Chordomas and Chondrosarcomas of the Axial Skeleton: Emerging Therapies and Future Directions

Abstract

Chordoma and chondrosarcoma are related malignant bone tumors with some unusual features, such as their ability to dedifferentiate into high-grade sarcoma and abundance of extracellular matrix. Surgery remains the mainstay of treatment of both, and new techniques may improve the extent of resection and thus local control. Intraoperative adjuvants such as cryotherapy may decrease the local recurrence. Staged approaches and aortic balloon pump, both of which can reduce blood loss, may improve outcomes. However, despite improved local control, metastasis can occur in up to 30% of cases. Although both tumors are relatively radioresistant, improved tumor control and safety in high-dose radiation may result from novel techniques such as heavy particle irradiation. And the newly discovered abscopal effect of radiation on immune response may be more important than its direct effects. There are currently no effective drugs for most chordomas (except poorly differentiated) and chondrosarcomas (except mesenchymal), but potentially useful new targets have been identified. These include the molecular pathways of cell cycle regulation and activated receptor tyrosine kinase cascade. Discovery of epigenetic events and antigens unique to these tumors may suggest additional targets for chemotherapeutic and immunotherapeutic suppression of metastatic spread. DNA methylation of tumor-suppressor genes affects notochord cell differentiation and malignant transformation of cells. New immunotherapy targets are enticing, but preparation and testing of chimeric antibodies against them is time-consuming. Metabolic pathways, such as that containing isocitrate dehydrogenase, may offer additional targets for single agents or combination therapies. The molecular analysis required to develop this list of innovative therapies should also identify novel biomarkers useful in diagnosis and prognosis. Cooperation within a multidisciplinary team will continue to be essential to improved patient outcomes.

Keywords

Chemotherapy, Chondrosarcoma, Chordoma, Dedifferentiation, Extracellular matrix, Molecular pathways, Radiation, Review, Surgery

Outline
Introduction: Barriers to Traditional Therapies 411
Surgical Methods: Improvement in Techniques 413
Advances in Radiation Therapy: Radiation Therapy Emerging as a Useful Adjuvant 413
Systemic Therapy: Innovative Approaches to Metastatic and Locally Recurrent Disease 414
- Chordoma: Potential Future Strategies 415
- Chondrosarcoma: Potential Future Strategies 416
References 416
Further Reading 418

Introduction: Barriers to Traditional Therapies

Chordoma and chondrosarcoma are closely related malignant tumors; in fact, a subtype of chordoma, chondroid chordoma, contains cartilage ( Fig. 39.1 ). The etiology of malignant cartilage tumors has been more thoroughly investigated than that of chordoma. In some hereditary tumor conditions of cartilage, such as hereditary multiple osteocartilaginous exostosis (HMOCE), genetic modifications have been identified in the EXT genes. Although some patients with HMOCE also have a chordoma ( Fig. 39.2 ), the benign exostotic tumor or osteochondroma in HMOCE is more likely to undergo malignant transformation to chondrosarcoma. In HMOCE and other conditions, enostotic cartilage tumors (inside bone) become malignant more frequently than do exostotic tumors (on the bone surface). Tumors in patients with either Ollier’s or Maffucci’s syndrome have a much higher rate of malignant transformation than those in HMOCE; the rate is highest in Mafucci’s syndrome. Maffucci’s syndrome includes vascular tumors of soft tissues as well as multiple enostotic cartilage tumors, but Ollier’s syndrome does not.

Chordomas are thought to arise from benign notochordal cell tumors (BNCTs), identified in about 20% of cadavers at autopsy. These benign tumors of notochordal cell rests can transform into a chordoma just as an enchondroma can transform into a chondrosarcoma. In some cases, there is no histologic separation between the chordoma tissue and notochordal cell rests ( Fig. 39.3 ). The precise mechanisms of these transformations from benign to malignant are unknown.

Almost all chordomas stain for T-brachyury. Comparative genomic hybridization (CGH) has identified unique duplications of chromosome 6q27, which contains the T-brachyury gene, in four families with chordomas. T-brachyury is a transcription factor that promotes cell movement and adhesion, which are fundamental to both morphogenesis and tumorigenesis. In sporadic cases of chordoma, although this duplication of T-brachyury has not been found, the T-brachyury transcript is highly expressed, and it is an excellent marker for the disease. T-brachyury has been detected in both the chondroid and chordoid components of chordomas, suggesting that both arise from the notochord. Thus T-brachyury links the notochord to cartilage as well as to chordoma.

T-brachyury has become a target for immunotherapy, but, thus far, clinical trials have met with little success. However, preclinical studies showing that a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury activated human T-cells in vitro is both safe and immunogenic have prompted a randomized phase-II clinical trial.

In general chordomas and chondrosarcoma may share mechanisms of origin. These include derivation from cancer stem cells. Both tumors can dedifferentiate into a variant containing a high-grade sarcomatous component.

Chordoma and chondrosarcoma both have abundant extracellular matrix (ECM) with overexpression of numerous genes, including aggrecan, type-II and X collagen, fibronectin, matrillin 3, CSPG4, matrix metalloproteinase MMP-9, and MMP-19. As this extracellular matrix provides a barrier to delivery of oxygen and chemotherapeutics, breaking down these matrix proteins may improve tumor responsiveness to radiation, by improving tumor cell oxygenation, and to chemotherapy, by increasing drug penetration to tumor cells; matrix proteins may also serve as targets for immunotherapy. Conjugation of melphalan (Mel) to quaternary ammonium (QA), which targets the complex to proteoglycan (PG)-rich tissues, may improve its therapeutic index.

Surgical Methods: Improvement in Techniques

Surgery remains the mainstay of treatment for both chordoma and chondrosarcoma. New techniques may improve extent of resection and thus local control. Intraoperative adjuvants such as cryotherapy may decrease local recurrence. Staged approaches and aortic balloon pump, both of which can reduce blood loss, may improve outcomes. Guidelines for their management are located in the NCCN Guidelines Version 2.2017 Bone Cancer chapter. Although staged resections have become more common—data from the Mayo Clinic have demonstrated improved outcomes, better resource management, and decreased hospital costs with staged approaches for chordoma —there is renewed enthusiasm for posterior-only approaches to spine tumors, aided by intraoperative navigation with real-time imaging ( Fig. 39.4 ). Control of the iliac vessels and their branches is better with a two-stage approach than with a posterior-only approach, but the greater blood loss of posterior-only approaches may be diminished by an aortic balloon pump. Increased use of vascularized flaps of rectus abdominus, gluteus maximus, or hamstring muscle to repair soft-tissue defects created by exposure and resection of spine chordoma has improved postoperative outcomes.

Minimally invasive surgical techniques, including heat ablation and cryotherapy are being tested for benign and malignant bone tumors. Heat ablation has limited applicability to chordomas and condrosarcomas because their gelatinous, myxoid matrix excessively absorbs heat. Cryotherapy, however, has more potential. It can be applied to solid tumor thorough a probe, either before or instead of surgery, or by incubating the tumor’s resection cavity in liquid nitrogen. Use of this approach should consider the affected site, local tumor extension, feasibility of surgery, and clinicopathologic tumor grade. Critically evaluating patients’ quality of life (QOL) after all treatments is extremely important and is becoming routine.

Advances in Radiation Therapy: Radiation Therapy Emerging as a Useful Adjuvant

Radiation therapy of chordoma and chondrosarcoma remains controversial. Recent studies have supported the efficacy of high-dose radiation therapy for chordomas, particularly those of the skull base, but some have argued that skull base tumors are inherently different than those of the mobile spine and sacrum. Radiation therapy has advanced significantly over the last few decades. The ability of the cyclotron to produce protons and heavy particle such as carbon ions has permitted high-dose radiation to tolerances of a fraction of a millimeter. In children, especially, decreasing the doses of radiation to normal structures permitted dose escalation to the tumor. Most patients with conventional radiotherapy after surgery die with local disease progression. The superior local tumor control and overall survival achieved with fractionated proton radiation therapy can be attributed to the improved dose localization characteristics of protons, resulting in higher doses delivered.

Proton therapy, until recently, possible only at a few places in the United States, is now available in multiple geographic regions. Heavy ion radiation, such as protons and carbon ions, can spare surrounding normal neurological and visceral tissues while delivering high-dose radiation to target tumor tissue, but we do not know all the long-term effects with these treatments, but these do include radiation-induced sarcoma (RIS), to which children are particularly vulnerable. Radiation weakens the bone, and pathologic fractures through the weakened remaining sacrum are a major complication. In combination with surgery, radiation has significantly improved short- and long-term results in terms of local recurrence. At our institution, radiation has been used alone in certain circumstances, such as patients who wish to avoid the morbidity of surgery or who have significant comorbidities. Carbon ion therapy seems better in the short-term for chordoma than for chondrosarcoma, but not as good in the long-term, as rates of local failure approach 50% after 10 years.

Radiation became very helpful at the skull base since en bloc resection is routinely not feasible or compatible with life. Stereotactic radiosurgery is also used for skull base chordoma and chondrosarcoma at some institutions, including the University of Pittsburgh, which reported good local tumor control in 15 chordomas and chondrosarcomas after cobalt-60 gamma knife therapy. Proton RT and radiosurgery may differ significantly in target definition. At most proton centers, a clinical volume that includes the operative site and other areas of microscopic risk peripheral to identifiable solid tumor is added to the gross tumor volume, whereas many radiosurgery centers target only the gross tumor volume. Treating only the GTV may be more effective and less morbid for the short-term but less conducive to long-term local tumor control or prevention of metastasis, particularly in the spine.

Intraoperative radiation is another option, particularly for treating residual microscopic chordoma and chondrosarcoma in spinal dura. This avoids introducing tumor cells into the cerebral spinal fluid posed by surgical resection of tumor-involved dura. We have safely delivered 8–12 Gy over 10 min to microscopically invaded dura ( Fig. 39.5 ).

Additional benefits of radiation therapy are its abscopal effects. By increasing the exposure of tumor antigens irradiation may enhance immunotherapy not just locally, but also systemically. Similar synergism may occur with combinations of radiation with chemotherapeutic or immunomodulatory agents such as check-point inhibitors.

Systemic Therapy: Innovative Approaches to Metastatic and Locally Recurrent Disease

The ability to manage the metastatic lesions is a significant challenge for all cancers. About one-third of patients with chordoma or intermediate to high-grade chondrosarcoma succumb to metastases. Axial tumors access venous channels, including the valveless Batson’s plexus, in spreading to the lung. Pulmonary metastases are generally indistinguishable histologically from the primary tumor in conventional chordomas or in chondrosarcomas that are not dedifferentiated. Patients with metastatic disease are candidates for experimental chemotherapeutic or immunotherapeutic research protocols or a palliative approach.

Chordoma and chondrosarcoma of the skull base and spine can also spread to other osseous sites and liver. In one study of 210 chordoma patients, 39 (17.8%) developed metastatic disease, most frequently to lung (>50%). Median duration of survival from the time of initial diagnosis was 130.4 months for patients who developed metastatic disease and 159 months for those who did not. Metastatic disease was most common in the youngest patients and 2.5 times more frequent among patients with local recurrence (26.3%) than in those without (10.8%). Metastasis to distal bone appeared early and had the worst prognosis. Screening for metastatic and multicentric disease by MRI in chordoma and by bone scan in chondrosarcoma is indicated ( Fig. 39.6 ).