- Department of Neurosurgery, Maastricht University Medical Centre, Maastricht, the Netherlands, Netherlands,
- Department of Radiology, King Fahad Hospital of Imam Abdulrahman Bin Faisal University, AL-Khobar, Saudi Arabia.
Department of Neurosurgery, Maastricht University Medical Centre, Maastricht, the Netherlands, Netherlands,
DOI:10.25259/SNI-213-2019Copyright: © 2019 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Mohammed Alahmari, Yasin Temel. Skull base chordoma treated with proton therapy: A systematic review. 07-Jun-2019;10:96
How to cite this URL: Mohammed Alahmari, Yasin Temel. Skull base chordoma treated with proton therapy: A systematic review. 07-Jun-2019;10:96. Available from: https://surgicalneurologyint.com/surgicalint-articles/9354/
Background:Chordoma located in the skull base is usually a challenging surgical condition. It is often not possible to achieve gross total resection. Residual tumors have been treated with adjuvant focal radiation therapy employing high-energy particles most commonly through proton beam. In this review, we systematically analyzed indications and outcomes of this treatment with respect to local control rates of the lesion and factors determining recurrence of skull base chordomas. In addition, we collected data on treatment-associated radiation-induced side effects.
Methods:In line with the PRISMA guidelines, the authors performed a literature search algorithm for relevant articles using three databases: PubMed, Embase, and Cochrane. Inclusion and exclusion criteria were applied to evaluate all identified studies published between 1980 and 2018.
Results:Our review included 11 studies for analysis (n = 511 patients). The mean age of the study population was 47.3 ± 5.8 years. The mean dose of postsurgical irradiation at the time of initial treatment was 71.1 ± 3.1 Gy. The mean follow-up duration was 45.0 ± 17.5 months. Within this follow-up duration, recurrence occurred in 26.8% of the patients. The mean time to recurrence was 34.5 ± 15.2 months. A significant number of patients experienced side effects varying from Grade 1 (mild dermatitis) to Grade 4 (temporal lobe necrosis and visual disorders).
Conclusion:Despite advances in proton therapy, recurrence rates in skull base chordoma remain high. The toxicity of proton therapy may be more prevalent than generally thought. Unfortunately, there is substantial variation in the methods of data reporting.
Keywords: Analysis, Chordoma, Proton, Recurrence, Safety, Skull base
Cranial chordoma is a rare skull neoplasm which is thought to arise from remnants of the embryonic notochord. It represents about 1%–4% of primary bone tumors.[
Skull base chordomas destroy bone and infiltrate to adjacent soft tissue. Neural and vascular structures such as cranial nerves, brainstem, carotid, and basilar artery can be compressed and/or encased by the expanding tumor. Since chordomas have no distinctly formed fibrous capsule, it is frequently difficult to identify tumor margins on magnetic resonance images.[
Subtotal resections are, therefore, common and residual tumors are meant to be treated by radiation therapy.[
Over the past few years, more information has become available on the effects of PT in patients with residual skull base chordomas. After PT, progression of residual tumor is often observed. In this review, we systematically analyzed the details of recurrence of skull base chordomas after PT therapy and collected data on side effects.
We performed a literature search for relevant articles using three databases: PubMed, Embase, and Cochrane. The search covered English language publications between 1980 and 2018 (the last search was conducted on January 8, 2018). The strategy and keywords used for the search were [(Chordoma*)] AND [(Proton) OR (Particles)] AND [(Radiotherapy) OR (Therapy) OR (Beam)]. Inclusion criteria were peer-reviewed original articles in patients reporting the recurrence of skull base chordoma who had undergone PT and/or combined photon-PT after surgery. The exclusion criteria were single case studies, review articles, abstracts, animal or phantom studies, questionnaires, and pediatric studies. In case of possible double reporting of patients by the same research groups in different publications, we included the report with the highest sample size and/or longest follow-up period. Authors’ names, characteristics of patients, period, and place of treatment were all cross-checked. Papers not reporting recurrence were excluded. Furthermore, some studies included different groups of patients who had received different types of radiation therapy. Hence, if recurrence was reported as overall without considering the type of radiation therapy, the paper was excluded as well.
The following details were extracted from the included papers: authors, year of publication, number of patients, gender, age, follow-up period, type of radiation therapy, volume of residual tumor postsurgery, radiation dose applied, dose per fraction, radiation-induced side effects, rate of recurrences, number of deaths, and control rates. The variations found in units of PT dosage were kept as reported. The dosage of PT in old studies is usually expressed as cobalt gray equivalent (CGE) units, which is a factor of 1.1 compared to photon dose (60Co). Recent reports used the units of Gy RBE (with 1.1 relative to that of 60Co) more frequently as required by the International Commission on Radiation Units and Measurements.[
Eleven studies qualified for the final overall analysis. These studies will be briefly discussed in the next paragraphs. All mean values and standard deviations were analyzed using the IBM Statistical Package for the Social Science software, version 24.
First, we will provide a summary of included papers. These studies are described chronologically. Then, we will describe the results of the overall analysis.
In 1989, Sen et al. published on the treatment of eight patients with skull base chordoma.[
In 1999, Terahara et al. described the outcome of 115 patients with skull base chordomas.[
In the same year, another group described the results of their treatment of 33 chordoma patients.[
In 2004, Igaki et al. evaluated 13 cases of skull base chordomas who underwent either combined proton-photon therapy or PT alone.[
Recurrences were noticed more frequently in females than in males. Patterns of failure were local recurrences outside the clinical target volumes in two patients, local recurrence at dose-limited regions near radiation-sensitive structures in two patients, and in-field local recurrence within the gross tumor volume in one patient as well as out-of-field regional nodal recurrence in one patient.
In 2005, Noël. et al. reported their data of 100 irradiated patients with chordomas in the base of the skull or upper cervical spine.[
In 2013, Deraniyagala et al. published their results of a cohort of 33 chordoma patients who had undergone adjuvant PT with a mean dose of 78.4 CGE.[
Grosshans et al. published, in 2014, the results of 15 patients who were treated by PT following surgery.[
In 2016, Weber et al. reported the outcome of utilizing PT in 151 cases of skull base chordomas.[
In the same year, McDonald et al. demonstrated that larger residual tumors and tumors receiving a lower dose were associated with poor control.[
In 2017, Jägersberg et al. published the analysis of 13 skull base chordomas treated between 2005 and 2015.[
Another recent study described the treatment of 22 clival chordomas.[
Overall statistical analysis
Our review resulted in a total of 511 patients which could be included for pooled analysis. The mean age of the study population was 47.3 ± 5.8 years. The mean dose of irradiation was 71.1 ± 3.1 Gy (RBE). The mean follow-up duration was 45.0 ± 17.5 months. Within this follow-up duration, recurrence was reported in 137 patients (26.8%). The mean time to recurrence was 34.5 ± 15.2 months. Forty-seven patients died due to their chordoma, and three deaths found to be due to radiation-induced side effects. From the dataset collected, we could not reconstruct a Kaplan–Meier plot illustrating local control rate. This is largely due to the lack of a given end time which is required for any survival analysis and which was missing here for individual patients in whom no recurrences were reported. Too many missing observations made it impossible to compute the Chi-squared contingency test to test for associations between recurrence and either the gross residual tumor volume, radiotherapy type, radiation dose, or gender.
Included studies and radiotherapy approach
The incidences of chordoma recurrence are presented in
Studies reporting on radiation-induced side effects
A summary of the reported acute and late radiation-induced effects, number of occurrences, and their toxicity grading levels are shown in
This study confirms that radiation therapy of skull base chordomas suffers from high recurrence rates despite high-intensity treatments.[
The reported local control rate at 5 years after surgery and either combined therapy or PT alone ranges between 40% and 75.8%.[
As an alternative to PT, modern technology in conformal photon irradiation can offer encouraging control rates which can be compared with those reported by PT. The intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) are developed to escalate, shape, and deliver the respective dose more effectively and more conformally toward the targeted disease.[
The phenomenon of Bragg peak in PT has generated the hypothesis of minimizing treatment-related side effects. This assumption will be tested more thoroughly now with the increase in a number of available PT facilities. The question arises whether secondary malignant neoplasms can occur. The current follow-up durations are insufficient to answer this question, and longer follow-up data are required (at least 10–15 years after treatment).[
We summarized the most frequently observed acute toxicities (Grade 1 or 2) within the duration of 6 months after PT. These included nausea and vomiting, fatigue, temporary hair loss, mucositis, headache, and loss of appetite [
Of note, during the review process, we have encountered difficulties which may limit the interpretation of our data. First, in some of the early studies, protons were combined with photon-based radiation. Second, missing data and not reporting data systematically limit performing a more extensive analysis.
Despite advances in PT, recurrence rates in skull base chordoma remain high. The toxicity of PT may be more prevalent than generally thought.
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