Chordoma: The Quest for Better Treatment Options

Oncology and Therapy, Mar 2016

Chordoma is an extremely rare cancer, with an incidence of about one case per million persons per year in the USA and Europe (about 300 and 450 cases per year, respectively). The estimated median overall survival of patients with chordoma is approximately 6–7 years, yielding a rough estimate of chordoma prevalence at about 2000 in the USA and 3000 in Europe. Primary tumor develops along the axial spine between the clivus and sacrum and develops from the residual embryonic notochord. Brachyury (T), a transcription factor required for normal embryonic development, is expressed in the notochord and overexpressed in almost all cases of chordoma. The primary treatment for chordoma is surgical excision with wide local margins, when possible. Radiotherapy also plays a significant role in the adjuvant setting and when surgery is not possible. Unfortunately, in the advanced and/or metastatic setting, where the role of surgery and/or radiation is less clear, treatment options are very limited. To date, there have been no randomized, controlled trials in chordoma that have resulted in defined agents of clinical benefit for systemic treatment. This review briefly describes the natural history and initial treatment of chordoma and focuses on treatment options for advanced disease and potential avenues of research that may lead to improved treatment options in the future.

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Chordoma: The Quest for Better Treatment Options

Oncol Ther Chordoma: The Quest for Better Treatment Options Christopher R. Heery 0 0 C. R. Heery (&) Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD 20892 , USA Chordoma is an extremely rare cancer, with an incidence of about one case per million persons per year in the USA and Europe (about 300 and 450 cases per year, respectively). The estimated median overall survival of patients with chordoma is approximately 6-7 years, yielding a rough estimate of chordoma prevalence at about 2000 in the USA and 3000 in Europe. Primary tumor develops along the axial spine between the clivus and sacrum and develops from the residual embryonic notochord. Brachyury (T), a transcription factor required for normal embryonic development, is expressed in the notochord and overexpressed in almost all cases of chordoma. The primary treatment for chordoma is surgical excision with wide local margins, when possible. Radiotherapy also plays a significant role in the adjuvant setting and when surgery is not possible. Unfortunately, in the advanced and/or metastatic setting, where the role of surgery and/or radiation is less clear, treatment options are very limited. To date, there have been no randomized, controlled trials in chordoma that have resulted in defined agents of clinical benefit for systemic treatment. This review briefly describes the natural history and initial treatment of chordoma and focuses on treatment options for advanced disease and potential avenues of research that may lead to improved treatment options in the future. Brachyury; Chordoma; Erlotinib; Imatinib; Immunotherapy; Radiotherapy; Spine tumor; Surgery; Vaccine INTRODUCTION Chordoma is an extremely rare cancer, with an incidence of about one case per million persons per year in the USA (about 300 cases per year) [ 1 ]. Chordoma has been called ‘‘bone cancer’’ [ 2 ], but this designation is debatable based on histologic features, which are more consistent with its presumed tumor of origin, namely, the residual embryonic notochord tissue [ 3, 4 ]. Designating chordoma as a ‘‘bone tumor’’ appears to be a holdover from the initial description of the disease by Virchow [5], but it was called into question soon thereafter by Ribbert [ 6 ], who coined the name ‘‘chordoma’’ based on its similarity to notochord tissue [ 7 ]. The relationship of chordoma to the notochord was strengthened by the finding that brachyury, a transcription factor found in notochord tissue and essential for embryonic development, is overexpressed in chordoma [ 3, 8 ]. Regardless of its historical designation, chordoma has unique histologic, radiographic, and clinical characteristics that call for chordoma-specific research to improve outcomes for patients with the disease. In this review, I briefly review the previously published natural history of the disease, including tumor characteristics, standard treatment paradigms, clinical management issues, and results of systemic treatment trials to date, to provide context for potential therapeutic targets and possible future treatment options. EPIDEMIOLOGY, PRESENTATION, AND DIAGNOSIS Chordoma is most commonly diagnosed between ages 50 and 60, and it is more common in men than women, and rare in children [ 1 ]. Primary tumors develop along the axial spine, with approximately one-third of cases presenting in the clivus, mobile spine, and sacrum, respectively [ 1 ]. Disease presentation depends on tumor location and is related to the structures near which the tumor is growing. For example, patients with clival chordomas may present with headache, diplopia, or impairment of other cranial nerves, while those with sacral chordomas may present with low back or buttocks pain, neuropathy, and/or gait disturbance [ 7 ]. Patients may be diagnosed with large tumor masses in the sacrum due to the slow-growing nature of the disease, non-specific symptom profile, and a relatively large space for tumors to occupy before causing significant focal symptoms. Imaging findings that would point to chordoma include a mass along the axial spine, likely invading surrounding bone, which has a similar intensity to surrounding tissue on T1-weighted images, but appears hyperintense on T2-weighted images [ 9, 10 ]. Unfortunately, due to the slow-growing nature of chordoma, which results in insidious, non-specific symptoms, diagnosis may be delayed for months or years. The median overall survival (OS) from time of diagnosis has been estimated at around 6 to 7 years [1], but the range of outcomes is very wide and may be related to prognostic markers, including treatment options at the time of diagnosis [ 11–13 ], as detailed below. After surgical resection or initial biopsy, the diagnosis of chordoma is confirmed based on the classical (conventional) appearance of ‘‘sheets and cords of round to polygonal’’ tumor cells filled with occasionally la (...truncated)


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Christopher R. Heery. Chordoma: The Quest for Better Treatment Options, Oncology and Therapy, 2016, pp. 35-51, Volume 4, Issue 1, DOI: 10.1007/s40487-016-0016-0