Prognostic Factors in Skull Base Chordoma: A Systematic Literature Review and Meta-Analysis

doi:10.1016/j.wneu.2017.10.010

World Neurosurgery

Volume 109, January 2018, Pages 307-327

https://doi.org/10.1016/j.wneu.2017.10.010 Get rights and content

Objective

Currently, there are a lack of reviews assessing the complete range of prognostic factors in skull base chordoma (SBC). This study aimed to systematically review the published literature on prognostic factors in SBC and establish pooled hazard ratios (HRs) of such factors.

Methods

MEDLINE and Embase searches (inception to April 4, 2017) were conducted. Two reviewers independently selected papers involving SBC prognostic factors, and studied them for methodologic quality and valuable factors. Pooled HRs and 95% confidence intervals (CIs) were calculated. The main end points determined were progression-free survival (PFS) and overall survival (OS).

Results

Twenty-two studies with 1754 subjects were included in this systematic review. However, only 18 of the studies provided sufficient data for quantitative synthesis. Preoperative visual deficit (pooled HR, 2.77; 95% CI, 1.57–4.89 for PFS), older patient age (pooled HR, 1.03; 95% CI, 1.1–1.05 for PFS; pooled HR, 1.03; 95% CI, 1.2–1.04 for OS), and nontotal or intralesional tumor resection (pooled HR, 2.01; 95% CI, 1.54–2.62 for PFS; pooled HR, 5.16; 95% CI, 2.27–11.70 for OS) were negative predictors of survival outcomes. However, adjunctive radiotherapy (pooled HR, 0.30; 95% CI, 0.16–0.56) and chondroid chordoma type (pooled HR, 0.5; 95% CI, 0.36–0.69) portended a favorable PFS. In addition, several prognostic biomarkers were promising.

Conclusions

This study demonstrated that several clinicopathologic or molecular parameters are associated with survival up to tumor progression or mortality in SBC patients. However, further methodologically high-quality reports are still required to clarify the effects of these factors.

Introduction

Chordoma is a very rare mesenchymal tumor with a low to intermediate malignant grade¹; it accounts for 1%–4% of all bone malignancies and has an age-adjusted incidence rate of 0.08 per 100,000.2, 3 Chordoma preferentially involves the axial skeleton; the most common site for chordoma occurrence is the sacrum (50%–60%), followed by the skull base region (25%–30%).⁴ Clinically, chordoma responds poorly to conventional chemotherapy or radiation therapy (RT); the mainstay of treatment for chordoma at present is complete surgical resection, which has been reported to offer the best chance of the long-term survival in patients.1, 5, 6, 7, 8, 9 However, a substantial number of patients will have a relapse after surgery, and 5%–40% of patients may develop metastases,7, 8, 9, 10 which pose a big challenge in efficient clinical treatment and predicting the clinical course of the disease. Given the current therapeutic challenge in chordoma, identification of the prognostic factors, especially new predictive markers, that contribute to chordoma prognosis may be helpful to allow stratification of patients into prognostic groups, customize postsurgical monitoring, and improve clinical outcomes of chordoma.

Currently, although many studies have been made to correlate clinical and histopathologic features and molecular biomarkers with chordoma prognosis, the results are still conflicting. Given this, we think a systematic review on prognostic factors in chordoma would be helpful to make a balanced treatment decision in clinical practice. We previously performed a systematic review on prognostic factors in spinal chordoma,11, 12 but there are still a lack of systematic reviews assessing the complete range of such factors in skull base chordoma (SBC). In this study, we aimed to systematically review the prognostic factors in SBC and grade the evidence according to the quality of included studies. We also attempted to establish pooled estimates of the effect of specific prognostic factors by performing a meta-analysis.

Section snippets

Literature Search

We performed an electronic search of MEDLINE and Embase from the start of each database to identify eligible studies. The last search was updated in April 4, 2017. Because SBCs include tumors of the clivus and the first vertebral body,¹³ the key word combinations used were (“chordoma” or “chordomas”) and (“skull base” or “clival” or “clivus” or “cranial” or “intracranial” or “atlas” or “C1”) and (“prognosis” or “prognostic factor” or “survival” or “recurrence” or “relapse” or “mortality” or

Search Results and Paper Selection

A total of 1416 citations were identified through the literature search by using the described search strategy. After initial screening by title and/or abstract for relevance and duplication, 75 full-text articles were then retrieved to evaluate for eligibility. Of these, 19 did not investigate SBC prognostic factors; 10 analyzed spinal chordoma and SBC patients simultaneously; and 24 had ≥1 methodologic flaws, including no multivariate analysis and/or without definition of outcome parameters.

Scope of the Review

In this systematic review, we included 22 studies for qualitative evaluation and 18 publications for meta-analysis. There were 5 factors identified to be independently predictive of poor prognosis in SBC, including older age, visual deficit, classical chordoma subtype, NTR or intralesional tumor resection, and lack of adjunctive RT after surgery. The heterogeneity analysis showed large homogeneity. The sensitivity analysis of most prognostic factors revealed no change in the pooled estimate of

Conclusions

We provided a comprehensive overview of the current knowledge regarding prognostic factors in SBC. With all such analyses, we have found that several clinical or pathologic parameters are associated with survival up to tumor progression or mortality in SBC patients. These data may be helpful in guiding treatment planning to prolong survival and for risk stratification of long-term survival. However, because of heterogeneity of the included studies, interpretation of the results in the present

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Chordoma of the Skull Base: A National Cancer Database Analysis of Current Practice Patterns and Outcomes
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Chordomas of the skull base are aggressive locally destructive tumors that arise from the remnants of the fetal notochord. Current guidelines recommend maximal safe surgical resection followed by adjuvant radiation therapy. However, because of the rarity of these tumors, the optimal radiotherapeutic regimen regarding dose and modality is unclear.
The National Cancer Database (NCDB) was queried from 2004 to 2016. Data from adult patients were extracted, including tumor characteristics, comorbidity indices, and details of treatment (surgery, radiation, and chemotherapy). The primary outcome of interest was overall survival (OS), which was evaluated for specific treatment cohorts using Cox univariate and multivariate regression constructs along with associated survival curves.
We identified 798 patients with a diagnosis of skull base chordoma. Mean OS in this cohort was 9.57 years. Most patients received surgical resection (89.1%), with 53.9% receiving radiotherapy and 6.5% receiving chemotherapy. After adjusting for baseline characteristics using multivariate regression, advanced age and increased tumor size were associated with decreased OS. Surgical resection was associated with increased OS, whereas neither radiotherapy nor chemotherapy was associated with OS. However, in patients who did receive radiation, dosage >6000 cGy was associated with increased OS (hazard ratio, 0.51; P = 0.038); OS did not vary significantly between traditional and proton-based methods.
Our multi-institutional analysis supports the use of partial and radical surgical resection to improve survival in patients with skull base chordomas. Among patients who receive radiotherapy, higher radiation dose is associated with improved survival.
Mediastinal extraosseous chordoma in a teenager: Diagnosis by ultrasound-guided percutaneous biopsy
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Pediatric chordomas are rarely described in the literature with most cases being managed surgically followed by adjuvant radiotherapy for local control. We present a case of an 18-year-old female with thoracic chordoma causing significant mass effect resulting in tracheal deviation, esophageal compression, and splaying of the great vessels. Ultrasound-guided anterior left transcervical percutaneous biopsy of the neck with surgical pathology immunohistochemistry confirmed the presence of chordoma. The patient underwent extensive palliative debulking followed by radiation therapy leading to clinical improvement. This case demonstrated that an ultrasound-guided percutaneous biopsy is an essential procedure in the diagnosis and treatment of chordoma, which led to successful treatment when followed by surgery and radiation.
Operative nuances and surgical limits of the endoscopic approach to clival chordomas and chondrosarcomas: A single-center experience of 72 patients
2021, Clinical Neurology and Neurosurgery
Citation Excerpt :
In a study of Rigante et al. on children who underwent ETS, the level of post-operative pain was lower than that of other children, and they also started doing daily activities, such as eating, playing, and walking, earlier [34]. The possibility of GTR is dependent on the tumor location and surgeon’s experience [8,14,35]. In our series, an increasing experience in endoscopic surgery significantly increases the GTR rates by widening the surgical limitations (p = 0.015).
Gross total resection (GTR) is the mainstay therapy for chordomas and chondrosarcomas to have the best prognosis. The aims of this study were to specify the limits of EEA, emphasize the need for additional combined approaches for tumors beyond these limitations for high resection rates, discuss the prognostic factors and operative nuances that affect GTR, and present the causes and characteristics of early and late recurrences.
We retrospectively analyzed the endoscopic endonasal surgeries in the Pituitary Research Center and Neurosurgery Department of the Kocaeli University Faculty of Medicine, Turkey between January 2004 and December 2019. We retrospectively reviewed the medical data, radiological images, and surgical videos of patients, and 72 patients with chordoma and chondrosarcoma were included in the study.
Based on pathology reports, 72 patients (seven pediatric) were identified, to whom 91 endoscopic operations were performed. We determined the surgical limitations for each clival segment as superior, middle, and inferior. Then, we divided these into three subgroups according to whether the tumor shows dural invasion (extradural chordoma, large extradural - minimal intradural component, and minimal extradural - large intradural component). The tumors of 19 (26.4%), 25 (26.4%), and nine (12.5%) patients originated from the superior, middle, and inferior clivus, respectively. Nineteen (26.4%) patients had panclival involvement. GTR was performed in 47 (65.3%) the patients. The GTR rate in patients with panclival tumors was 47.3% (9/19). The experience, lateralization, dural involvement, and origin of the clivus affecting GTR were analyzed. Extradural – intradural extensions were verified as negative predictor factors for GTR, whereas tumors located in the superior (OR: 16.710, p = 0.030) and middle (OR: 11.154, p = 0.023) segments were positive predictive factors for GTR.
An increasing experience in endoscopic surgery significantly increases the GTR rates by widening the surgical limitations. Due to dense bone infiltration and adhesion to critical neurovascular structures, recurrence rates are high despite performing GTR. Although surgery and adjuvant treatments improve the 5-year survival of patients, the mortality rates remain high. Therefore, surgery of these tumors should be performed by experienced centers. In addition to surgical and adjuvant therapies, targeted molecular and translational biological therapies are also needed for chordomas and chondrosarcomas in the future.
Outcomes, Prognostic Factors and Salvage Treatment for Recurrent Chordoma After Pencil Beam Scanning Proton Therapy at the Paul Scherrer Institute
2020, Clinical Oncology
Citation Excerpt :
We observed that recurrences in patients with skull base chordoma (versus extracranial) and with early post-proton therapy failure (i.e. within 31 months) were predictive of significantly worse DSS. Prognostic factors for chordoma are well described [1,22], but less is known about the prognosis of patients beyond initial disease failure. Raza et al. [17] reviewed 29 patients with recurrent skull base chordoma and found early failure (<6 months from treatment) and distant metastases to portend significantly worse DSS.
The outcome of chordoma patients with local or distant failure after proton therapy is not well established. We assessed the disease-specific (DSS) and overall survival of patients recurring after proton therapy and evaluated the prognostic factors affecting DSS.
A retrospective analysis was carried out of 71 recurring skull base (n = 36) and extracranial (n = 35) chordoma patients who received adjuvant proton therapy at initial presentation (n = 42; 59%) or after post-surgical recurrence (n = 29; 41%). The median proton therapy dose delivered was 74 GyRBE (range 62–76). The mean age was 55 ± 14.2 years and the male/female ratio was about one.
The median time to first failure after proton therapy was 30.8 months (range 3–152). Most patients (n = 59; 83%) presented with locoregional failure only. There were only 12 (17%) distant failures, either with (n = 5) or without (n = 7) synchronous local failure. Eight patients (11%) received no salvage therapy for their treatment failure after proton therapy. Salvage treatments after proton therapy failure included surgery, systemic therapy and additional radiotherapy in 45 (63%), 20 (28%) and eight (11%) patients, respectively. Fifty-three patients (75%) died, most often from disease progression (47 of 53 patients; 89%). The median DSS and overall survival after failure was 3.9 (95% confidence interval 3.1–5.1) and 3.4 (95% confidence interval 2.5–4.4) years, respectively. On multivariate analysis, extracranial location and late failure (≥31 months after proton therapy) were independent favourable prognostic factors for DSS.
The survival of chordoma patients after a treatment failure following proton therapy is poor, particularly for patients who relapse early or recur in the skull base. Although salvage treatment is administered to most patients with uncontrolled disease, they will ultimately die as a result of disease progression in most cases.
Skull base chordomas review of current treatment paradigms
2020, World Journal of Otorhinolaryngology - Head and Neck Surgery
Chordomas are locally invasive neoplasms, arising from notochordal remnants and can appear anywhere along the axial skeleton. Local recurrences are common, and distant metastases may occur years after the initial presentation.
Literature review of current treatment strategies for chordomas of the skull base.
Surgery is the mainstay of treatment and complete resection has paramount importance for prognosis.
When complete resection is not achieved recurrent disease is common. The anatomical complexity of the skull base makes resection complex. Endonasal endoscopic approaches to the clivus has become increasingly favored in recent years although addressing reconstruction of the skull base to prevent CSF leak may be challenging.
Evidence suggests that radiotherapy should not be considered as a primary single modality when trying to achieve cure of the disease. Nonetheless, immediate post-operative radiotherapy improves survival. Many strategies have been suggested to preserve sensitive vital structures in the skull base during treatment but as for survival there is no evidence of advantage when comparing adjuvant therapy with photon radiotherapy, gamma knife surgery, proton beam therapy, and carbon ion radiation therapy.
There is no evidence to support cytotoxic chemotherapy in the treatment of chordomas but targeted therapies have started to show promise. Several optional molecular targets exist. Brachyury is overexpressed in 95% of chordomas but not in other mesenchymal neoplasms. However, its precise role in chordoma pathogenesis is currently unclear, and its cellular location in the nucleus makes it difficult to target. The inhibition of brachyury in chordoma cell lines induces growth arrest and apoptosis. This does not have clinical application to date. There are retrospective results with different molecular targeted therapies for advanced chordomas with some effectiveness.
Despite improvements made in the past 10 years in our knowledge of chordoma biology, available therapies still offer a limited benefit. There is an unmet need for new therapeutic options for patients with advanced disease. Therefore, patients with advanced disease should be encouraged to participate in clinical trials when and where available.
Sellar Tumors
2020, Surgical Pathology Clinics

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: Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Literature ReviewPrognostic Factors in Skull Base Chordoma: A Systematic Literature Review and Meta-Analysis

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Literature Search

Search Results and Paper Selection

Scope of the Review

Conclusions

World Neurosurg

Clin Neurol Neurosurg

Eur J Surg Oncol

World Neurosurg

World Neurosurg

Int J Radiat Oncol Biol Phys

J Clin Neurosci

World Neurosurg

J Clin Neurosci

Int J Radiat Oncol Biol Phys

World Neurosurg

World Neurosurg

World Neurosurg

Spine J

Int J Radiat Oncol Biol Phys

Radiother Oncol

World Neurosurg

J Neurosurg

J Clin Neurosci

World Neurosurg

Hum Pathol

Ann Oncol

Oral Oncol

Operative treatment of sacrococcygeal chordoma. A review of twenty-one cases

J Bone Joint Surg Am

Novel therapeutic targets in chordoma

Expert Opin Ther Targets

Chordoma: incidence and survival patterns in the United States, 1973-1995

Cancer Causes Control

Chordoma: the nonsarcoma primary bone tumor

Oncologist

Current comprehensive management of cranial base chordomas: 10-year meta-analysis of observational studies

J Neurosurg

Operative management of sacral chordoma

J Bone Joint Surg Am

Clinical and pathologic review of 48 cases of chordoma

Cancer

Chordoma: an analysis of twenty cases treated over a twenty-year span

J Surg Oncol

Chordoma: natural history and results in 28 patients treated at a single institution

Ann Surg Oncol

Prognostic factors in spinal chordoma: an update of current systematic review and meta-analysis

J Surg Oncol

The prognostic value of Ki-67, p53, epidermal growth factor receptor, 1p36, 9p21, 10q23, and 17p13 in skull base chordomas

Arch Pathol Lab Med

Evaluation of the quality of prognosis studies in systematic reviews

Ann Intern Med

Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints

Stat Med

A new system for grading recommendations in evidence based guidelines

BMJ

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

Ann Intern Med

Literature Review
Prognostic Factors in Skull Base Chordoma: A Systematic Literature Review and Meta-Analysis