Carbon Ion Radiotherapy for Skull Base and Paracervical Chordomas
Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 23, 2008
Presenter: Azusa Hasegawa Presenter's Affiliation: Research Center for Charged Particle Therapy Type of Session: Scientific
Chordomas are rare, slow growing, locally aggressive neoplasms of bone that arise from embryonic remnants of the notochord.
They typically occur in the axial skeleton and arise most commonly in the skull base and sacral regions.
50% of adult chordomas involve the sacrococcygeal region
35% occur at the base of the skull
15% are found in the vertebral column
Craniocervical chordomas most often involve the dorsum sella, clivus, and nasopharynx. Treatment of tumors in locations such as these is particularly difficult because of the proximity of other, vital, structures such as the brainstem, spinal cord, optic chiasm, and optic nerves.
Complete or near-complete surgical resection is often impossible because of intimate involvement of tumor tissue with vital structures.
Achievement of adequate radiotherapy doses is also often limited by the tolerance of these normal structures.
Treatment of skull base and spinal cord/ paraspinal chordomas with an approach using a combination of photon and proton-based radiotherapy has been utilized at Massachusetts General Hospital (MGH) since 1973 (Hug, 1995).
Dose characteristics of proton beam radiotherapy, including finite range and steep dose fall of beyond the Bragg peak, may allow safer tumor dosing while promoting sparing of normal structures.
Carbon ion radiotherapy has many of the same dose sculpting benefits as proton beam radiotherapy; however, carbon ion radiotherapy may potentially be delivered with increased precision when compared to proton beam. Additionally, carbon ions have approximately three times the radiobiologic effectiveness (RBE) of protons.
For these reasons, carbon ion radiotherapy is of particular interest as it may allow even further dose escalation and precision in treatment of skull base tumors.
This study describes the results of phase I/II and phase II trials that were carried out in order to evaluate dose escalation safely, tolerability, local control, and overall survival rates for carbon ion radiotherapy in treatment of skull base and paracervical tumors, specifically chordomas.
Materials and Methods
Between April, 1997 and August, 2007, the authors carried out two trials evaluating the use of carbon ion radiotherapy in treatment of skull base and paracervical tumors.
From 1997 to 2004, patients were enrolled on a phase I/II dose escalation study evaluating carbon ion dose delivered in 16 fractions over four weeks. This trial was performed to the fourth planned dose level [48 Gray equivalents (GyE), 52.8 GyE, 57.6 GyE, and 60.8 GyE].
Beginning in April, 2004, a phase II trial was initiated, enrolling patients on a treatment scheme involving delivery of 60.8GyE delivered in 16 fractions over four weeks.
Carbon ion radiotherapy planning was carried out using planning CT fused with T1-weighted MRI for improved tumor visualization.
GTV was delineated based on MRI findings.
CTV was defined as GTV + 3 -5 mm, and included suspected subclinical lesions.
CTV margins were reduced in areas of overlap with spinal cord, brainstem, and optic chiasm/ nerves.
Plans were accepted when the CTV was planned to receive 96-97% of the prescribed dose.
Dose constraints to organs at risk were as follows:
Brainstem/ spinal cord surface: 60 GyE
Brainstem/ spinal cord center: 50 GyE
Optic chiasm/ contralateral optic nerve: 55 GyE
Optic chiasm/ nerve constraints were based on prior findings by the authors that vision loss was increased with maximum dose exceeding 55 Gy.
Patients from both of these trials are analyzed here.
Inclusion criteria included age > 15 years, histologic tumor diagnosis, Karnofsky performance status of at least 60%, and absence of prior radiotherapy and chemotherapy. A four week period between carbon ion radiotherapy and any planned chemotherapy was also required.
46 total patients were enrolled on the two trials, combined; 29 of these had diagnosis of chordoma, 6 meningioma, 7 chondrosarcoma, 3 olfactory neuroblastoma, and 1 giant cell sarcoma. Outcomes for the 29 chordoma patients are analyzed here.
Of chordoma patients, 11 had tumors located in the skull base, 11 in the clivus region, and 7 in or near the cervical spine.
Of 29 patients with histologically diagnosed skull base and paracervical chordomas, 12 were male and 17 female.
Ages ranged from 16 – 76 years, with a median age of 47 years.
Median follow up was 44 months (range 8 – 112 months).
Patients were retrospectively analyzed in two groups, a low-dose group (n = 10, having received dose from 48 – 57.8 GyE), and a high-dose group (n = 19, having received dose of 60.8 GyE).
Local control rates at 5 years are 60% and 91% for the low- and high-dose groups, respectively.
One patient within the high-dose group developed a marginal failure 29 months after having completed treatment.
Overall survival rates at 5 years are 90% and 95% for the low- and high-dose groups, respectively.
Toxicity in both groups involved skin and mucosa most commonly, with no long-term skin/ mucosal toxicity reported.
One late grade 2 brain toxicity (asymptomatic brain parenchymal change) was detected in a patient in the high-dose group; no other long-term nervous system toxicity was observed.
No visual loss was observed.
One patient in the high-dose group died of hepatic toxicity, the etiology of which was not discussed.
The authors conclude that carbon ion radiotherapy will provide improved local control rates in definitive treatment of skull base and paracervical chordomas when compared with proton and/ or photon-based radiotherapy.
They note that this treatment has been associated with low toxicity to surrounding normal tissues in the patient population treated at their institution.
The authors present promising data from a relatively small cohort of patients with skull base/ paracervical chordomas, demonstrating excellent local control and overall survival rates following carbon ion radiotherapy.
A much larger cohort of patients (n = 290) treated with combined photon/ proton radiotherapy at MGH has been analyzed; local control was substantially lower (64%) (Munzenrider, 1999). Median follow-up was 41 months, but extended to almost 22 years. Severe toxicity was reported in 8% of patients, including asymptomatic brain changes, unilateral/ bilateral blindness, and unilateral deafness. Doses ranged from 60 – 68 GyE. Given that these patients were treated some time ago (beginning in 1975) changes in technology with regards to treatment planning must be considered.
Other publications have from the Centre de Protontherapie d’Orsay, Orsay, France, demonstrated 71% 3-year local control and 75% 3-year overall survival in a cohort of 67 patients with skull-base chordomas treated with proton beam irradiation to a dose of 67 GyE (Noel, 2003).
Certainly, the data presented here appear interesting and promising, with potentially improved results than other, historical, data with use of proton/ photon irradiation; however, the small sample size and relatively short follow-up time presented preclude making statements regarding effectiveness comparedto proton therapy.
Very late recurrences, particularly in female patients, have been observed, and further local recurrences may well be observed in the patient cohort presented here (Munzenrider, 1985).
The data presented here demonstrate that delivery of adequate dose to the skull base/ paracervical regions is feasible and tolerable with carbon ions and continued study with reports including longer follow up are warranted.