Stereotactic Radiosurgery for Skull Base Chordomas and Chondrosarcomas

© 2018 Elsevier Inc. All rights reserved. Please note that the copyright for the original figures submitted by the contributors is owned by Contributors.

Background

Chordomas are relatively rare tumors, with an overall incidence of 8.4 per 10 million population. They arise from embryonic notochordal remnants along the neuraxis. These remnants usually remain in or close to the midline, entrapped within bone. Therefore, chordomas are typically restricted to the axial skeleton and most commonly occur within the base of skull (32%), spine (33%), and sacrum (29%).

Historically, chordomas have been divided into three histopathologic subtypes: typical, chondroid, and dedifferentiated. Chondroid chordomas can resemble low-grade chondrosarcoma but have a better prognosis than typical chordoma. Dedifferentiated chordomas have a more aggressive profile.

The majority of skull base tumors are 2–5 cm in size, slow-growing, expansile, and infiltrative. Mobile spine tumors tend to present with late diagnosis and are therefore larger. In general, chordomas usually contain lytic and soft-tissue components. Both intra- and extracranial lesions present challenges as they can cause significant local destruction given the anatomical constraints imposed by the skull and spinal column. Metastasis typically only occurs in the very late stages of the disease.

Clinical presentation depends on the site of origin and direction of growth and symptoms usually develop once tumors have developed a significant size. For example, clival chordomas, which tend to encase critical vessels and cranial nerves, mimic those of other skull-based tumors with headaches or cranial nerve palsies reported commonly. Visual disturbance secondary to abducens nerve palsy is the most frequently reported symptom. Other symptoms caused by clival chordomas include difficulty with balance, hearing loss, dysphagia, orbital pain, and facial numbness. In many cases these lesions adhere to the brainstem and/or have frank bony invasion with pressure on nearby brain tissue. In these cases it is common for incoordination and motor weakness to be reported. Nasal congestion and rhinorrhea can be a sign of skull base erosion.

Spinal and sacral chordomas can present with pain and radiculopathy. Spinal chordomas can be adjacent to the spinal cord or vertebral arteries. Sacral chordomas can irritate the sciatic nerve or iliolumbar trunk, or extend anteriorly into the pelvis to displace pelvic organs.

MR imaging is equivalent to CT in detecting intracranial chordomas. However, MRI is considerably superior to CT in delineating the extent of the lesion because it offers anatomic detail and tissue contrast. In comparison to CT, however, it inadequately evaluates cortical bone and calcification. Classic intracranial chordoma has high signal intensity on T2-weighted images. Heterogeneous hypointensity on T2-weighted images represents intratumoral calcification, hemorrhage, or mucus pools. Most intracranial chordomas demonstrate moderate to marked enhancement following contrast material injection but occasionally this enhancement is minimal or absent. There are variations in imaging noted for different histologic subtypes. For example, chondroid chordomas may not enhance as much as typical chordomas on T2-weighted images.

Radiobiological Principles

The alpha/beta ratio is used to quantify the fractionation sensitivity of normal tissues and tumors. α and β describe the linear and quadratic components, respectively, of the cell-survival curve. In general low alpha/beta values (1.5–5 Gy) indicate greater sensitivity to higher radiation doses per fraction. In these cases, radiation is less effective if the dose fractions are smaller than 2 Gy, the daily dose typically used in conventional radiotherapy. By contrast, high alpha/beta values (6–14 Gy) indicate a linear dose response to radiation and comparatively greater sensitivity to regimens of lower dose per fraction.

For tumors with a low alpha/beta ratio and thus relative resistance to low fractionation doses, hypofractionation with large daily doses given over a shorter period of time may be preferable. The slow proliferation, long potential doubling time, and the 1.5 Gy alpha/beta ratio for prostate cancer, much lower than the typical value of 10 Gy for many other tumors, have prompted multiple trials employing hypofractionation. Recently published phase-III trials suggest that late toxicity is equivalent between the conventional fractionation regimens and hypofractionation, and that hypofractionated schedules are similar or superior to conventional fractionation in terms of biochemical failure. In addition, with hypofractionation, overall treatment times are reduced.

Similarly, chordomas can exhibit very slow, indolent progression over many years. They also likely have a low alpha/beta ratio. Henderson et al. estimated the alpha/beta ratio for chordomas to be 2.45. High total doses of conventional radiotherapy, given in small daily doses with large fractionation number, have provided only modest palliation and local control. Similar to prostate cancer, local control may therefore be improved with hypofractionation, larger daily doses given with smaller fractionation number. Limited data exists for hypofractionated treatment with stereotactic radiosurgery (SRS), but early results are promising.

Indications for Radiotherapy

Chordomas of the skull base and spine present a therapeutic challenge. Ideally, chordomas are treated with complete surgical excision that does not disrupt the tumor margin. Violation of the tumor margin and extent of initial resection correlates with local recurrence. To date, local recurrence is the most important predictor of mortality. Multiple groups have shown that local recurrence is significantly associated with an increased risk of metastasis and tumor-related death. Bergh et al. found that local recurrence was associated with a 21-fold increased risk for tumor-related death ( P < .001).

Chordomas’ predilection to develop midline within the axial skeleton adjacent to neurologic and vascular structures, coupled with their infiltrative nature, makes total resection difficult to achieve. A variety of surgical techniques are typically used. For base of skull lesions complex procedures are necessary. Transsphenoidal and transcranial approaches have been reported in the literature. Regarding more distal extracranial tumors, en bloc resection is advocated. For tumor below the sacroiliac joint, i.e., S3 level, en bloc sacral resection with wide margins can be used. This is thought to prevent seeding and recurrence and has been proven to lengthen survival and maintain local control better than other surgical techniques.

Despite more advanced techniques, most patients have some degree of residual tumor postoperatively. Afflicted patients usually receive surgery plus external beam radiotherapy or radiotherapy alone as part of their treatment regimen. Fractionated photon therapy, stereotactic radiosurgery in one to five fractions, and particle radiotherapy have been reported.

Postoperative radiotherapy is generally recommended for skull base tumors, given that wide surgical resection cannot be achieved. There is controversy whether postoperative radiotherapy is needed following wide or en bloc resection of a sacral chordoma. In some studies, the benefit of radiation therapy has not been clear. For example, Fuchs et al. suggested that observation following an adequate resection is possible. Here radiation did not demonstrate improved survival or disease status. This study found a significantly higher survival rate when an adequate (wide) margin had been achieved in comparison to an inadequate margin. Wide resection alone led to a crude local control in 95% (20 of 21) of patients, compared to 29% (9 of 31) with inadequate margin. However, in this same study, fewer than half of the patients received radiation, and of these patients, two-thirds received it only for recurrence.

Radiation Techniques

Tumors in different locations may require different radiation techniques, patient immobilization, and dosing strategies. Frameless systems permit treatment of skull base, spinal and sacral tumors; frame-based systems are specialized for treating cranial tumors. In the frameless robotic method of SRS, employed by CyberKnife and some linac-based devices, patients are typically immobilized supine with an Aquaplast mask and a thin-slice interval CT scan is obtained for positioning during treatment and fused with an MRI scan for targeting. In frame-based techniques for cranial irradiation, the frame is applied after mild sedation and application of local scalp anesthesia, and an MRI scan is obtained for dose planning.

The efficacy of SRS relies on both dose escalation and advanced neuroimaging techniques. High-resolution CT and MRI permit accurate diagnosis and precision planning with submillimeter accuracy. MRI defines the anatomic detail of soft tissue. Chordoma tumors are hypointense or isointense on T1-weighted images and very hyperintense on T2-weighted images. However, bone destruction, tumor infiltration of the surrounding soft tissue, and postoperative changes can obscure a chordoma’s margin, thus complicating definition of the target for SRS. This can be of particular concern with frame-based SRS where MRI alone is often used for dose planning. High-resolution CT with bone and soft-tissue windowing better defines cortical bone, margins of bone erosion, and calcification. The combination of MRI and CT is very sensitive and specific in delineating chordomas. Regardless of technique, the use of fused images of high-resolution thin-sliced MRI and CT to help define the clinical tumor volume (CTV) and surrounding critical structures is essential.

Different centers define the CTV differently, particularly in regard to including areas thought to harbor microscopic disease. For skull base tumors, some groups suggest liberal inclusion of the whole bony clivus. For spinal disease, the CTV often includes the body, pedicles, and laminae of the vertebra involved by tumor and any associated soft-tissue extension. The peritumoral margin added to the CTV differs with SRS technique. In some cases, no margin is added. MSKCC, using linac-based treatment for spinal disease, uses a PTV with a 2 mm expansion from the CTV, excluding neighboring critical structures such as the thecal sac and esophagus. In postoperative cases, surgical hardware need not be included. Spinal cord contours should encompass an area that is 5 mm superior and inferior to the vertebral body of origin.

Traditionally, conventionally fractionated proton or photon radiation, with two- or three-dimensional techniques, has been used to treat skull base chordomas. Plans include two opposed lateral fields with anterior wedges. A combination of photons with either proton or electron beams has also been used. IMRT can achieve lower dosing of organs at risk in treating both skull base and spinal chordomas. Stereotactic techniques can be used to deliver to chordomas particle or photon radiation in one to five fractions (radiosurgery) or fully fractionated courses of radiotherapy.

SRS can be delivered via frame-based, frameless robotic, or linear accelerator (linac)-based machines. Dosing techniques are machine specific. The high degree of precision permits delivery of a very high dose of radiation to the target with minimal exposure of normal tissues and structures surrounding the tumor.

The Gamma Knife contains 192–201 cobalt-60 sources of approximately 30 Ci. These sources are fixed within a hemispherical shielded shell and converge at a focal point or isocenter. Thus treatments are isocentric and typically only within the skull or skull base. New generation GK systems can treat tumors adjacent to the C2 vertebral body. Dose is typically prescribed to the 50% isodose line, maximizing dose at the center of the target and minimizing dose at the target edge with a steep dose falloff.

The CyberKnife or frameless robotic system consists of a compact 6 MV linear accelerator mounted on a multi-jointed robotic arm. The robotic arm has six degrees of freedom and can direct energy to any part of the body from multiple directions. A noninvasive head restraint or body mold is typically used. One can use a single isocenter, multi-isocenter or nonisocentric radiation planning techniques. A nonisocentric plan may provide the greatest flexibility, while isocentric coplanar arc plans provide good dose homogeneity. Various forms of image guidance—skull-based tracking, Xsight, fiducials, and synchrony—help with onboard tracking and accuracy. During radiation delivery, the patient’s position is monitored with submillimeter accuracy and delivery is modified as necessary. The CK can thus be used for intra- and extracranial disease, has the capacity to treat tumors with complex shapes, and can correct for patient movement during treatment.