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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.

Results

Conventional Fractionation (Photons or Protons)

As chordomas traditionally have been thought to be radioresistant, high doses of conventional fractionated treatment have been used. These treatments were given in either the primary definitive, neoadjuvant, adjuvant, or salvage setting. For skull base disease, photon doses of 50–60 Gy in 2 Gy fractions have been used. Catton et al. treated 20 skull base chordomas, postoperatively, with a median dose of 50 Gy. Median duration of survival was 62 months and no difference was seen for doses <50 Gy or >50 Gy. Overall, adjuvant treatment provided useful and prolonged palliation but was rarely curative. A combination of photon and electron beams has been used for spinal disease. Usually all histopathologic subtypes are treated with the same dose.

Despite advances in delivery of photon therapy, it often entails significant exit dose to surrounding normal tissue. Fractionated proton beam therapy can deliver high tumor dose with less collateral radiation. The Bragg peak of protons permits low entrance dose, focused energy deposition at the targeted volume, and steep dose drop-off thereafter. However, historically conventionally fractionated photon or proton radiotherapy with final doses nearing 78 Gy has resulted in poor local control rates of 46%–81%. Use of carbon ions has resulted in better local control rates, i.e., rates of tumor control at 5 years of 72%–85%. However, proton or carbon ion therapy facilities are rare and expensive to maintain. In addition, to date no randomized controlled trial has compared the efficacies of SRS and proton beam therapy for chordomas. However, given the low α/β ratio of chordoma, investigators have explored ways to escalate dose through stereotactic radiosurgery.

Spine Versus Skull Base SRS

As with conventional treatment, the role of SRS in chordoma tends to be control of residual disease or treatment of recurrence after surgery. For primary definitive treatment, SRS is particularly useful for treating small, relatively asymptomatic lesions. Several studies have demonstrated promising results using SRS for skull base and spine or sacrum chordomas. Local control rates vary widely. Although only a few studies have a median follow-up of at least 10 years, they do suggest that various factors, such as radiation dose and tumor volume, determine treatment outcomes.

Henderson and colleagues treated 24 chordomas of the skull base, mobile spine or sacrum in 18 patients with frameless robotic SRS. The mean tumor volume was 128 cc, and the median dose was 35 Gy delivered in five sessions. Median follow-up duration was 46 months. About 11 patients had either a partial response or stable disease. The rate of local control at 65 months was 59% and of overall survival was 74%.

Between 1994 and 2010, 20 patients with skull base and spinal chordomas were treated with frameless robotic SRS at the Stanford CyberKnife Center. The average tumor volume was 16.1 cc and the mean marginal dose was 32.5 Gy. Median duration of follow-up was 34 months, and 55% of patients showed tumor control within this time. Those treated in the adjuvant setting had a better chance of having improved or stable outcome compared to those treated for recurrence. A more recent update of this series including chordomas treated with from 2000 to 2015 included 31 skull base (65%) or spinal (35%) chordomas in 30 patients treated adjuvantly (58%) or at recurrence (42%). Ten of the recurrent tumors had received prior fractionated radiotherapy to a median dose of 70 Gy (range, 60–75.5 Gy). Newly diagnosed tumors were treated with a median SRS dose of 38.75 Gy in 5 fractions (range, 20–45 Gy in 1–5 fractions). Fig. 31.1 shows a representative hypofractionated radiosurgery plan. The rate of LC at 3 years was 93% (CI, 63%–98%). At last follow-up, all newly diagnosed patients were still alive, but 6 of 13 patients (46%) treated at recurrence were deceased; median duration of OS was 71 months. These data suggest better local control than that of fractionated radiotherapy, and that SRS given adjuvantly is more effective than that given for recurrent disease.

Multiple other studies have shown that frameless robotic SRS as initial treatment can achieve long-term tumor control. Yamada et al. treated 24 skull base and spine chordomas with SRS to a median tumor dose of 24 Gy in the neoadjuvant, adjuvantor salvage setting. The median duration of follow-up was 24 months. 95% of the patients demonstrated stable or reduced tumor burden on serial MRI. One patient had radiographic progression of tumor 11 months after SRS. Only 6 of 13 patients who underwent neoadjuvant SRS proceeded to surgery.

Skull Base SRS

Most centers using a frame-based system for skull base chordomas employ the Gamma Knife. Hasegawa et al. treated 37 skull-based chordomas and chondrosarcomas , most in the adjuvant setting after maximal safe resection. Out of which 30 were chordomas, 4 were chondrosarcomas, and 3 were of unknown histology. The mean tumor volume was 20 cc and the mean marginal and maximum doses were 14 and 28 Gy, respectively. The mean duration of follow-up was 59 months from treatment. The actuarial rates of local tumor control at 5 and 10 years were 76% and 67%, respectively. The treating physicians recommended use of generous treatment volumes to avoid marginal failure and a marginal dose of at least 15 Gy. Koga et al. used doses greater than 16 Gy and Kondziolka et al. used a margin dose of >20 Gy for tumors <30 cc in volume.

The North American Gamma Knife Consortium, comprising 6 academic medical centers , retrospectively evaluated the outcomes of 71 chordomas treated with surgery and SRS regimen chondroid chordomas and chondrosarcomas were excluded. The median tumor volume was 7.1 cc. The median prescription dose delivered to the tumor margin was 15.0 Gy and the maximum dose varied from 18 to 50 Gy. Follow-up imaging showed treated tumor progression in 23 patients (32%), stable disease in 23 patients (32%), partial tumor regression in 23 patients (32%), and complete resolution of tumor in 2 patients (3%). 60% of patients required additional treatment, either surgery, XRT, or SRS, for progression of treated or remote tumor. Older age, prior XRT, tumor recurrence, and large tumor volume were significantly associated with worse tumor control.

Liu and colleagues treated 31 skull base and cervical junction chordomas with a frame-based system in the adjuvant setting after maximal safe resection. Three patients had received radiation therapy before radiosurgery. The postoperative tumor volume treated ranged from 0.47 to 27.6 cc, with a mean of 11.4 cc. The mean tumor margin radiation dose was 12.7 Gy (range: 10–16 Gy), and the mean maximum dose was 29.2 Gy. Tumor volume within 20% of the original volume was defined as stable whereas a decrease of more than 20% was considered volume reduction. 9 of 15 tumors with MRI follow-up 2–7 years after treatment were either decreased or stable. The actuarial rate of tumor control rate at 5 years was 21.4%. Most recurrent tumors were found outside of the prescription isodose volume, suggesting that properly targeted radiosurgery can achieve local control.

Dassoulas et al. related 15 skull base chordomas 10 of which were in the clivus, 3 in the cavernous sinus, and 2 predominantly in the petrous bone. Out of these, 12 (80%) had been operated on. The mean prescription dose was 12.7 and the mean maximal dose was 36.7 Gy. No patient received prior radiation therapy. Three patients received repeat GK for out of field progression. Clinical follow-up was available for 11 patients, with a median duration of 70 months. Symptomatic progression occurred in 75% of patients; there was no statistically significant difference in prescription or maximal doses between those who achieved local tumor control and those who exhibited tumor progression. Margin doses, tumor volume, number of isocenters, age, or gender were not predictive of outcome.

MSKCC used linac-based SRS for 12 spinal chordomas in either the adjuvant setting after maximal safe resection or intralesional curettage or in the salvage setting. Patients who had spinal SBRT within 4 months after surgery were included in the adjuvant group. Most patients in each group received 24 Gy in 1 fraction or 27 Gy in 3 fractions. Patients treated for initial disease had a median follow-up time of 65.9 months and a local control rate of 80%. About 85.7% of those treated at recurrence had received prior radiation therapy, i.e., SBRT or conventional radiotherapy, before being retreated at MSKCC. The rate of local control in this group was 57.1%.

Jung and colleagues treated eight patients with spinal chordoma with single fraction SRS on a Novalis Linac. The median targeted volume was 48 cc and the median prescription dose was 16 Gy. Local control was achieved in 75% of cases, but the median duration of follow-up was only 9.7 months . Table 31.1 shows treatment planning and outcome data for select series of radiosurgery for chordoma.

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