptomatic radiation necrosis was present in 8.3%. An example of a metastatic tumor located in an eloquent region is shown in Fig. 23‑1 .

Our group published the results of radiosurgery in 161 patients harboring 189 metastases in the brainstem, where 52% of them had received whole brain radiotherapy (WBRT) prior to SRS. The median margin dose was 18 Gy prescribed to 50% isodose line. Overall local control was 87.3% at the last follow-up (95.2, 90.1, and 84.9% at 3, 6, and 12 months, respectively). Regression of tumor after SRS was found in 68% of patients and stable tumors in 19% of patients on follow-up imaging ²³ . After controlling for other factors including number of brain metastases, Karnofsky Performance Status (KPS), WBRT, and brainstem tumor volume, a margin dose of at least 16 Gy was associated with superior local control on multivariate analysis. ²³ Severe SRS-induced toxicity (grade ≥ 3) happened in 1.8% of treated tumors, and none of these received WBRT prior to SRS.

These results suggest that SRS can be safely administered after WBRT, even in eloquent locations. However, after this report, we conducted an international cooperative study to define response and toxicity in brainstem metastases and demonstrated an increased risk of injury when SRS is administered after WBRT. As the interval from SRS to WBRT grows, it is possible that sublethal damage recovery occurs and the risk of SRS decreases. ²⁴ It is clear that previous intracranial therapies, specifically radiation, should be considered during treatment decision making.

This international study also demonstrated that, depending on tumor volume, margin doses of 16 to 24 Gy provide an adequate balance of the risks of severe toxicity while maintaining tumor control. ²⁴ These data form the basis for our current practice, where we consider SRS for any patient with a brainstem metastasis who is otherwise fit for radiosurgery (KPS >70, limited intracranial disease, etc.) and adjust margin dose based on tumor volume, location, and timing, as well as history of prior WBRT. We generally recommend a margin dose of 18 Gy. For patients who have received previous WBRT, we reduce the margin dose to 16 Gy. For larger brainstem tumors (>2 cm diameter) or tumors adjacent to optic structures, fractionated SRS is considered. An example of a metastatic brain lesion within the brainstem is shown in Fig. 23‑2 .

In general, an experienced team can perform SRS to brain metastases located in eloquent areas. Of note, in these clinical scenarios, the target consists solely of tumor (i.e., nonneural tissue), and therefore accurate targeting rarely results in clinical toxicity. Moreover, patients with brain metastases have a generally poor prognosis, and may not live long enough to otherwise develop late toxicity. In patients with large metastases, particularly when located in eloquent areas, multisession SRS (i.e., fractionated radiosurgery) has been shown to improve tumor control and reduce radionecrosis. ²⁵ Multisession radiosurgery for brain metastases is the topic of future prospective clinical research.