Keywords
head and neck tumors - chordoma - outcomes - proton therapy - particle therapy
Introduction
Chordoma is a rare aggressive tumor that arises from the remnants of the notochord,
which is the precursor to the nucleus pulposus or intervertebral disc.[1] According to Surveillance Epidemiology and End Results data, the annual incidence
is ∼0.08 for 100,000 people.[2] Chordomas, although rarely metastatic, typically occur in a location adjacent to
critical structures. The anatomical distribution of chordomas has been found to be
32.8% spinal, 32% cranial, and 29.2% sacral.[3]
[4] Local progression of a base of skull chordoma can lead to severe neurologic deficits
or death. The average time to death in an untreated skull base chordoma is between
6 and 24 months.[5] Symptoms can be insidious, leading to a delay in diagnosis; Volpe et al showed that
the median time from identification of symptoms to diagnosis was 14.6 months.[6]
The mainstay of treatment for a skull base chordoma is maximal tumor debulking. A
gross total resection, however, is difficult to achieve, often leaving residual tumor.
Local recurrence with surgery alone has been found to be at least 58% and is associated
with a significant postsurgical toxicity and mortality.[7] Adjuvant radiotherapy (RT) is critical to achieve tumor control.
Adjuvant photon RT has been used extensively in the past. Historically, conventional
opposed photon fields treating to a median dose of 60 Gy yielded local control rates
from 23 to 39% and survival rates from 35 to 51% at 5 years.[8]
[9] Debus et al used more conformal photon techniques and achieved a higher median dose
to 66.6 Gy, resulting in a 5-year local control rate of 50%.[10] While suggesting a dose–response relationship, it appears that photon RT is limited
by its conformality to achieve the necessary dose. Stereotactic radiosurgery (SRS)
for skull base chordomas has shown improved or comparable local control for small
tumors or recurrent disease. A study from Japan reported on 30 patients with skull
base chordomas with a mean volume of 19.7 cm3 treated to a mean margin dose of 14 Gy. The 5-year overall local control rate of
76% correlated only with a tumor volume of greater or less than 20 cm3 on univariate and multivariate analyses.[11] Martin et al treated 18 chordoma patients with SRS to a mean marginal dose of 16.5 Gy
and achieved a 5-year local control rate of 53%.[12]
Proton RT has an advantage over photon-based RT by using the Bragg peak to deliver
a high conformal tumor dose to a target volume with very steep dose falloff, thus
minimizing irradiation to adjacent critical structures. Physicians at the Massachusetts
General Hospital (Boston, MA) have the most extensive experience using proton therapy
for skull base chordomas.[13] Their 5- and 10-year local control rates were 73% and 54%, respectively, using a
tumor dose ranging from 66 to 83 CGE. We report our experience at the University of
Florida Proton Therapy Institute (UFPTI) treating base of skull chordomas with protons.
Methods and Materials
A total of 33 patients with histologically confirmed skull base chordoma were enrolled
from 2007 through 2011 in a prospective study approved by the institutional review
board. Inclusion criteria were a primary site arising from the base of skull (sphenoid,
clivus, petrous, or basiocciput), age 18 years or older at the time of consent, Karnofsky
performance status ≥ 50, neurologic function allowing the patient to cooperate with
treatment, and surgery ranging from biopsy to gross total resection before RT. [Table 1] lists the patient and tumor characteristics for our study population.
Table 1
Tumor and treatment characteristics
|
Characteristic
|
Number (%) of patients
|
|
Presenting cranial nerve deficit
|
|
VI
|
11 (33)
|
|
XII
|
4 (12)
|
|
Brainstem involvement
|
|
Yes
|
11 (33)
|
|
No
|
22 (67)
|
|
Optic pathway involvement
|
|
Yes
|
3 (9)
|
|
No
|
30 (91)
|
|
Resection
|
|
GTR
|
9 (27)
|
|
STR
|
22 (67)
|
|
Biopsy Only
|
2 (6)
|
Abbreviations: GTR, gross total resection; STR, subtotal resection.
Exclusion criteria included the following: prior RT to the head and neck, evidence
of metastatic disease, serious medical or psychiatric illness that would preclude
treatment compliance or informed consent, and pregnant or breastfeeding women. Only
27% of our patients had a gross total resection of the tumor.
For the simulation and treatment setup, each patient's head was supported on a carbon
fiber Base of Skull (BoS) frame (Qfix, Avondale, PA) and immobilized with a customized
thermal mask. The BoS frame is fabricated to ensure uniform attenuation of the proton
beam over its entire surface area. The design also allows maximum flexibility in field
arrangements in conjunction with a robotic couch and a 360-degree proton gantry. Patient
setup was conducted with care to ensure shoulder clearance and minimize the air gaps
(and the lateral penumbra) of the treatment fields. Computed tomography (CT) images
with and without intravenous contrast were acquired at 1-mm spacing from the vertex
to the base of skull. The CT image sets were registered with magnetic resonance imaging
(MRI) data sets to guide the delineation of the target volumes and critical structures.
[Fig. 1] shows a patient with a clivus chordoma treated with proton therapy. The prescriptions
were 50.4 CGE to the initial planning target volume (PTV 50.4) and 73.8 CGE to the
boost volume (PTV 73.8). Because of the tendency of the target volume to wrap around
the brainstem, and the target's close proximity to the visual apparatus, a patch-field
technique unique to proton treatment is often used as part of the field arrangement.
In the example shown, the initial target volume, PTV 50.4, was treated with five fields
including a pair of patch fields. In the first pair, the left anterior oblique through
field (LAO-T) was intentionally blocked to avoid the brainstem, missing the posterior
aspect of the target as a result. The residual target was treated, or “patched,” with
a left posterior oblique patch field (LPO-P), which was feasible because of the finite
range characteristics of the proton beam. The 50% dose level of the distal falloff
of the LPO-P was adjusted to match the 50% dose corresponding to the field edge of
the LAO-T beam. Ideally, the dose gradient of the distal falloff should closely match
that of the lateral penumbra to achieve a homogeneous dose at the junction and within
the target volume. In reality, there could be hot and cold spots near the junction.
The second pair, composed of the right anterior oblique (RAO-T) through beam and the
right posterior oblique patch (RPO-P) beam, somewhat mirrored the first so as to minimize
the uncertainties and the impact of the hot and cold spots that could arise at the
junctions. Note that both the RAO and LAO fields were selected so that the chiasm
and optic nerves could be blocked. To further improve the target coverage, a superior
anterior oblique (SAO) field was added with an angle that allowed the brainstem to
be shielded ([Fig. 1B]). The boost volume was treated with a similar field arrangement.
Fig. 1 A patient with a clivus chordoma. Five treatment fields were used for the planning
target volume (PTV) 50.4 CGE (delivered dose: 54 CGE). (A) Axial view showing the
two pairs of patch fields: First pair is left anterior oblique–through (LAO-T) and
left posterior oblique–patch (LPO-P); second pair is right anterior oblique–through
(RAO-T) and right posterior oblique–patch (RPO-P). The through beams (LAO-T and RAO-T)
are laterally blocked to avoid the brainstem. The residual target volumes are covered
by the patch fields (LPO-P and RPO-P) coming from the posterior. (B) Sagittal view
showing the 5th superior anterior oblique (SAO) beam. This beam angle allows the brainstem
to be blocked while essentially covering the whole target. Also shown is the boost
target volume, PTV 73.8 CGE.
[Fig. 2] shows the isodose in color wash and the dose-volume histogram of the composite plan.
The dose plan was designed with high priority to limit the dose to the critical structures.
The 0.1 cm3 doses to the brainstem, spinal cord, chiasm, and optic nerves as well as the expanded
volume (5 mm for spinal cord and 3 mm for brainstem, chiasm, and optic nerves) are
tabulated in [Table 2]. The dose levels achieved were well under the established dose tolerances for these
structures. Despite our conservative approach, adequate doses for the target volumes
were also achieved. Nearly 100% of the initial target volume received the treatment
dose of 50.4 CGE; 90% of the boost volume received the treatment dose of 73.8 CGE.
To minimize the risk of necrosis, the hot spot within the target (2% volume) was limited
to 114% of the prescription dose. Daily treatments were delivered with a digital online
image guidance system, and a setup accuracy >2 mm was achieved.
Table 2
Dose constraint results
|
Constraint
|
Number (%) of patients who met the goal
|
|
PTV D95 = 100%
|
29 (88)
|
|
Brainstem (center) 0.1 cm3 <55 CGE
|
29 (88)
|
|
Cord 0.1 cm3 <50 CGE
|
33 (100)
|
|
Chiasm 0.1 cm3 <55 CGE
|
31 (94)
|
|
Right optic nerve 0.1 cm3 <55 CGE
|
32 (97)
|
|
Left optic nerve 0.1 cm3 <55 CGE
|
33 (100)
|
Abbreviation: PTV, planning target volume.
Fig. 2 (A–C). Isodose shown in color wash for the composite plan. The prescription dose
to the planning target volume (PTV) was 50.4 CGE for the initial target volume and
73.8 CGE for the boost volume. (D) Dose-volume histogram distribution for the composite
plan. Note: BS + 3 = brainstem plus 3-mm expansion.
Patients received a median PTV dose of 74 CGE (range: 70–79 CGE). Patients were followed
for a median of 21 months (range: 3–58 months). Skull base MRs were obtained every
6 months.
Toxicities were scored using a modified Radiation Therapy Oncology Group/European
Organization for the Research and Treatment of Cancer Late Radiation Morbidity Scoring
Scheme.
All statistical computations were accomplished with SAS and JMP software (SAS Institute,
Cary, NC). The Kaplan-Meier product limit provided estimates of local control and
overall survival.[14]
Results
With regard to surgical toxicities, 10 patients experienced a cerebrospinal fluid
leak, 4 patients had postoperative meningitis, and 4 patients experienced a new cranial
nerve deficit after resection.
The local control and overall survival rates at 2 years were 86% and 92%, respectively
([Fig. 3]). One patient progressed through treatment and was put on salvage immunomodulator
therapy. Three patients (9%) had an in-field recurrence after treatment. No patient
experienced a marginal recurrence or distant metastases. One patient died from disease
progression.
Fig. 3 Kaplan-Meier curves for overall survival and freedom from recurrence rates at 2 years.
The only radiation-related grade 2 or higher toxicity was unilateral hearing loss
partially corrected by a hearing aid, which was observed in 18% of our patients. Endocrine
toxicity data were largely unavailable to us because many of our patients were located
in different states or internationally. There were no grade 2 or higher brainstem
or visual toxicities.
Discussion
Skull base chordomas are locally aggressive and infiltrative tumors surrounded by
critical structures and often cause debilitation or death.[15] Surgery is the primary treatment, but the high likelihood of residual tumor requires
optimal adjuvant RT. Our outcomes when treating this disease with adjuvant proton
therapy are similar to those reported by investigations at other proton therapy institutions.
Maximal debulking is critical to control of a skull base chordoma, but, as seen in
our experience, gross total resection is difficult to achieve.[16] At the University of Arkansas, gross total resection was achieved in 10 of 25 patients
(40%).[17] Gay at el reported a 47% rate of near-total resection among 60 patients with skull
base chordomas and chondrosarcomas.[18] Although most of our patients underwent multiple operations, our gross total resection
rate was 27%. Thus adjuvant proton therapy was predominantly delivered in the setting
of gross residual disease. Furthermore, 30% of our patients experienced a cerebrospinal
fluid leak, and 12% had postoperative meningitis following surgery. These surgical
toxicities are similar to other reported series.[17]
[18]
As with other studies,[13]
[19]
[20] our volume definition was based on preoperative and postoperative MRI and CT images.
Our normal-tissue constraints were also similar, as shown in [Table 2]. We saw only in-field recurrences and achieved a local control rate of 86% at 2
years, which makes our findings comparable with the published data. Hug et al reported
a series of 33 patients with chordoma treated at Loma Linda University to a median
dose of 70.7 CGE with a 5-year local control of 59%.[19] A series from Massachusetts General Hospital in which 621 patients were treated
with a mixture of photons and protons to between 66 and 83 CGE showed 5- and 10-year
local control rates of 73% and 54%, respectively.[13] Ares et al reported on their experience using the spot-scanning technique of proton
delivery to treat 42 patients with skull base chordomas and observed a 5-year local
control rate of 81% with this highly conformal technique.[20]
Because the main site of recurrence is local and the salvage of local recurrences
is unlikely, particularly in previously resected patients, survival is directly correlated
with local control. Other institutions have reported 5-year survival rates of 59%,
73%, and 81%.[13]
[19]
[20]
At 2 years, our patients have not experienced any brainstem or optic toxicities, and
other series have shown low toxicity rates as well. Debus et al reported a 5.5% rate
of brainstem symptoms in 19 of 348 evaluable patients. The median time to symptoms
was 17 months. On multivariate analysis, there was a statistically significant increase
in the rate of brainstem symptoms when the volume of brainstem receiving 60 CGE was
>0.9 cm3.[21]
[22] Of our patients, 88% of patients received <55 CGE to 0.1 cm3 of the brainstem. Pai et al reported on endocrine toxicity for 107 patients with
skull base chordomas and chondrosarcomas. The 5- and 10-year rates for hyperprolactinemia
were 72% and 84% and for hypothyroidism were 30% and 63%.[3] These endocrinopathies were observed when the minimum dose to the pituitary exceeded
50 CGE Dmin >50. At present, we do not have the endocrine laboratory results for our patients.
Conclusions
Our experience treating patients with skull base chordomas with proton therapy is
promising in terms of control of this locally aggressive tumor. In view of the high
dose delivered and the proximity of adjacent critical structures, the toxicity profile
is acceptable. With longer follow-up, we expect our 5-and 10-year local control and
survival rates to approach those reported by other investigators.
