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)