Image-guided, intensity-modulated radiation therapy (IG-IMRT) for skull base chordoma and chondrosarcoma: preliminary outcomes

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1 Neuro-Oncology Neuro-Oncology 17(6), , 2015 doi: /neuonc/nou347 Advance Access date 27 December 2014 Image-guided, intensity-modulated radiation therapy (IG-IMRT) for skull base chordoma and chondrosarcoma: preliminary outcomes Arjun Sahgal, Michael W. Chan, Eshetu G. Atenafu, Laurence Masson-Cote, Gaurav Bahl, Eugene Yu, Barbara-Ann Millar, Caroline Chung, Charles Catton, Brian O Sullivan, Jonathan C. Irish, Ralph Gilbert, Gelareh Zadeh, Michael Cusimano, Fred Gentili, and Normand J. Laperriere Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada (A.S.); Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada (A.S., L.M.-C., G.B., B.-A.M., C.C., C.C., B.O., N.J.L.); Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada (M.W.C.); Department of Biostatistics, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada (E.G.A); Department of Radiology, University Health Network, University of Toronto, Toronto, Ontario, Canada (E.Y.); Department of Otolaryngology Head and Neck Surgery/Surgical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada (J.C.I., R.G.); Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada (G.Z., F.G.); Department of Neurosurgery, St Michaels Hospital, University of Toronto, Toronto, Ontario, Canada (M.C.) Corresponding Author: Arjun Sahgal, MD, Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada (arjun.sahgal@sunnybrook.ca). Background. We report our preliminary outcomes following high-dose image-guided intensity modulated radiotherapy (IG-IMRT) for skull base chordoma and chondrosarcoma. Methods. Forty-two consecutive IG-IMRT patients, with either skull base chordoma (n ¼ 24) or chondrosarcoma (n ¼ 18) treated between August 2001 and December 2012 were reviewed. The median follow-up was 36 months (range, 3 90 mo) in the chordoma cohort, and 67 months (range, ) in the chondrosarcoma cohort. Initial surgery included biopsy (7% of patients), subtotal resection (57% of patients), and gross total resection (36% of patients). The median IG-IMRT total doses in the chondrosarcoma and chordoma cohorts were 70 Gy and 76 Gy, respectively, delivered with 2 Gy/fraction. Results. For the chordoma and chondrosarcoma cohorts, the 5-year overall survival and local control rates were 85.6% and 65.3%, and 87.8% and 88.1%, respectively. In total, 10 patients progressed locally: 8 were chordoma patients and 2 chondrosarcoma patients. Both chondrosarcoma failures were in higher-grade tumors (grades 2 and 3). None of the 8 patients with grade 1 chondrosarcoma failed, with a median follow-up of 77 months (range, ). There were 8 radiation-induced late effects the most significant was a radiation-induced secondary malignancy occurring 6.7 years following IG-IMRT. Gross total resection and age were predictors of local control in the chordoma and chondrosarcoma patients, respectively. Conclusions. We report favorable survival, local control and adverse event rates following high dose IG-IMRT. Further follow-up is needed to confirm long-term efficacy. Keywords: chondrosarcoma, chordoma, image-guided intensity modulated radiotherapy, photon radiation. Skull base chondrosarcoma arises from endochondral bone in the cerebellopontine angle, paranasal sinuses, parasellar area, and clivus. Chordoma arises from ectopic notochord remnants, and approximately a third are within the skull base. 1 Although both tumors are generally indolent and considered low grade, they are locally destructive, invasive, and fatal if not properly managed. The focus of this report is on skull base chordoma and chondrosarcoma. Surgery is the first line of therapy, with the aim to maximally debulk gross tumor. 2 Optimally, a gross total resection (GTR) is performed; however, in the skull base, the location is such that critical structures are inevitably intricate to the tumor position, making an en bloc, or GTR, often not possible. In fact, residual tumor is often left intentionally as a Received 22 October 2014; accepted 21 November 2014 # The Author(s) Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please journals.permissions@oup.com. 889

2 consequence of preserving function depending on where the tumor is, and subtotal resection (STR) is often the postoperative result. Regardless of the extent of resection, local failure rates with surgery alone can be significant, and adjuvant radiation is considered a standard therapeutic option postoperatively. Within the radiation oncology department at the University of Toronto, our practice has been to offer all patients with skull base chordoma and chondrosarcoma adjuvant radiotherapy. As the therapeutic intent of radiation is to reduce the risk of local recurrence and increase survival, high doses of radiation are required, as these tumors are considered relatively radioresistant. 3,4 However, similar to surgery, the inherent proximity to several organs at risk (OAR) presents a major challenge with respect to covering the target volume with the prescribed high dose. While we often make sacrifices to respect the OAR radiation tolerance, we also frequently allow greater dose exposure than traditionally deemed acceptable. Hence, radiation is also a high-risk procedure and requires treatment in centers with experienced practitioners. The historical inability of previous linear accelerator technology to shape and modulate the radiation beam is why largely ineffective low doses of radiation (ranging from 40 to 54 Gy in Gy/d fraction sizes) were delivered, and yielded suboptimal local control (LC) rates. 5 As a result, some even questioned the role of radiation altogether, in particular for chordoma. As proton therapy became available for medical use, chordoma and chondrosarcoma were amongst the first to be considered for this technology. The advantage for protons compared with conventional radiation lies in the dose profile, which allows a predictable edge in the dose fall-off with minimal exit dose. 6 As a result, protons allow for higher doses to be deposited adjacent to the OAR, hence protons have become a standard of care. Over the last decade, photon-based linear accelerator technology has undergone a transformation. Multileaf collimators (MLCs) allow for intensity modulated radiotherapy (IMRT), while on-board image-guidance (IG) systems permit near-realtime tracking during delivery, and robotic technology has been incorporated to ensure millimeter precision in dose delivery. Ultimately, this translates into the ability to create sophisticated dose distributions with steep dose gradients that differentially dose the OAR and target, a reduction in the planning target volume margin, and excellent precision in the delivery, such that several centers have adopted IG-IMRT for skull base chordoma and chondrosarcoma, delivering equivalent doses to those typical of proton therapy We report initial outcomes using high-dose IG-IMRT. Materials and Methods A total of 42 consecutive patients with skull base chordoma or chondrosarcoma operated upon and treated with IG-IMRT between August 2001 and December 2012 were identified from the Princess Margaret Hospital tumor registry and retrospectively reviewed. Institutional research ethics board approval was obtained. All patients had their pathology reviewed at the University of Toronto. No patient received concurrent or adjuvant chemotherapy. Forty of 42 patients were treated with postoperative adjuvant radiotherapy within 6 months of surgery, and 2 of 42 were treated within 10 months of surgery. With respect to the latter 2 cases, the delay in starting radiation was to maximize postoperative healing, as our practice is to radiate typically within 6 months of the initial surgery. Thirteen patients were immobilized using a relocatable stereotactic frame, treated using stereotactic fixed field IMRT with an MLC-based system, and planned using Radionics. In these patients, cone-beam CT was not required, and the Radionics stereotactic localization approach applied. The remaining patients were immobilized using a thermoplastic mask, treated using MLC-based fixed field IMRT, and planned using Pinnacle (Philips Healthcare). Cone-beam CT was used for daily image guidance. Treatment planning consisted of thin-slice CT simulation (typically, mm) and fusion of T1 post-gadolinium and T2 axial and/or T2 fluid attenuation inversion recovery volumetric MR sequences. The gross tumor volume (GTV) was defined as all gross disease visible on imaging and the postoperative surgical bed. The clinical target volume (CTV) consisted of a 0.5-cm margin beyond the GTV and, where applicable, a more generous margin to include those anatomic areas at risk of microscopic extension (for example, if the cavernous sinus is invaded, then the relevant portion of the cavernous sinus is taken as CTV). The planning target volume (PTV) typically consisted of a 0.2- to 0.3-cm margin beyond the CTV depending on the immobilization technique. With respect to the PTV, the aim was to achieve 90% 95% coverage with the prescribed dose (our practice is to prescribe to the International Commission on Radiation Units and Measurements point). In circumstances where the PTV overlapped with dose limiting OAR, then compromises in target coverage were allowed such that coverage of the PTV by 85% 90% of the prescribed dose was permitted. Of note, our typical practice is to plan on one PTV, and not designated multiple CTVs and PTVs with different dose levels (for example, separate high-dose and low-dose volumes). A representative dose distribution for a chordoma case treated with 78 Gy in 39 fractions is shown in Fig. 1. The primary endpoints of this study were LC and overall survival (OS). LC was defined as imaging-based disease progression using the postoperative radiation treatment planning imaging as reference, and a dedicated neuroradiologist reviewed each case. Radiation-related injuries were graded according to the National Cancer Institute s Common Terminology Criteria for Adverse Events v4.0. Statistical Analysis Descriptive statistics were used to assess selected patient demographics, disease characteristics, and treatment details. Expressed as count and proportions were categorical variables such as gender, primary diagnosis, Eastern Cooperative Oncology Group performance status, clinical signs and symptoms at presentation (presence of pain, cranial nerve palsy, neurologic deficits, and hydrocephalus), location of the tumor within the skull base, and extent of surgery, whereas continuous variables such as age, maximum diameter of the tumor at presentation, total dose, dose per fraction, and follow-up were expressed as mean+sd or median and range. The outcome variable of interest was the time to local failure and OS. The time-to-event data 890

3 Fig. 1. (A) Axial T1-weighted MRI of a skull base chordoma involving the clivus and cavernous sinus that was subtotally resected. The patient received 78 Gy in 39 fractions with IG-IMRT. (B) Axial treatment planning CT slice with the dose distribution and representative isodose lines and (C) sagittal treatment planning CT slice with the dose distribution and representative isodose lines. were calculated in months from the date of radiation to the date of the event (date of local failure and death data for OS), or last follow-up if the event had not yet occurred. OS survival probabilities were calculated using the Kaplan Meier product-limit method. LC was based on the competing risk model with death as the competing risk. The log-rank test was used as a univariate analysis to compare OS probability with a potential predictor of interest, and Fine and Gray s method was used to compare LC. A multivariate Cox proportional hazards regression model was used to determine the joint effect of potential factors for OS, and Fine and Gray s model was used to determine the joint effect of factors for LC that were found to be potential on univariate analysis. All P-values were 2-sided. Results were considered significant if P,.05. Statistical analyses were performed using SAS v9.3 and the user s guide and the open source statistical software R v3.0. Results The baseline characteristics separated according to the chordoma and chondrosarcoma cohorts are summarized in Table 1. Of the 18 cases of chondrosarcoma, 8 were grade 1; 9 were grade 2; and 1 was grade 3. The median total dose was 76 Gy (range, Gy) and 70 Gy (range, Gy) for the chordoma and chondrosarcoma groups, respectively. The dose per fraction was uniformly 2.0 Gy per day. The median follow-up in the chordoma cohort was 36 months (range, 3 90), and in the chondrosarcoma cohort 67 months (range, ). The total dose exposures to the critical OAR are summarized in Table 2. In total, 10 patients exhibited local disease progression. Eight of the 10 were in the chordoma cohort (n ¼ 24) and 2/10 in the chondrosarcoma cohort (n ¼ 18) (P ¼.077). With respect to the chondrosarcoma failures, both were in highergrade disease (grades 2 and 3). The grade 3 chondrosarcoma patient also developed systemic metastases 13 months following radiation, in addition to a local recurrence. None of the 8 grade 1 chondrosarcoma patients experienced a local failure, with a median follow-up of 77 months (range, ). Four patients died in the chordoma group, and 3 of these patients died as a consequence of local disease progression. Three patients died in the chondrosarcoma group, with 2 cases as a consequence of local disease progression. Table 3 summarizes the local failure characteristics in detail for each of the 10 cases. To summarize the 8 chordoma failures, 8/8 patients (100%) underwent STR, and 1 had been treated with,66 Gy. Of the 2 chondrosarcoma failures, one was grade 2 and the other grade 3. Both patients had undergone an initial STR and were treated with a total dose of 70 Gy. Of the chordoma and chondrosarcoma patients who progressed, the median time to progression was 1.5 and 1.3 years, respectively. The Kaplan Meier OS curves are shown in Fig. 2. The 3- and 5-year OS rates were 100% and 85.6% and 87.8% and 84.1% for the chordoma and chondrosarcoma cohorts, respectively. The 5-year cumulative incidences of local failure were 34.7% and 11.9% for the chordoma and chondrosarcoma cohorts, respectively (Fig. 3). Specific to the chordoma cohort, a trend was observed for age as a continuous variable with respect to OS such that the rate of dying increased with increasing age (P ¼.05). With respect to LC, multivariable analysis confirmed GTR as a significantpredictorcomparedwithstrandbiopsy(p,.0001). With respect to dose, we did not find any significance with total dose as a continuous variable. For chondrosarcoma, we could not identify any significant prognostic factors for OS, although age was a predictor for LC associated with an increased risk of local progression (hazard ratio ¼ [ ], P ¼.0007). There were 6 patients with 8 radiation-induced late injuries. The median and mean times to injury from the start of radiation were 2.2 years and 3.2 years, respectively. Three of 8 were cases of radiation-induced hearing loss (2 cases grade 2, one case grade 3), 1 was radiation-induced hypothyroidism (grade 2), 1 was radiation-induced hypopituitarism (grade 3), 1 was radiation-induced vestibular nerve injury (grade 2), 1 was a cranial nerve IV injury resulting in diplopia (grade 2), and 1 was a radiation-induced secondary malignancy that resulted in death (grade 5). This last was consistent with the development of a radiation-induced malignant glioma based on MRI findings; Neuro-Oncology 891

4 Table 1. Descriptive statistics for the chordoma and chondrosarcoma patients Variable Chordoma (n ¼ 24) Chondrosarcoma (n ¼ 18) Sex, F 8 (33.3%) 8 (44.4%) Site of disease Petroclival 17 (70.8%) 12 (66.7%) Parasellar 2 (8.3%) 1 (5.6%) Cervical spine/foramen magnum 2 (8.33%) 0 (0%) Cerebellopontine angle 1 (4.2%) 0 (0%) Posterior fossa 1 (4.2%) 0 (0%) Sellar 1 (4.2%) 0 (0%) Cavernous sinus 0 (0%) 3 (16.7%) Other 0 (0%) 2 (11.1%) Cranial nerve palsy present 10 (41.7%) 13 (72.2%) Neurologic deficit present 4 (16.7%) 3 (16.7%) Surgical outcome GTR 8 (33.3%) 7 (38.9%) STR 15 (62.5%) 9 (50.0%) Biopsy only 1 (4.2%) 2 (11.1%) Median age, y (range) 46 (21 76) 32 (21 69) Median total dose (range)/median dose per fraction Gy ( )/2.0 Gy Gy ( )/2.0 Gy Median range tumor diameter, cm (range) 3.50 ( ) 3.10 ( ) Median GTV, cc (range) 14.5 ( ) 24.6 ( ) Median time from surgery to radiation, d (range) 86.5 (11 229) 69 (27 298) Median follow-up, mo (range) 36.1 ( ) 66.5 ( ) Table 2. Median (range) total dose for selected critical organs at risk Variable Chordoma (n ¼ 24) Chondrosarcoma (n ¼ 18) Optic chiasm max dose Gy ( ) Gy ( ) Optic chiasm mean dose Gy ( ) Gy ( ) Right optic nerve max dose Gy ( ) Gy ( ) Right optic nerve mean dose Gy ( ) Gy ( ) Left optic nerve max dose Gy ( ) Gy ( ) Left optic nerve mean dose Gy ( ) Gy ( ) Brainstem max dose Gy ( ) Gy ( ) Brainstem mean dose Gy ( ) Gy ( ) location within the prior radiation field (developed within the brainstem), prolonged time to diagnosis at 6.7 years following the initial chordoma radiation, and the patient had no evidence of primary tumor recurrence. Mature follow-up is required to assess the long-term consequences of this treatment. Discussion We report favorable preliminary rates of LC for both chondrosarcoma and chordoma following high-dose photon linear accelerator IG-IMRT. We observed crude LC in 67% of chordoma patients and 88% of chondrosarcoma patients. The 5-year actuarial LC and OS rates were 65.3% and 88.1% and 85.6% and 84.1% in the chordoma and chondrosarcoma cohorts, respectively. With respect to grade 1 chondrosarcoma, no failures were observed, with a median follow-up of 77 months (range, ). These data are consistent with expected outcomes following proton therapy as summarized in a recent review by Combs and colleagues. 11 There has been controversy over the years as to the importance of high-dose versus low-dose photon-based radiation and which radiation technology is best suited for these patients. Prior to IG-IMRT, rates of LC with conventional photon radiation delivering total doses in the range of 40 to 54 Gy were suboptimal. Local control rates, especially after incomplete resection, were well below 50%, and the utility of radiation was questioned and even considered to be a palliative treatment. 5,12 14 The inability to dose escalate without IG-IMRT led to the referral of these patients to highly specialized particle therapy radiation centers. The advantage of particle therapy lies in the predictable dose deposition at a given depth, essentially allowing for maximal dosing at the tumor/oar interface and consequent dose escalation within the tumor. 6 Therefore, 892

5 Table 3. Summary of clinical factors in those patients who subsequently failed locally Variable Chordoma (n ¼ 8) Chondrosarcoma* (n ¼ 2) Sex, F 3 (37.5%) 1 (50%) Site of disease Petroclival 4 (50%) 2 (100%) Parasellar 2 (25%) 0 (0%) Cervical spine/foramen magnum 1 (12.5%) 0 (0%) Sellar 1 (12.5%) 0 (0%) Initial surgical outcome STR 8 (100%) 2 (100%) Median age, y (range) 63 (29 76) 55 (49 61) Median total dose (range)/dose per fraction Gy ( )/2.0 Gy Gy ( )/2.0 Gy Median maximum tumor diameter, cm (range) 2.90 ( ) 3.90 ( ) Median tumor volume, cc (range) ( ) ( ) Median time from surgery to radiation, d (range) 73 (11 205) 30.5 (27 34) Median time from start of radiation to failure, y (range) 1.5 ( ) 1.3 ( ) *Note that the chondrosarcoma failures were patients with grade 2 and 3 disease; no patient with grade 1 chondrosarcoma relapsed. Fig. 2. Kaplan Meier survival curve illustrating OS by tumor type. higher doses were able to be delivered than otherwise possible with conventional radiation. The outcomes were favorable compared with low-dose conventional radiation; however, with IG-IMRT the landscape has changed and similar doses to those typical of proton therapy are now being delivered with photon therapy as per our series. 4 The advantage of IMRT is modulation of the beam to create exquisitely shaped radiation dose distributions with steep dose fall-offatthetumor/oarinterface.imageguidanceallows millimetric precision in delivery, allowing for the PTV margins to be kept to a minimum. Although the integral dose will undoubtedly be greater with photons versus protons, the clinical significance relates to the potential for adverse effects as opposed to tumor control. Both the tumor control and adverse late-effects results presented in this series are consistent with those with proton-based radiation for both chordoma and chondrosarcoma and the few series reported with IG-IMRT to date. 4,7 10,15,18 A recent series evaluating carbon ion therapy for chordoma also report reasonably consistent results with Fig. 3. Cumulative incidence curve of tumor recurrence according to tumor type. our data. 19 Therefore, we conclude both efficacy and safety with modern linear accelerator based IG-IMRT technology. We acknowledge that comparability between series is difficult due to the heterogeneity of the disease characteristics at the time of treatment, complexity of the radiation dose distribution, and at this time the lack of molecular subclassifications to clarify biological aggressiveness. With respect to our chondrosarcoma patients (n ¼ 18), our results were consistent with the high-dose proton and photon literature, with only 2 failures observed. 4,7 10,15 17 Both failures occurred in the patients with higher-grade disease, also known to be associated with failure. One case was grade 2 and the other grade 3 chondrosarcoma, and both were treated with 70 Gy in 35 fractions. This result may suggest that patients with higher-grade chondrosarcoma should be dose escalated; however, the limited sample size in this study must be considered before any firm recommendations can be made. Importantly, none of the grade 1 tumors relapsed. Neuro-Oncology 893

6 In the chordoma cohort (n ¼ 24), the median total dose was 76 Gy and only one patient was treated with,66 Gy. We did not observe a dose response relationship within the narrow dose range employed. Surgery for chordoma was predictive of better outcomes when a GTR was performed compared with STR and biopsy alone. This likely reflects the therapeutic benefit of resecting as much tumor as possible given that chordoma is considered radioresistant, and less residual disease to control with radiation likely increases the chance for radiation to achieve long-term control. With respect to the toxicities observed, these are in keeping with most major series. 4,7 10,15 18 The one case of radiationinduced malignancy highlights the discussion that must take place when consenting patients for radiation; as this is a serious late effect, albeit low risk, of radiation in long-term survivors. Our preliminary data support our practice of treating with linear accelerator based photon IG-IMRT, and we now routinely treat with 70 Gy in 35 fractions for chondrosarcomas and 78 Gy in 39 fractions for chordomas. We acknowledge that analogous IG-IMRT technology is emerging for protons, with the advent of intensity-modulated proton therapy and in-room cone-beam CT. Ultimately, future evaluation will determine if these advances in proton technology can yield better results with respect to LC. Funding There are no funding sources to disclose. Conflict of interest statement. Dr Arjun Sahgal has received honoraria for previous educational seminars and research funding from Elekta AB. There are no other conflicts of interest to disclose. References 1. Walcott BP, Nahed BV, Mohyeldin A, et al. Chordoma: current concepts, management, and future directions. Lancet Oncol. 2012;13(2):e69 e Colli BO, Al-Mefty O. Chordomas of the skull base: follow-up review and prognostic factors. Neurosurg Focus. 2001;10(3):E1. 3. Fagundes MA, Hug EB, Liebsch NJ, et al. Radiation therapy for chordomas of the base of skull and cervical spine: patterns of failure and outcome after relapse. Int J Radiat Oncol Biol Phys. 1995;33(3): Koga T, Shin M, Saito N. Treatment with high marginal dose is mandatory to achieve long-term control of skull base chordomas and chondrosarcomas by means of stereotactic radiosurgery. J Neurooncol. 2010;98(2): Catton C, O Sullivan B, Bell R, et al. Chordoma: long-term follow-up after radical photon irradiation. Radiother Oncol. 1996;41(1): Amichetti M, Amelio D, Minniti G. Radiosurgery with photons or protons for benign and malignant tumours of the skull base: a review. Radiat Oncol. 2012;7: Kano H, Iqbal FO, Sheehan J, et al. Stereotactic radiosurgery for chordoma: a report from the North American Gamma Knife Consortium. Neurosurgery. 2011;68(2): Martin JJ, Niranjan A, Kondziolka D, et al. Radiosurgery for chordomas and chondrosarcomas of the skull base. J Neurosurg. 2007;107(4): Hasegawa T, Ishii D, Kida Y, et al. Gamma knife surgery for skull base chordomas and chondrosarcomas. J Neurosurg. 2007; 107(4): Ito E, Saito K, Okada T, et al. Long-term control of clival chordoma with initial aggressive surgical resection and gamma knife radiosurgery for recurrence. Acta Neurochir (Wien). 2010;152(1): 57 67; discussion Combs SE, Laperriere N, Brada M. Clinical controversies: proton radiation therapy for brain and skull base tumors. Semin Radiat Oncol. 2013;23(2): Cummings BJ, Hodson DI, Bush RS. Chordoma: the results of megavoltage radiation therapy. Int J Radiat Oncol Biol Phys. 1983;9(5): Zorlu F, Gurkaynak M, Yildiz F, et al. Conventional external radiotherapy in the management of clivus chordomas with overt residual disease. Neurol Sci. 2000;21(4): Fuller DB, Bloom JG. Radiotherapy for chordoma. Int J Radiat Oncol Biol Phys. 1988;15(2): Amichetti M, Cianchetti M, Amelio D, et al. Proton therapy in chordoma of the base of the skull: a systematic review. Neurosurg Rev. 2009;32(4): Amichetti M, Amelio D, Cianchetti M, et al. A systematic review of proton therapy in the treatment of chondrosarcoma of the skull base. Neurosurg Rev. 2010;33(2): Orecchia R, Vitolo V, Fiore MR, et al. Proton beam radiotherapy: report of the first ten patients treated at the Centro Nazionale di Adroterapia Oncologica (CNAO) for skull base and spine tumours. Radiol Med. 2014;119(4): Hauptman JS, Barkhoudarian G, Safaee M, et al. Challenges in linear accelerator radiotherapy for chordomas and chondrosarcomas of the skull base: focus on complications. Int J Radiat Oncol Biol Phys. 2012;83(2): Uhl M, Mattke M, Welzel T, et al. Highly effective treatment of skull base chordoma with carbon ion irradiation using a raster scan technique in 155 patients: first long-term results. Cancer. 2014; 120(21):