Chordomas and chondrosarcomas are rare, slow-glowing, locally aggressive tumors with high recurrence rates. Stereotactic radiosurgery (SRS) is an important management option for patients with recurrent or residual chordomas and chondrosarcomas. Glomus jugulare tumor are rare highly vascularized tumors that arise from the paraganglionic structures of the glossopharyngeal and vagal nerves. Because of their highly vascular nature and surgically formidable anatomic location, curative resection often proves challenging. SRS can be used as an up-front treatment or as an additional treatment for patients with recurrent or residual glomus jugulare tumor after surgical resection.
Key points
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Chordomas and chondrosarcomas are rare, slow-glowing, locally aggressive tumors with high recurrence rates that may prove disabling or fatal.
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Patients with intracranial chordomas and chondrosarcomas often require multimodality treatment, including surgical resection, fractionated radiation therapy, and stereotactic radiosurgery (SRS).
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SRS is an important management option for patients with recurrent or residual chordomas and chondrosarcomas that failed to respond to initial surgical resection and adjuvant radiation therapy.
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The local tumor control rate and prognosis is generally better for patients with chondrosarcomas than for those with chordomas.
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SRS can be used as an up-front treatment or as an adjuvant treatment for patients with recurrent or residual glomus jugulare tumors after surgical resection.
Introduction
Chordomas are slowly-growing, locally aggressive tumors that arise from embryonic remnants of the notochord and show a dural epithelial-mesenchymal differentiation. They arise from the sacrococcygeal region in 50% to 60% of patients, from the skull base region in 25% to 35%, and from the vertebrae in 15%. The natural history of untreated clival chordomas is dismal, with a mean survival of less than 1 year. Neurologic deficits tend to vary based on the location of the tumor. An abducens nerve deficit causing diplopia is the most frequent presenting sign.
Introduction
Chordomas are slowly-growing, locally aggressive tumors that arise from embryonic remnants of the notochord and show a dural epithelial-mesenchymal differentiation. They arise from the sacrococcygeal region in 50% to 60% of patients, from the skull base region in 25% to 35%, and from the vertebrae in 15%. The natural history of untreated clival chordomas is dismal, with a mean survival of less than 1 year. Neurologic deficits tend to vary based on the location of the tumor. An abducens nerve deficit causing diplopia is the most frequent presenting sign.
Chordomas
Therapeutic Options
Aggressive initial management, beginning with radical resection when possible and followed by fractionated radiation therapy or radiosurgery, improves overall outcome. Earlier recognition of these tumors facilitates aggressive therapy. Complete resection without significant morbidity is rarely feasible because these tumors tend to encase critical vessels and cranial nerves, or adhere to the brainstem. The recurrence rate, even after virtually complete resection, remains high. Recurrent tumors are even more challenging for extirpation. Most patients undergo adjuvant radiation therapy to reduce the risk of tumor recurrence. Chordomas are considered radioresistant tumors that require total fractionated radiation therapy doses in excess of 60 Gy to reduce recurrence rates. Fractionated stereotactic radiation therapy using high-energy photons or fractionated charged particle radiation (most often protons) are the 2 most commonly administrated forms of radiation for chordomas. Prior reports comparing results of photon irradiation with proton beam therapy rarely take into account the more recent evolution of photon-based treatments in which energies are higher, and targeting and delivery methods have been enhanced. Regardless of the radiation modality, the maximum dose of radiation that can be safely delivered is limited by the tolerance of the surrounding critical cranial nerve, brainstem, or temporal lobe structures.
Based on the principle of Bragg peak deposition of energy that reduces exit dose, fractionated, charged-particle radiation delivered by protons or carbon ions is thought by some to deliver a more radiobiologically potent dose to the tumor. The Bragg peak effect results in a rapid energy deposition at the target volume, with a steep dose drop-off beyond the target volume treated. With proton beam radiation therapy, doses greater than 70 cobalt gray equivalent (CGE) are prescribed. CGE is an empiric measure of estimated radiation effect obtained through multiplying the conventional photon radiation dose in Gy by 1.2, a value that has been postulated but unproven to be the potential radiobiological advantage of proton Bragg peak radiation therapy. Published data indicate that experienced centers may achieve local tumor control rates of 67% to 88% at 3 years, 46% to 73% at 5 years, and 54% at 10 years. The overall survival rates are 67% to 81% at 5 years and 54% at 10 years. These results are often interpreted as superior to those reported for chordomas treated by older fractionated photon radiation therapy techniques before the era of intensity-modulated radiation therapy (IMRT). Using carbon ion therapy, Castro and colleagues treated 53 patients with doses of 60 to 80 CGE. They reported 5-year local tumor control and overall survival rates of 63% and 75%, respectively. Schulz-Ertner and colleagues reported that 96 patients with chordoma who underwent carbon ion fractionated radiation therapy showed 5-year local tumor control and overall survival rates of 70% and 88.5%, respectively. Late toxicity consisted of optic nerve neuropathy Radiation Therapy Oncology Group (RTOG)/European Organisation for Research and Treatment of Cancer (EORTC) grade 3 in 4.1% of the patients. Minor temporal lobe injury (RTOG/EORTC grade 1–2) occurred in 7.2% of the patients.
Noel and colleagues reported the results of combined fractionated photon and proton radiation therapy in 90 patients with either chordomas ( n = 64) or chondrosarcomas ( n = 26) of the skull base. The tumors were treated to a median total dose of 67 CGE (range, 22–70 CGE). Photons represented two-thirds of the total delivered dose, and protons represented one-third. At a median follow-up of 34 months, local tumor control was achieved in 65 patients (72%). All 90 patients developed immediate adverse radiation effects, usually mild. However, 6% reported late grade III or IV radiation toxicities, including cranial nerve deficits and visual loss. Proton fractionated radiation therapy remains a relatively expensive strategy that is available in a limited but increasing number of facilities in the United States and abroad.
Clinical Outcomes of Stereotactic Radiosurgery
Stereotactic radiosurgery (SRS) is a surgical technique designed to achieve a greater radiobiological effect than conventional 3-dimensional conformal radiation therapy or IMRT. SRS has been used as a minimally invasive primary or adjuvant management option for chordomas ( Fig. 1 , Table 1 ). SRS using the Leksell Gamma Knife (Elekta Inc, Norcross, GA) is a surgical procedure that delivers cross-fired photon radiation generated from the decay of cobalt 60 sources in a single wheels-in-to-wheels-out procedure. Using linear accelerator technologies, such as the Accuray CyberKnife (Accuray, Sunnyvale, CA), SRS may be delivered in up to 5 treatment sessions. Delivery of such highly focused radiation in 1 to 5 sessions significantly increases the radiobiological effect of SRS compared with conventional fractionated radiation therapy. Using methods to evaluate radiobiological effects, the center of the tumor may receive a radiobiological effect 4 times of what can be safely delivered using conventional fractionated radiation or IMRT. SRS seems especially valuable for the treatment of relatively small residual or recurrent chordomas after prior surgical resection. SRS has been frequently added as a radiobiological boost to conventional fractionated radiation therapy. Krishnan and colleagues treated 25 patients with cranial base chordoma with SRS using a median tumor margin dose of 15 Gy. The 5-year treated tumor control rate was 52% at a median follow-up of 4.5 years. Hasegawa and colleagues performed SRS on 27 patients with chordoma with median tumor margin doses of 14 Gy. They noted 5-year local tumor control and overall survival rates of 42% and 80%, respectively, at a median follow-up of 59 months. In their series, only tumor volumes of less than 20 cm 3 were significantly associated with a longer progression-free survival (PFS). Liu and colleagues reported on 28 patients with residual skull base chordoma who underwent SRS with median margin dose of 12.7 Gy. The average follow-up was 28 months and the mean tumor volume was 11.4 ± 7.4 cm 3 . The 5-year overall survival and in-field tumor control rates were 75.8% and 21.4%, respectively. No serious adverse radiation effects (AREs) were reported.
| Reference | N | Radiation | Median Margin Dose (range) | Tumor Volume | % Local Control | % Survival | Median Follow-up (mo) |
|---|---|---|---|---|---|---|---|
| Krishnan et al, 2005 | 19 | SRS ± RT | 15.0 Gy (10.0–20.0 Gy) ± 50.4 Gy (45.0–54.0 Gy) | 14.4 cm 3 | 4 y: 55 | NA | 58 |
| Hasegawa et al, 2007 | 27 | SRS | 14 Gy (9–20 Gy) | 19.7 cm 3 | 5 y: 72 10 y: 72 | 5 y: 84 10 y: 67 | 59 |
| Liu et al, 2008 | 31 | SRS | 12.7 Gy (10.0–16.0 Gy) | 11.4 cm 3 | 3 y: 64 5 y: 21 | 3 y: 91 5 y: 76 | 28 |
| Kano et al, 2011 | 71 | SRS ± RT | 15 Gy (9–25 Gy) | 7.1 cm 3 | 3 y: 79 5 y: 66 | 5 y: 80 7 y: 69 | 60 |
Kano and colleagues reported that 6 participating centers of the North American Gamma Knife Consortium identified 71 patients who underwent Gamma Knife SRS for chordomas. The median patient age was 45 years (range, 7–80 years). The median SRS target volume was 7.1 cm 3 (range, 0.9–109.0 cm 3 ) and the median tumor margin dose was 15.0 Gy (range, 9–25 Gy). At a median follow-up of 5 years after SRS (range, 0.6–14.0 years), 23 patients died because of tumor progression. The 5-year actuarial overall survival after SRS for the entire group was 80%. Tumor control was higher (93%) in patients who had not undergone prior fractionated radiation therapy ( n = 50). Tumor control was reduced to 43% in patients who underwent prior fractionated radiation therapy ( n = 21). Factors associated with longer patient survival included younger age, longer interval between initial diagnosis and SRS, no prior radiation therapy, fewer than 2 cranial nerve deficits, and smaller total tumor volumes. The 5-year treated tumor control rates after SRS for the entire group was 66% (69% for the no prior fractionated radiation therapy group and 62% for the prior fractionated radiation therapy group). Significant factors associated with reduced tumor control included older age, recurrent tumors, prior fractionated radiation therapy, and larger tumor volumes. Of 57 patients with pretreatment neurologic deficits, 17 (30%) experienced neurologic improvement. Of 65 patients with clinical follow-up, 31 (48%) remained stable, but 17 (26%) eventually had deterioration in neurologic function. Deterioration was related to treated tumor progression in 8 patients, adjacent tumor progression in 3, treatment-associated AREs in 4, and both treated tumor progression and AREs in 2.
Summary
Maximal safe resection should be the primary initial treatment for chordomas. After recovery from surgery, fractionated Bragg peak proton radiation therapy at an experienced center remains an option for the additional treatment of chordomas. Careful planning and reduction of dose delivered to adjacent critical structures are critical components, whether using particle beam or modern fractionated photon radiation techniques. Long-term evaluation of neurocognitive effects are warranted because of the relatively higher dose that may be delivered via the entrance pathway within the temporal lobes. SRS after surgical resection also provides a reasonable benefit-to-risk profile for small- to medium-sized chordomas. SRS is an important option for patients with recurrent tumors that failed to respond to initial surgical resection. Current data suggest that it might well supplant radiation therapy as the next best option for residual smaller-volume tumors.
Chondrosarcoma
Chondrosarcomas are relatively slow-growing, locally invasive tumors that usually do not metastasize until very late in the natural history. Cranial chondrosarcomas originate from primitive mesenchymal cells within the cartilaginous matrix of the skull base. The imaging features and clinical presentations of patients harboring either chordomas or chondrosarcomas are similar. Chordomas have a tendency to cause brainstem compression because they arise from the clivus, whereas chondrosarcomas tend to affect the lower cranial nerves because they frequently originate from the occipitotemporal bone synchondrosis. The most common presenting symptom of chondrosarcoma is diplopia, secondary to an abducens nerve palsy. Using imaging alone to distinguish chondrosarcomas from chordomas is often difficult but important, because the prognosis is generally considered better for chondrosarcomas.
Therapeutic Options
Chondrosarcomas are rarely completely resectable, and additional management options must be considered for residual tumors. Gay and colleagues reported a 90% overall survival at 5 years for 14 patients who underwent either skull base surgery or surgery followed by radiation therapy. Crockard and colleagues reported a 93% 5-year survival rate for 17 patients who underwent surgery alone. Bloch and colleagues found a recurrence rate of 44% in patients who underwent surgical resection alone, compared with 9% in patients who had surgery followed by radiation therapy. A recent review of the literature described 560 patients with intracranial chondrosarcomas, which were associated with a 5-year mortality rate of 11.5% and a median survival of 24 months. No association was seen between the rate of recurrence and the histologic grade of the tumor. In a study of 8 patients with chondrosarcomas and 8 with chordomas of the skull base who underwent proton radiation therapy, Fuji and colleagues reported a local control rate at 3 years of 86% and a median follow-up of 42 months. Other studies using proton radiation therapy have also reported overall survival and local tumor control rates at 5 years to be greater than 90%.
Clinical Outcomes of SRS
Relatively few data exist to define the use of SRS in the multimodal management of chondrosarcoma ( Fig. 2 , Table 2 ). SRS has been shown to result in less toxicity to surrounding structures and have fewer complications than fractionated radiation therapy in the management of chondrosarcomas. Koga and colleagues reported the results of 4 patients who had surgical resection followed by SRS at a median follow-up of 99 months. Three of the patients, who received margin doses of 15, 16, and 20 Gy, had no change in tumor size during follow-up. One patient who received a lower tumor margin dose of 12 Gy developed tumor recurrence 100 months after SRS. Hasegawa and colleagues studied 30 patients with chordomas and 7 patients with chondrosarcomas who underwent SRS. The 5-year PFS rate in patients with low-grade chondrosarcomas was 76%. A tumor volume of less than 20 mL significantly improved PFS. Krishnan and colleagues reported that 4 patients with chondrosarcomas who underwent SRS had tumor control at 5 years.
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