Adjuvant stereotactic radiosurgery with or without postoperative fractionated radiation therapy in adults with skull base chordomas: a systematic review

Othman Bin-AlamerDepartment of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;

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Arka N. MallelaDepartment of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;

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Paolo PalmiscianoDepartment of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, Ohio;

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Zachary C. GerseyDepartment of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;

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Turki ElarjaniDepartment of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida;

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Mohamed A. LabibDepartment of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland;

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Georgios A. ZenonosDepartment of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;

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Amir R. DehdashtiDepartment of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York;

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Jason P. SheehanDepartment of Neurosurgery, University of Virginia Health System, Charlottesville, Virginia; and

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William T. CouldwellDepartment of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah

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L. Dade LunsfordDepartment of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;

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Hussam Abou-Al-ShaarDepartment of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;

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OBJECTIVE

The objective of this retrospective study was to compare the survival of patients with biopsy-proven skull base chordoma who had undergone stereotactic radiosurgery (SRS) with versus without prior fractionated radiation therapy (RT).

METHODS

Relevant articles from database inception to September 2021 were retrieved from the PubMed, Scopus, Web of Science, and Cochrane databases for a systematic review of treatment protocols. Studies were included if they 1) involved adult patients (age ≥ 18 years) with histologically and radiologically confirmed chordomas located within the clival skull base region and treated with SRS; 2) reported data on clinical features, SRS protocols, and outcomes; and 3) were written in the English language. Studies were excluded if they 1) were literature reviews, case reports, technical notes, abstracts, or autopsy reports; 2) did not clearly differentiate the data of patients with chordomas from the data of patients with different tumors or the data of patients with chordomas in locations other than the skull base; or 3) lacked histological confirmation or treatment and outcome data. Extracted data included the following: study author and publication year, patient age and sex, symptoms, cranial nerve involvement, invaded structures, lesion size, treatment modality, surgical details, histopathological type, RT modality, SRS parameters, complications, postradiosurgery outcomes, complications, and survival outcomes.

RESULTS

After the selection process, 15 articles describing 130 patients met the study eligibility criteria, including 94 patients who had undergone postresection SRS (NoRT group) and 36 who had undergone postresection fractionated RT and subsequent SRS (RT group). The NoRT and RT groups were comparable in age (51.3 vs 47.4 years, respectively), sex (57.1% vs 58.3% male), tumor volume (9.5 vs 11.2 cm3), SRS treatment parameters (maximum dose: 35.4 vs 42.2 Gy, marginal dose: 19.6 vs 20.6 Gy, treatment isodose line: 60.2% vs 65.2%), and SRS adverse effects (10.9% vs 17.6%). For the entire cohort, the 3-, 5-, and 10-year progression-free survival (PFS) rates were 23%, 9%, and 3%, respectively, and the overall survival (OS) rates were 94%, 82%, and 76%, respectively. In the NoRT group, SRS was adjuvant treatment after resection in 38 patients (40.4%), salvage treatment for recurrent tumor treated with resection alone in 10 (10.6%), and not specified in 46 (48.9%). In the RT group, SRS was boost treatment in 9 patients (25.0%), salvage treatment after recurrence in 22 (61.1%), and not specified in 5 (13.9%). There was no difference between the two groups in terms of median PFS (24.0 months [Q1 34.0, Q3 15.0] vs 23.8 months [34.0, 18.0], respectively; p = 0.8) or median OS (293.0 months [not reached, 137.4] vs not reached [not reached, 48.0], respectively; p = 0.36). The adverse radiation effect rates were comparable between the groups (10.9% vs 17.6%, respectively; p = 0.4).

CONCLUSIONS

The role of SRS in the management of skull base chordomas is still evolving. This systematic literature review of biopsy-proven chordoma revealed that tumor control and survival rates for SRS alone after chordoma surgery were not inferior to those encountered after SRS plus fractionated RT.

ABBREVIATIONS

ARE = adverse radiation effect; CK = CyberKnife radiosurgery; EEA = endoscopic endonasal approach; GKRS = Gamma Knife radiosurgery; GTR = gross-total resection; LINAC = linear accelerator radiosurgery; OS = overall survival; PFS = progression-free survival; PR = partial resection; RT = radiation therapy; SRS = stereotactic radiosurgery; STR = subtotal resection; TCA = transcranial approach.

OBJECTIVE

The objective of this retrospective study was to compare the survival of patients with biopsy-proven skull base chordoma who had undergone stereotactic radiosurgery (SRS) with versus without prior fractionated radiation therapy (RT).

METHODS

Relevant articles from database inception to September 2021 were retrieved from the PubMed, Scopus, Web of Science, and Cochrane databases for a systematic review of treatment protocols. Studies were included if they 1) involved adult patients (age ≥ 18 years) with histologically and radiologically confirmed chordomas located within the clival skull base region and treated with SRS; 2) reported data on clinical features, SRS protocols, and outcomes; and 3) were written in the English language. Studies were excluded if they 1) were literature reviews, case reports, technical notes, abstracts, or autopsy reports; 2) did not clearly differentiate the data of patients with chordomas from the data of patients with different tumors or the data of patients with chordomas in locations other than the skull base; or 3) lacked histological confirmation or treatment and outcome data. Extracted data included the following: study author and publication year, patient age and sex, symptoms, cranial nerve involvement, invaded structures, lesion size, treatment modality, surgical details, histopathological type, RT modality, SRS parameters, complications, postradiosurgery outcomes, complications, and survival outcomes.

RESULTS

After the selection process, 15 articles describing 130 patients met the study eligibility criteria, including 94 patients who had undergone postresection SRS (NoRT group) and 36 who had undergone postresection fractionated RT and subsequent SRS (RT group). The NoRT and RT groups were comparable in age (51.3 vs 47.4 years, respectively), sex (57.1% vs 58.3% male), tumor volume (9.5 vs 11.2 cm3), SRS treatment parameters (maximum dose: 35.4 vs 42.2 Gy, marginal dose: 19.6 vs 20.6 Gy, treatment isodose line: 60.2% vs 65.2%), and SRS adverse effects (10.9% vs 17.6%). For the entire cohort, the 3-, 5-, and 10-year progression-free survival (PFS) rates were 23%, 9%, and 3%, respectively, and the overall survival (OS) rates were 94%, 82%, and 76%, respectively. In the NoRT group, SRS was adjuvant treatment after resection in 38 patients (40.4%), salvage treatment for recurrent tumor treated with resection alone in 10 (10.6%), and not specified in 46 (48.9%). In the RT group, SRS was boost treatment in 9 patients (25.0%), salvage treatment after recurrence in 22 (61.1%), and not specified in 5 (13.9%). There was no difference between the two groups in terms of median PFS (24.0 months [Q1 34.0, Q3 15.0] vs 23.8 months [34.0, 18.0], respectively; p = 0.8) or median OS (293.0 months [not reached, 137.4] vs not reached [not reached, 48.0], respectively; p = 0.36). The adverse radiation effect rates were comparable between the groups (10.9% vs 17.6%, respectively; p = 0.4).

CONCLUSIONS

The role of SRS in the management of skull base chordomas is still evolving. This systematic literature review of biopsy-proven chordoma revealed that tumor control and survival rates for SRS alone after chordoma surgery were not inferior to those encountered after SRS plus fractionated RT.

Intracranial chordomas are rare tumors that arise from prenatal remnants of the notochord located in the midline skull base clivus.14 They account for 0.5% of all intracranial tumors and have an incidence of 1 case per million persons.5,6 Despite initial surgery, chordomas are locally aggressive and have a high rate of local recurrence. Their proximity to critical neurovascular structures renders initial management challenging and impedes gross-total resection (GTR). Adjuvant treatment modalities are essential to improving outcomes in chordoma patients.7,8

The management paradigm for clival chordoma typically begins with maximal safe resection using advanced cranial microsurgical or endoscopic endonasal techniques.9 Despite aggressive resection, additional strategies such as fractionated proton or photon radiation therapy (RT) and stereotactic radiosurgery (SRS) are often deemed necessary for residual or recurrent disease.10,11 Recent reports have demonstrated that SRS after surgery can improve long-term tumor control and survival in chordoma patients.12,13

Despite the increasing role of SRS in the management of skull base chordomas, the lack of evidence regarding its impact on long-term outcomes, survival, and complications has impeded consensus on this critical topic. The chordoma literature consists mostly of single-center observational studies that limit the ability to clearly establish the timing and outcomes of SRS after resection, specifically with or without prior RT use. Therefore, we performed a systematic review to compare the outcomes and survival rates of chordoma patients who had undergone SRS with prior RT (RT group) to those of patients who had undergone SRS without prior RT (NoRT group).

Methods

Literature Search

This systematic review was conducted according to PRISMA guidelines.14 The PubMed, Scopus, Web of Science, and Cochrane databases were searched from database inception to September 2021. A medical subject headings (MeSH) term and keyword search of each database was conducted using the Boolean operators "OR" and "AND." The terms used were as follows: ("Chordoma") AND ("GK" OR "Gamma knife" OR "LINAC" OR "Linear accelerator" OR "CyberKnife" OR "stereotactic radiosurgery" OR "radiosurgery"). Any duplicates were removed.

Study Selection

Inclusion and exclusion criteria were predetermined. Studies were included if they 1) involved adult patients (age ≥ 18 years) with histologically and radiologically confirmed chordomas located within the clival skull base region and treated with SRS; 2) reported data on clinical features, SRS protocols, and outcomes; and 3) were written in the English language. Studies were excluded if they 1) were literature reviews, case reports, technical notes, abstracts, or autopsy reports; 2) did not clearly differentiate the data of patients with chordomas from the data of patients with different tumors or the data of patients with chordomas in locations other than the skull base; or 3) lacked histological confirmation or treatment and outcome data.

Two authors (O.B.A. and P.P.) independently reviewed the titles and abstracts of all extracted citations and then appraised the full text of articles meeting the inclusion criteria. Three authors (A.N.M., Z.C.G., and H.A.A.S.) settled any disagreements. References from eligible studies were screened to retrieve additional relevant studies.

The initial literature search yielded 495 citations (Fig. 1). After duplicate elimination, there were 323 articles. A total of 274 studies were excluded based on title and abstract screening. Forty-nine papers were sought for retrieval; however, 2 articles were inaccessible. A total of 47 articles were evaluated for inclusion. Of these assessed papers, 32 failed to meet our inclusion criteria and were subsequently excluded. Thus, 15 articles were included in this systematic review on the basis of the prespecified criteria (Supplementary Tables 1 and 2).13,1528

FIG. 1.
FIG. 1.

PRISMA flowchart illustrating the search strategy and data selection based on the inclusion and exclusion criteria.

Data Extraction

One author (O.B.A.) extracted data from the included articles, and these data were confirmed by three independent authors (A.N.M., Z.C.G., and H.A.A.S.) to ensure accuracy. Data were considered available and subsequently extracted if they were explicitly stated in the text, tables, or figures and were sufficiently distinguishable to be extracted from a larger cohort. Missing data were either not reported or indistinguishable from other data. Extracted data included the following: study author and publication year, patient age and sex, symptoms, cranial nerve involvement, invaded structures, lesion size, treatment modality, surgical details, histopathological type, RT modality, SRS parameters, complications, postradiosurgery outcomes, complications, and survival outcomes.

Data Synthesis and Quality Assessment

The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS). We also examined clinical characteristics, the effect of various SRS techniques, and complications. Because of the limited data, we could not classify the cohort based on treatment type (i.e., adjuvant, boost, and salvage). Instead, patients who had postresection SRS as either adjuvant therapy for a primary tumor or salvage therapy following recurrence with no prior fractionated RT were classified as the NoRT group, whereas patients who had boost SRS after postresection fractionated RT for a primary tumor or salvage SRS following recurrence of a tumor treated with postresection fractionated RT were classified as the RT group.

The level of evidence of each article was evaluated following the 2011 Oxford Centre for Evidence-Based Medicine guidelines, and all articles were categorized as level 4 evidence.29 The risk of bias for each article was independently assessed by 2 authors (O.B.A. and P.P.) using the Joanna Briggs Institute checklists for case series.30 Risk-of-bias assessment revealed a low risk of bias in all included papers (Supplementary Fig. 1).

Statistical Analysis

R software (version 4.1.1, R Foundation for Statistical Computing, http://www.R-project.org/) was used for all statistical analyses. Continuous variables were summarized as means, standard deviations, and ranges, whereas categorical variables were summarized as frequencies and percentages. The survival data were reported as median months (25th percentile [Q1], 75th percentile [Q3]); in some cases, percentile levels were not reached statistically. Chi-square analyses were used to test significant differences between categorical variables, whereas the Student t-test was conducted to assess differences between continuous variables.

Using the R package survival, OS and PFS were calculated using Kaplan-Meier curves, and the log-rank test was used to compare survival curves. The Cox proportional hazards model was used for univariate and multivariate analyses to assess factors potentially affecting survival. For testing the proportional hazards assumption, Schoenfeld’s global test was used to estimate time-varying covariance, and none of the variables violated the proportional hazards assumption. Using the R package survMisc, continuous variables were binarized on the basis of the most significant point using the log-rank test. If not specified, the OS times reported by the included papers were assumed to be the time from diagnosis to the last follow-up or death. Unless survival status was specified, survival status at the last follow-up was considered censored. A two-tailed p value < 0.05 was deemed to be significant for all analyses.

Results

Cohort Characteristics

This study included 130 adult patients who had undergone SRS for skull base chordoma. The mean age of patients in the study cohort was 50.1 ± 14.4 years (range 23–80 years), and there was a male predominance (57.5%; Table 1). Diplopia was the most common presentation (48.1%), followed by headache (17.1%), dysphagia (4.7%), and visual impairment (4.7%). The most commonly affected cranial nerves were the abducens, oculomotor, and trochlear in 40 cases (45.5%), 18 (20.5%), and 9 (10.2%), respectively.

TABLE 1.

Summary of clinical characteristics, management strategies, and outcomes in 130 patients who underwent SRS for chordoma

VariableValue
Demographics
 Mean age in yrs (n = 116)*50.1 ± 14.4, 23–80
 Male sex (n = 127)73 (57.5)
Most invaded structure (n = 126)
 Clivus 85 (67.5)
 Cavernous sinus17 (13.5)
 Petrous bone10 (7.9)
 Parasellar region6 (4.8)
 Cerebellopontine angle5 (4.0)
 Others3 (2.4)
Histopathological type (n = 28)
 Chondroid chordoma 4 (14.3)
 Conventional chordoma24 (85.7)
Approach for surgical cases (n = 130)
 EEA30 (23.1)
 TCA 25 (19.2)
 TCA & EEA combined6 (4.6)
 Not reported69 (53.1)
Extent of resection (n = 130)
 GTR4 (3.1)
 STR34 (26.2)
 PR19 (14.6)
 Not reported or indistinguishable73 (56.2)
Previous RT
 Patients w/ previous RT36 (27.7)
 Mean dose in Gy (n = 11)63.7 ± 7.2, 50–75.5
SRS treatment strategy (n = 130)
 Postsurgery (NoRT group)94 (72.3)
 Post-RT (RT group)36 (27.7)
SRS modality (n = 130)
 GKRS91 (70.0)
 CK29 (22.3)
 LINAC8 (6.2)
 GKRS & CK2 (1.5)
Mean SRS parameters
 Tumor vol in cm3 (n = 107)9.8 ± 8.8, 0.47–40.5
 Marginal dose in Gy (n = 121)19.8 ± 7.5, 10–50
 Max dose in Gy (n = 58)36.2 ± 10.2, 15–70
 Isodose line in % (n = 87)61.1 ± 18.4, 35–90
SRS AREs (n = 81)10 (12.3)
 Unspecified CN neuropathy2 (20.0)
 Diplopia & gait disturbance1 (10.0)
 Dizziness1 (10.0)
 Neurological deterioration1 (10.0)
 Dysphagia, facial numbness, dysarthria, & decreased visual acuity1 (10.0)
 Unspecified endocrinopathy, unspecified CN neuropathy, & hemiparesis1 (10.0)
SRS AREs (n = 81)10 (12.3)
 Diplopia1 (10.0)
 Visual field deficits & hearing loss1 (10.0)
 Headache1 (10.0)
Status at last follow-up (n = 130)
 Dead20 (15.4)
 Alive110 (84.6)
PFS
 3 yrs23%
 5 yrs9%
 10 yrs 3%
OS
 3 yrs94%
 5 yrs82%
 10 yrs76%

CN = cranial nerve.

Values are reported as the mean ± standard deviation, range or as number (%), unless indicated otherwise.

Ages of 14 patients were not distinguishable because Ogawa et al.13 reported only the age range of their patients and Pedroso et al.26 combined age data for the SRS cohort and the non-SRS cohort.

Sexes of 3 patients were not distinguishable because Pedroso et al.26 combined sex data for the SRS cohort and the non-SRS cohort.

Patients received both treatment modalities.

Among the cases with available data on tumor location (n = 126), the most commonly involved structure was the clivus (85 cases [67.5%]), followed distantly by the cavernous sinus (17 cases [13.5%]) and petrous bone (10 cases [7.9%]). The histopathological type was reported in 28 patients: 14.3% had chondroid chordoma, whereas the rest (85.7%) had conventional chordoma. Tumor genetic profiles were not reported in any of the included papers.

Thirty patients (23.1%) underwent resection via an endoscopic endonasal approach (EEA), 25 (19.2%) via a transcranial approach (TCA), and 6 (4.6%) via a combined TCA and EEA approach (Table 1). The initial surgical approach was not specified in 69 cases (53.1%). GTR was achieved in only 4 patients (3.1%), whereas subtotal resection (STR) and partial resection (PR) were achieved in 34 (26.2%) and 19 (14.6%), respectively. The extent of resection in the 73 remaining patients (56.2%) was not reported. Thirty-six patients (27.7%) underwent postoperative fractionated proton or photon RT (mean dose 63.7 ± 7.2 Gy, range 50–75.5 Gy) before SRS (RT group), and 94 patients (72.3%) underwent postoperative SRS without prior RT (NoRT group).

Ninety-one patients (70.0%) underwent Gamma Knife radiosurgery (GKRS; Elekta), whereas 29 (22.3%) and 8 (6.2%) underwent CyberKnife radiosurgery (CK; Accuray) and linear accelerator radiosurgery (LINAC; Novalis), respectively. Two patients (1.5%) underwent both GKRS and CK (Table 1).

The mean SRS tumor volume was 9.8 ± 8.8 cm3 (range 0.47–40.5 cm3), and the mean maximum dose was 36.2 ± 10.2 Gy (range 15–70 Gy; Table 1). The mean marginal dose was 19.8 ± 7.5 Gy (range 10–50 Gy) at an isodose line of 61.1% ± 18.4% (range 35%–90%).

The data on SRS adverse radiation effects (AREs) were reported in 81 patients, and 10 patients (12.3%) developed AREs. These AREs were unspecified cranial nerve neuropathy (2 patients); diplopia and gait disturbance (1 patient); dizziness (1 patient); neurological deterioration (1 patient); dysphagia, facial numbness, dysarthria, and decreased visual acuity (1 patient); unspecified endocrinopathy, cranial neuropathy, and hemiparesis (1 patient); diplopia (1 patient); visual field deficits and hearing loss (1 patient); and headache (1 patient).

OS

The cumulative 3-, 5-, and 10-year OS rates were 94%, 82%, and 76%, respectively (Fig. 2A). EEA and TCA prior to SRS yielded comparable OS (Fig. 3A; p = 0.88, log-rank test), and none of the studied factors were significant on univariate or multivariate analyses (Table 2).

FIG. 2.
FIG. 2.

Kaplan-Meier survival curves for OS (A) and PFS (B) of the entire cohort.

FIG. 3.
FIG. 3.

Kaplan-Meier survival curves comparing the OS for TCA and EEA (A, p = 0.88, log-rank test) and for the NoRT group and RT group (B, p = 0.36, log-rank test).

TABLE 2.

Univariate analysis of Cox proportional hazards of patient and treatment characteristics

VariableOSPFS
HR (95% CI)p ValueHR (95% CI)p Value
Male sex0.7 (0.29–1.7)0.40.44 (0.24–0.81)0.0078
Age <40 yrs1.9 (0.64–5.3)0.31.3 (0.61–2.8)0.5
Tumor vol <10 cm30.7 (0.25–1.7)0.40.6 (0.32–1.1)0.1
NoRT group (vs RT group)1.6 (0.64–4.1)0.31.1 (0.57–2)0.8
No. of operations >11.3 (0.5–3.4)0.51.6 (0.76–3.6)0.2

Boldface type indicates statistical significance.

PFS

The 3-, 5-, and 10-year PFS rates for the entire cohort were 23%, 9%, and 3%, respectively (Fig. 2B). Our univariate analysis showed that male sex was associated with a higher likelihood of tumor control, demonstrating a 44% relative risk reduction in tumor progression (p < 0.01; Table 2). However, none of the studied factors were significant on multivariate analysis.

RT Versus NoRT Outcomes

A total of 94 patients (72.3%) underwent postresection SRS as either adjuvant therapy or salvage therapy following a recurrence with no prior fractionated RT (NoRT group), and 36 patients (27.7%) had SRS after postresection fractionated RT as either boost treatment or salvage treatment following a recurrence (RT group; Table 3). The groups were comparable in age (51.3 ± 15.2 vs 47.4 ± 13.8 years, respectively) and sex (57.1% vs 58.3% males). The groups were also comparable in terms of median PFS (24.0 months [Q1 34.0, Q3 15.0] vs 23.8 months [34.0, 18.0], p = 0.8) and median OS (293.0 months [not reached, 137.4] vs not reached [not reached, 48.0], p = 0.36; Table 3 and Fig. 3B).

TABLE 3.

Comparative analysis of NoRT and RT groups

VariableNoRT GroupRT Group p Value
No. of patients94 (72.3)36 (27.7)
Mean age in yrs51.3 ± 15.2, 23.0–80.047.4 ± 13.8, 23.0–67.00.2*
Male sex52 (57.1)21 (58.3)<0.9
Mean dose of prior RT in Gy (n = 11)NA63.7 ± 7.2, 50.0–75.5
SRS indication
 Adjuvant38 (40.4)NA
 BoostNA9 (25.0)
 Salvage10 (10.6)22 (61.1)
 NA46 (48.9)5 (13.9)
SRS modality
 GKRS65 (69.1)26 (72.2)<0.01
 CK20 (21.3)9 (25.0)
 LINAC8 (8.5)0 (0)
 GKRS & CK§1 (1.1)1 (2.8)
Surgical approach
 EEA28 (52.8)2 (25.0)0.3
 TCA20 (37.7)5 (62.5)
 EEA & TCA§5 (9.4)1 (12.5)
SRS parameters
 Tumor vol in cm39.5 ± 9.1, 0.47–40.511.2 ± 7.5, 1.9–27.00.5*
 Max dose in Gy35.4 ± 9.4, 15.0–52.442.2 ± 14.1, 32.0–67.60.1*
 Marginal dose in Gy19.6 ± 6.8, 12.0–43.520.6 ± 10.3, 10.0–50.00.6*
 Isodose line in %60.2 ± 19.1, 35.0–90.065.2 ± 14.9, 50.0–82.00.4*
SRS adverse effects**7 (10.9)3 (17.6)0.4
Median survival in mos (Q1, Q3)
 PFS24.0 (34.0, 15.0)23.8 (34.0, 18.0)0.8††
 OS 293.0 (not reached, 137.4)Not reached (not reached, 48.0)‡‡0.36††

NA = not applicable.

Values are expressed as the mean ± standard deviation, range or number (%), unless specified otherwise. Missing data were either not reported or indistinguishable from another cohort. Boldface type indicates statistical significance.

Two-tailed t-test.

The sexes of 3 patients were not distinguishable, as Pedroso et al.26 combined sex data for the SRS cohort and the non-SRS cohort.

Chi-square test.

Patients underwent treatment with both modalities.

Number of patients for whom surgical approach data were available: 53 (NoRT), 8 (RT).

Number of patients for whom complication data were available: 64 (NoRT), 17 (RT).

Log-rank test.

Median survival was not reached.

The SRS treatment indication was not specified in 46 patients (48.9%) in the NoRT group and 5 (13.9%) in the RT group. In the NoRT group, SRS was adjuvant treatment after resection in 38 patients (40.4%) and salvage treatment after recurrence in 10 patients (10.6%). In the RT group, SRS was boost treatment in 9 patients (25.0%) and salvage treatment after recurrence in 22 patients (61.1%).

Although all cases had prior resection, the surgical approach was specified in only 53 cases in the NoRT group and 8 cases in the RT group (Table 3). The groups were not significantly different in surgical approach rates. A total of 52.8% versus 25.0% underwent an EEA in the NoRT versus RT groups, respectively, whereas 37.7% and 62.5% underwent a TCA, respectively (p = 0.3).

The NoRT and RT groups were also comparable in terms of tumor volume (9.5 ± 9.1 cm3 [range 0.47–40.5 cm3] vs 11.2 ± 7.5 cm3 [range 1.9–27.0 cm3], respectively), maximum SRS dose (35.4 ± 9.4 Gy [range 15.0–52.4 Gy] vs 42.2 ± 14.1 Gy [32–67.6 Gy]), and marginal SRS dose (19.6 ± 6.8 Gy [range 12.0–43.5 Gy] vs 20.6 ± 10.3 Gy [range 10–50 Gy]). ARE rates were not significantly different between the two groups (10.9% vs 17.6%, respectively; p = 0.4).

Discussion

Skull base chordomas are highly aggressive tumors with high recurrence rates.31 Although resection, especially its aggressive form, has been associated with high morbidity and mortality rates, it remains the cornerstone of initial diagnosis and management.9,32,33 Adjuvant RT is frequently given to reduce the recurrence rate after resection. Various fractionated proton or photon RT protocols are used, in part related to patient access to advanced RT delivery centers. The role and potential timing of SRS as an alternative to or in addition to surgery and fractionated RT remain controversial.34

In this retrospective analysis of data from the literature, RT and NoRT SRS strategies showed statistically comparable PFS and OS rates. The data did not reveal any survival difference, and SRS alone after surgery may provide survival rates comparable to those of patients who have RT plus SRS after surgery. However, stratifying our results based on SRS indication was not possible because of the limited data available. Neither could we detect a significant benefit to survival rates between TCA and EEA. This finding may be related to the lack of sufficient data reported on surgical details, tumor volumes, and tumor locations, each of which may favor one approach or the other.

SRS Treatment Outcomes

Although the average survival rate for patients with untreated skull base chordomas ranges from 6 to 24 months, those who undergo adjuvant treatment have better 5-year survival rates, ranging from 50% to 85%.3537 The results of our study align with these rates, showing 5- and 10-year OS rates of 82% and 76%, respectively. The PFS rates of 9% and 3% at 5 and 10 years, respectively, demonstrate the difficulty in controlling these tumors despite both initial resection and adjuvant SRS with or without prior RT. Despite local recurrence rates, multimodal management paradigms including SRS maintained a high 5-year survival rate.

The mean SRS marginal dose in the included studies was 19.8 Gy, and the mean maximum dose was 36.2 Gy. Such doses are considerably higher than those needed to control skull base meningiomas or schwannomas.3841 Additionally, in a recent multicenter study, Pikis et al.42 investigated the impact of SRS on chordomas and found that a marginal dose > 17 Gy had a protective value in the univariate analysis but not the multivariate analysis. These authors also found that a maximal dose > 29 Gy provided a 24% decrease in the likelihood of neurological deterioration and a 40% decrease in the likelihood of tumor progression.

While higher doses are typically required to provide satisfactory outcomes, these come at the expense of ARE risks, suggesting caution during dose planning. In our systematic review, 10 (12.3%) of 81 patients with available data developed AREs. This rate is at the higher end of the range reported in the literature for SRS of skull base tumors (5.4%–11.4%).43 Therefore, close clinical monitoring and imaging surveillance are crucial for early detection and rapid intervention in these patients.

Our univariate analysis revealed a 44% relative risk reduction in tumor progression among males (p < 0.01). In contrast, Rachinger et al.44 investigated the effect of sex on the survival of chordoma patients and found reduced survival among males, who had a shorter median PFS than women (4.8 vs 9.8 years, respectively; p = 0.04). Similarly, Zou et al.45 also found a statistical association between male sex and poor prognosis.

SRS Without RT After Chordoma Surgery

Most recent studies have suggested that initial resection of chordomas should be followed by fractionated proton or photon RT.46,47 Our systematic review demonstrated that outcomes of postsurgery SRS without prior RT were comparable to those of patients who underwent surgery followed by adjuvant fractionated RT prior to SRS. However, the indication for SRS (i.e., adjuvant, boost, or salvage) was not specified for half of the patients in the NoRT group and 14% of those in the RT group; therefore, firm conclusions remain unestablished. The RT and NoRT groups had statistically comparable complication rates (10.9% in postsurgery SRS vs 17.6% in post-RT SRS, p = 0.4). Similarly, Kano et al.48 investigated the effect of GKRS on 71 skull base chordomas in a multivariate analysis and found that, besides younger age and < 2 cranial nerve deficits, avoiding RT was significantly associated with prolonged OS.

Study Limitations

There are several limitations to this study. The heterogeneity of reported data and the small sample size, along with a potential selection bias and the inconsistency of study methodology among the included articles, challenge the robustness of our analysis. Most articles did not clarify the treatment course or surgical details; therefore, the role of surgical treatment was not sufficiently discussed. Most included articles did not specify whether SRS was adjuvant, boost, or salvage treatment for recurrence, and thus presenting our results based on SRS indication was not possible. Various fractionated proton and photon RT techniques were used in the articles but often were not clarified.

The number of cases that had undergone prior RT in our cohort was small, limiting our ability to compare among the different RT modalities before SRS. Complications were not well reported, and accurate rate estimation was limited because of the retrospective nature of the included studies. Tumor histology was seldom reported, and genetic profile was not reported in any articles. These will be increasingly important to note in future reports, as genetic markers are increasingly used to stratify chordomas.

Conclusions

This retrospective outcome study of patients with skull base chordomas in the literature demonstrated that tumor control and survival rates for SRS alone after chordoma surgery were not inferior to those after SRS plus fractionated RT. Future prospective clinical trials that evaluate tumor histology, invasiveness, genetics, and residual volumes after initial resection are necessary to provide additional insight.

Acknowledgments

We thank Kristin Kraus, MSc, for her editorial assistance.

Disclosures

Dr. Lunsford owns stock in Elekta, is a consultant for Teledoc Inc., and serves as the chair of the Data Safety Monitoring Board for Insightec. Dr. Couldwell receives royalties from Bioplate Inc.

Author Contributions

Conception and design: Abou-Al-Shaar, Bin-Alamer. Acquisition of data: Bin-Alamer, Palmisciano, Elarjani. Analysis and interpretation of data: Abou-Al-Shaar, Bin-Alamer, Mallela, Palmisciano, Gersey. Drafting the article: Abou-Al-Shaar, Bin-Alamer. Critically revising the article: Abou-Al-Shaar, Mallela, Gersey, Labib, Zenonos, Dehdashti, Sheehan, Couldwell, Lunsford. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Abou-Al-Shaar. Statistical analysis: Bin-Alamer, Mallela, Palmisciano. Administrative/technical/material support: Bin-Alamer, Gersey, Labib, Couldwell. Study supervision: Abou-Al-Shaar, Sheehan, Couldwell, Lunsford.

Supplemental Information

Online-Only Content

Supplemental material is available online.

References

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    • Crossref
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    Uysal E, Cohen MA, Abou-Al-Shaar H, Palmer C, Couldwell W. Hemorrhagic skull base chordoma presenting as chordoma apoplexy. Cureus. 2021;13(11):e19187.

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    Bakker SH, Jacobs WCH, Pondaag W, et al. Chordoma: a systematic review of the epidemiology and clinical prognostic factors predicting progression-free and overall survival. Eur Spine J. 2018;27(12):30433058.

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    Jones PS, Aghi MK, Muzikansky A, Shih HA, Barker FG II, Curry WTJ Jr. Outcomes and patterns of care in adult skull base chordomas from the Surveillance, Epidemiology, and End Results (SEER) database. J Clin Neurosci. 2014;21(9):14901496.

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    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):542551.

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    • Search Google Scholar
    • Export Citation
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    Henderson FC, McCool K, Seigle J, Jean W, Harter W, Gagnon GJ. Treatment of chordomas with CyberKnife: Georgetown University experience and treatment recommendations. Neurosurgery. 2009;64(2)(suppl):A44A53.

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    • Export Citation
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    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):233238.

    • Crossref
    • Search Google Scholar
    • Export Citation
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    Kondziolka D, Lunsford LD, Flickinger JC. The role of radiosurgery in the management of chordoma and chondrosarcoma of the cranial base. Neurosurgery. 1991;29(1):3846.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Martin JJ, Niranjan A, Kondziolka D, Flickinger JC, Lozanne KA, Lunsford LD. Radiosurgery for chordomas and chondrosarcomas of the skull base. J Neurosurg. 2007;107(4):758764.

    • Crossref
    • Search Google Scholar
    • Export Citation
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    Pedroso AG, De Salles AAF, Frighetto L, et al. Preliminary Novalis experience in the treatment of skull base chordomas with stereotactic radiosurgery and stereotactic radiotherapy. In: Kondziolka D. Radiosurgery. 6th International Stereotactic Radiosurgery Society Meeting, Kyoto, June 2003. Vol 5. Karger; 2004:82-90.

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    • Export Citation
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    • Search Google Scholar
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    • Search Google Scholar
    • Export Citation
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    Howick J, Chalmers I, Glasziou P, et al. The Oxford 2011 Levels of Evidence. Oxford Centre Evidence-Based Medicine. Accessed August 31, 2022. https://www.cebm.ox.ac.uk/resources/levels-of-evidence/ocebm-levels-of-evidence

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    • Search Google Scholar
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    Al-Mefty O. Chordoma. Acta Neurochir (Wien). 2017;159(10):18691871.

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    • Search Google Scholar
    • Export Citation
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    Yaniv D, Soudry E, Strenov Y, Cohen MA, Mizrachi A. Skull base chordomas review of current treatment paradigms. World J Otorhinolaryngol Head Neck Surg. 2020;6(2):125131.

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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    Bin Alamer O, Palmisciano P, Mallela A, et al. stereotactic radiosurgery in the management of petroclival meningiomas: a systematic review and meta-analysis of treatment outcomes of primary and adjuvant radiosurgery. J Neurooncol. 2022;157(2):207219.

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  • Collapse
  • Expand
  • View in gallery
    FIG. 1.

    PRISMA flowchart illustrating the search strategy and data selection based on the inclusion and exclusion criteria.

  • View in gallery
    FIG. 2.

    Kaplan-Meier survival curves for OS (A) and PFS (B) of the entire cohort.

  • View in gallery
    FIG. 3.

    Kaplan-Meier survival curves comparing the OS for TCA and EEA (A, p = 0.88, log-rank test) and for the NoRT group and RT group (B, p = 0.36, log-rank test).

  • 1

    Chauvel A, Taillat F, Gille O, et al. Giant vertebral notochordal rest: a new entity distinct from chordoma. Histopathology. 2005;47(6):646649.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Walcott BP, Nahed BV, Mohyeldin A, Coumans JV, Kahle KT, Ferreira MJ. Chordoma: current concepts, management, and future directions. Lancet Oncol. 2012;13(2):e69e76.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Abou-Al-Shaar H, Gallia G. Intracranial chordoma. In: Neurosurgery Case Review: Questions and Answers. Thieme; 2020:112-115.

  • 4

    Uysal E, Cohen MA, Abou-Al-Shaar H, Palmer C, Couldwell W. Hemorrhagic skull base chordoma presenting as chordoma apoplexy. Cureus. 2021;13(11):e19187.

    • Search Google Scholar
    • Export Citation
  • 5

    Bakker SH, Jacobs WCH, Pondaag W, et al. Chordoma: a systematic review of the epidemiology and clinical prognostic factors predicting progression-free and overall survival. Eur Spine J. 2018;27(12):30433058.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Chambers KJ, Lin DT, Meier J, Remenschneider A, Herr M, Gray ST. Incidence and survival patterns of cranial chordoma in the United States. Laryngoscope. 2014;124(5):10971102.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7

    Jones PS, Aghi MK, Muzikansky A, Shih HA, Barker FG II, Curry WTJ Jr. Outcomes and patterns of care in adult skull base chordomas from the Surveillance, Epidemiology, and End Results (SEER) database. J Clin Neurosci. 2014;21(9):14901496.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Chibbaro S, Cornelius JF, Froelich S, et al. Endoscopic endonasal approach in the management of skull base chordomas–clinical experience on a large series, technique, outcome, and pitfalls. Neurosurg Rev. 2014;37(2):215217.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9

    Koutourousiou M, Gardner PA, Tormenti MJ, et al. Endoscopic endonasal approach for resection of cranial base chordomas: outcomes and learning curve. Neurosurgery. 2012;71(3):614625.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Haubner F, Rachinger W. Multidisciplinary management of clival chordoma. Article in German. Laryngorhinootologie. 2021;100(5):357363.

    • Search Google Scholar
    • Export Citation
  • 11

    Labidi M, Watanabe K, Bouazza S, et al. Clivus chordomas: a systematic review and meta-analysis of contemporary surgical management. J Neurosurg Sci. 2016;60(4):476484.

    • Search Google Scholar
    • Export Citation
  • 12

    Kano H, Lunsford LD. Stereotactic radiosurgery of intracranial chordomas, chondrosarcomas, and glomus tumors. Neurosurg Clin N Am. 2013;24(4):553560.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Ogawa Y, Jokura H, Tominaga T. Midterm prognosis and surgical implication for clival chordomas after extended transsphenoidal tumor removal and gamma knife radiosurgery. BMC Neurol. 2021;21(1):207.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14

    Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.

  • 15

    Förander P, Bartek J Jr, Fagerlund M, et al. Multidisciplinary management of clival chordomas; long-term clinical outcome in a single-institution consecutive series. Acta Neurochir (Wien). 2017;159(10):18571868.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16

    Hafez RFA, Fahmy OM, Hassan HT. Gamma knife surgery efficacy in controlling postoperative residual clival chordoma growth. Clin Neurol Neurosurg. 2019;178:5155.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Cahill J, Ibrahim R, Mezey G, et al. Gamma Knife stereotactic radiosurgery for the treatment of chordomas and chondrosarcomas. Acta Neurochir (Wien). 2021;163(4):10031011.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Cho YH, Kim JH, Khang SK, Lee JK, Kim CJ. Chordomas and chondrosarcomas of the skull base: comparative analysis of clinical results in 30 patients. Neurosurg Rev. 2008;31(1):3543.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Dassoulas K, Schlesinger D, Yen CP, Sheehan J. The role of Gamma Knife surgery in the treatment of skull base chordomas. J Neurooncol. 2009;94(2):243248.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    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):542551.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Henderson FC, McCool K, Seigle J, Jean W, Harter W, Gagnon GJ. Treatment of chordomas with CyberKnife: Georgetown University experience and treatment recommendations. Neurosurgery. 2009;64(2)(suppl):A44A53.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22

    Jiang B, Veeravagu A, Lee M, et al. Management of intracranial and extracranial chordomas with CyberKnife stereotactic radiosurgery. J Clin Neurosci. 2012;19(8):11011106.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23

    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):233238.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24

    Kondziolka D, Lunsford LD, Flickinger JC. The role of radiosurgery in the management of chordoma and chondrosarcoma of the cranial base. Neurosurgery. 1991;29(1):3846.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Martin JJ, Niranjan A, Kondziolka D, Flickinger JC, Lozanne KA, Lunsford LD. Radiosurgery for chordomas and chondrosarcomas of the skull base. J Neurosurg. 2007;107(4):758764.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Pedroso AG, De Salles AAF, Frighetto L, et al. Preliminary Novalis experience in the treatment of skull base chordomas with stereotactic radiosurgery and stereotactic radiotherapy. In: Kondziolka D. Radiosurgery. 6th International Stereotactic Radiosurgery Society Meeting, Kyoto, June 2003. Vol 5. Karger; 2004:82-90.

    • Search Google Scholar
    • Export Citation
  • 27

    Yoo SK, Strickland BA, Zada G, et al. Use of salvage surgery or stereotactic radiosurgery for multiply recurrent skull base chordomas: a single-institution experience and review of the literature. J Neurol Surg B Skull Base. 2021;82(2):161174.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Zorlu F, Gultekin M, Cengiz M, et al. Fractionated stereotactic radiosurgery treatment results for skull base chordomas. Technol Cancer Res Treat. 2014;13(1):1119.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Howick J, Chalmers I, Glasziou P, et al. The Oxford 2011 Levels of Evidence. Oxford Centre Evidence-Based Medicine. Accessed August 31, 2022. https://www.cebm.ox.ac.uk/resources/levels-of-evidence/ocebm-levels-of-evidence

    • Search Google Scholar
    • Export Citation
  • 30

    Munn Z, Barker T, Moola S, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth. 2020;18(10):21272133.

    • Search Google Scholar
    • Export Citation
  • 31

    Al-Mefty O. Chordoma. Acta Neurochir (Wien). 2017;159(10):18691871.

  • 32

    Crockard HA, Steel T, Plowman N, et al. A multidisciplinary team approach to skull base chordomas. J Neurosurg. 2001;95(2):175183.

  • 33

    Gay E, Sekhar LN, Rubinstein E, et al. Chordomas and chondrosarcomas of the cranial base: results and follow-up of 60 patients. Neurosurgery. 1995;36(5):887897.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34

    Yaniv D, Soudry E, Strenov Y, Cohen MA, Mizrachi A. Skull base chordomas review of current treatment paradigms. World J Otorhinolaryngol Head Neck Surg. 2020;6(2):125131.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Amichetti M, Cianchetti M, Amelio D, Enrici RM, Minniti G. Proton therapy in chordoma of the base of the skull: a systematic review. Neurosurg Rev. 2009;32(4):403416.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Boari N, Gagliardi F, Cavalli A, et al. Skull base chordomas: clinical outcome in a consecutive series of 45 patients with long-term follow-up and evaluation of clinical and biological prognostic factors. J Neurosurg. 2016;125(2):450460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Kamrin RP, Potanos JN, Pool JL. An evaluation of the diagnosis and treatment of chordoma. J Neurol Neurosurg Psychiatry. 1964;27(2):157165.

  • 38

    Iwai Y, Yamanaka K, Ikeda H. Gamma Knife radiosurgery for skull base meningioma: long-term results of low-dose treatment. J Neurosurg. 2008;109(5):804810.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39

    Bin Alamer O, Palmisciano P, Mallela A, et al. stereotactic radiosurgery in the management of petroclival meningiomas: a systematic review and meta-analysis of treatment outcomes of primary and adjuvant radiosurgery. J Neurooncol. 2022;157(2):207219.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40

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