Incidence and centralization of chordoma in the Netherlands: A nationwide study between 1991 and 2020.

INTRODUCTION: Chordomas are rare malignant bone tumors arising in the axial skeleton, with an incidence of 0.3-0.88 per million inhabitants. We studied the annual incidence rate and centralization of treatment for chordoma in the Netherlands. METHODS: We retrieved pathology excerpts from the PALGA nationwide Dutch Pathology Registry between 1991 and 2019 for patients with a chordoma to calculate incidence rates. From pathology reports we extracted patient age at diagnosis, sex, year of diagnosis, localization of primary tumor, histologic chordoma subtype (conventional including chondroid, poorly differentiated or dedifferentiated), center of diagnosis (bone tumor referral center (BTC) or other hospital), and partial identification of the BTCs. RESULTS: A total of 420 individual chordoma patients were identified in the given time period. The incidence of chordoma increased from 0.593 per million inhabitants between 1991-1995 to 1.111 from 2015-2019 (P = 0.001). Median age at diagnosis was 63 years (range 1-95), 252 patients (60%) were male. The proportion of samples analyzed in a BTC either primarily or secondary, as a consultation, revision or referral, increased significantly from 29.3% to 84.4% (P < 0.001). Most primary and secondary samples were analyzed at the Leiden University Medical Center (LUMC, 54.4% and 57% respectively). CONCLUSIONS: This study shows an increase in the standardized incidence of pathology proven chordoma in the Netherlands. We observed an increase in samples being analysed in the specialized BTCs as well, which is in line with current guidelines and will hopefully lead to more accurate diagnoses and optimal treatment plans for chordoma patients in specialized treatment centers.

Sacral Chordoma: A Population-based Analysis of Epidemiology and Survival Outcomes.

BACKGROUND/AIM: Sacral chordoma is a rare primary bone neoplasm associated with high morbidity. The aim of this study is to identify demographic and clinicopathological characteristics of this tumor and evaluate their impact on survival outcomes. PATIENTS AND METHODS: The Surveillance, Epidemiology and End Results (SEER) database collecting data between 2000 and 2018 was searched for all cases of sacral chordoma. We analyzed demographic aspects, cancer stage and treatment patterns. Overall survival was calculated using the Kaplan-Meier method and compared between subgroups using the log-rank test. A multivariate Cox hazard regression analysis was conducted to identify independent predictors of overall survival. RESULTS: Four hundred and forty-two patients were identified with a mean age of 62.7 years. Most tumors presented regional invasion at diagnosis (43.2%). Mean overall survival was 124.7 months. No significant difference in terms of overall survival was found between surgery alone and surgery associated with radiotherapy. Both options provided a significantly increased survival than radiotherapy alone. Age of less than 50 years or between 50 and 69 correlated significantly with improved survival. CONCLUSION: Age and stage at diagnosis impact significantly survival outcomes. Surgery remains the mainstay treatment with the highest overall survival. Its association with radiotherapy is currently questionable and needs further research.

Association between TBXT rs2305089 polymorphism and chordoma in Iranian patients identified by a developed T-ARMS-PCR assay.

BACKGROUND: Chordoma is a locally aggressive bone tumor with a high capability of recurrence. Because chordoma often occurs at critical locations next to neurovascular structures, there is an urgent need to introduce validated biomarkers. T-box transcription factor T (TBXT; OMIM: 601397) plays an important role in the pathogenesis and survival of chordoma cells. METHODS: Herein, we aimed to show whether rs2305089 polymorphism is correlated with chordoma in the Iranian population. In order to detect rs2305089, tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) was used. In total, 19 chordoma patients and 108 normal healthy individuals were recruited and screened using T-ARMS-PCR. The results were subsequently validated by Sanger sequencing. RESULTS: The genotype distributions and allele frequencies were significantly different among the patient and healthy groups (p-value <0.05). The A allele of rs2305089 showed a significant positive association with chordoma risk (p-value <0.05). DNA sequencing verified the T-ARMS-PCR results as well. This study demonstrated the association between TBXT rs2305089 and chordoma in an Iranian population using a simple, accurate, and cost-effective T-ARMS-PCR assay. CONCLUSIONS: Our results were in line with those of previous studies showing that TBXT rs2305089 is associated with chordoma development. We also developed an efficient T-ARMS-PCR assay to determine the genotype of rs2305089.

A Novel Nomogram for Predicting Cancer-Specific Survival in Patients With Spinal Chordoma: A Population-Based Analysis.

BACKGROUND: Chordoma is a rare malignant bone tumor, and the survival prediction for patients with chordoma is difficult. The objective of this study was to construct and validate a nomogram for predicting cancer-specific survival (CSS) in patients with spinal chordoma. METHODS: A total of 316 patients with spinal chordoma were identified from the SEER database between 1998 and 2015. The independent prognostic factors for patients with spinal chordoma were determined by univariate and multivariate Cox analyses. The prognostic nomogram was established for patients with spinal chordoma based on independent prognostic factors. Furthermore, we performed internal and external validations for this nomogram. RESULTS: Primary site, disease stage, histological type, surgery, and age were identified as independent prognostic factors for patients with spinal chordoma. A nomogram for predicting CSS in patients with spinal chordoma was constructed based on the above 5 variables. In the training cohort, the area under the curve for predicting 1-, 3-, and 5-year CSS were 0.821, 0.856, and 0.920, respectively. The corresponding area under the curve in the validation cohort were 0.728, 0.804, and 0.839, respectively. The calibration curves of the nomogram showed a high degree of agreement between the predicted and the actual results, and the decision curve analysis further demonstrated the satisfactory clinical utility of the nomogram. CONCLUSIONS: The prognostic nomogram provides a considerably more accurate prediction of prognosis for patients with spinal chordoma. Clinicians can use it to categorize patients into different risk groups and make personalized treatment methods.

Early Major Complications After Radical Resection of Primary C2-Involved Upper Cervical Chordoma Through the Combined Anterior Retropharyngeal-Posterior Approach: Incidence and Risk Factors.

BACKGROUND: We investigated the frequency of postoperative major complications, length of stay (LOS), and associated risk factors for primary C2-involved upper cervical chordoma through the combined anterior retropharyngeal-posterior approach. METHODS: Clinical data were collected from 102 patients with primary C2-involved upper cervical chordoma treated at our institute from January 2016 to January 2021. Additionally, the Changzheng Hospital (CZH) surgical classification system was designed to describe the different anatomic types of C2 chordomas. A multivariate logistic regression analysis was performed and a multivariate Cox proportional hazards model was used to identify the risk factors associated with the occurrence of major complications and prolonged length of stay (LOS), respectively. RESULTS: The incidence of major complication was 29.41% (30 of 102) in our cohort. A long surgical duration (P = 0.001), increased age (P = 0.001), more preoperative comorbidities (P = 0.008) and CZH types indicating extensive tumor involvement (P < 0.001) were identified as significant predictors of the occurrence of a major complication postoperatively. The mean LOS for the entire study population was 21.50 ± 0.64 days. The patients who experienced complications required a significant longer LOS (25.50 ± 1.26 days) than those without complications (19.83 ± 0.65; P < 0.001). The independent factors affecting LOS included age (P = 0.001), Frankel grade (P = 0.001), CZH classification (P < 0.001), and surgical duration (P = 0.001). CONCLUSIONS: Patients who are older, experience longer operative duration, or have larger tumor extension have a greater risk of postoperative major complication. The LOS can be predicted by age, preoperative neurological deficit, CZH classification, surgical approach, and surgical duration. Accordingly, patients with these risk factors should be monitored and targeted with preventative measures.

Chordoma: Current status, problems, and future directions.

Chordoma is a rare tumor that occurs along the axial spine in pediatrics and adults, with an incidence of approximately 350 cases per year in the United States. While typically described as slow-growing, many patients will eventually develop loco-regional relapse or metastatic disease with few treatment options. Despite numerous efforts over the last 10+ years, effective treatments for patients are lacking. As subtypes of chordoma are identified and described in more detail, further knowledge regarding the natural history of each type, tumor location, age differences, genomic variability, and an overall better understanding of chordoma may be the key to developing meaningful clinical trials and effective therapies for patients with chordoma.

Characteristics and overall survival in pediatric versus adult skull base chordoma: a population-based study.

PURPOSE: Less than 5% of chordomas occur in pediatric patients. While many studies have explored the treatment and outcomes of skull base chordomas, few have focused on the differences between pediatric and adult populations. The aim of this study is to analyze the epidemiological variables and clinical outcomes between pediatric and adult skull base chordomas using a large-sample, population-based cancer database. METHODS: The National Cancer Database was queried between 2004 and 2015 for skull base chordomas. We stratified patients as pediatric (<18 years) and adults (≥18 years). We compared several clinical covariates between the two groups. RESULTS: Our cohort consisted of 658 patients, 61 pediatric (9.3%), and 597 adults (90.7%). Pediatric patients were more likely to have larger tumor size (41.4 ± 15.7 mm versus 34.1 ± 15.8 mm, p < 0.01) and universally treated at academic facilities. There was no significant difference in overall survival. CONCLUSIONS: Pediatric skull base chordomas are rare tumors that are managed with aggressive surgical resection, followed by radiation. While there may be difference between tumor presentation, outcomes between pediatric and adult patients are similar.

Epidemiological characteristics of 1385 primary sacral tumors in one institution in China.

BACKGROUND: Sacral tumors and tumor-like lesions are a rare group of lesions that can affect children and adults of all ages. Little is known about clinical characteristics of age, gender, histologic type, and anatomic site in China. METHODS: A total of 1385 patients with sacral tumors and tumor-like lesions, which had the clinical record at our bone tumor center from January 2000 to November 2018 were analyzed. The metastatic cancers were not included in the present study. RESULTS: A total of 51.7% (716 cases) were malignant and 48.3% (669 cases) were benign tumors or tumor-like lesions. Of malignant tumors, chordoma was the most common malignant tumor (316 cases, 22.8% of all tumors), followed by chondrosarcoma, myeloma, and other histologic types. The most common histological type of benign tumors was a giant cell tumor accounting for 14.8% (205 cases) of all tumors, followed by neurofibroma, schwannoma, and other types. The most common age group affected by malignant bone tumors was the 51- to 60-year-old group, followed by the 41- to 50-year-old group. The most commonly affected age group for benign tumors and tumor-like lesions was the 31- to 50-year-old group, followed by the 21- to 30-year old group. Furthermore, the following histologic types had gender predilection. Chordoma, chondrosarcoma, myeloma, and osteosarcoma affected more frequently males than females. Malignant peripheral nerve sheath tumor, lymphoma, giant cell tumor, neurofibroma, tuberculosis, teratoma, and epidermoid cyst more frequently affected females than males. CONCLUSIONS: The large cohort of sacral tumors and tumor-like lesions in our database may reveal their clinical characteristics of age, gender, histologic type, and anatomic site in China and features of sacral tumors and tumor-like lesions are fairly distinct from the mobile spine and extremities.

Apatinib in patients with advanced chordoma: a single-arm, single-centre, phase 2 study.

BACKGROUND: No standard treatment exists for advanced chordoma. Apatinib has been found to have promising efficacy and manageable adverse effects for the treatment of solid tumours. We aimed to investigate the safety and antitumour activity of apatinib in patients with advanced chordoma. METHODS: We did a single-arm, phase 2 study at one tertiary hospital in Shanghai, China. Eligible patients were aged 18-75 years, with histologically confirmed advanced chordoma that was unresectable or resectable only through demolitive surgery, who had previously received surgical treatment, with at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, evidence of tumour progression on enhanced CT or MRI in the previous 6 months, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received oral 500 mg apatinib once daily until disease progression or unacceptable toxicity. The co-primary endpoints were progression-free survival and objective response rate according to RECIST 1.1 and Choi criteria by investigator assessment. Progression-free survival was assessed in the intention-to-treat population. Objective response rate was assessed in the per-protocol population, which included all enrolled patients who were compliant with the protocol and had at least one post-baseline assessment. Safety was analysed in all patients with complete safety data. This study is ongoing, but recruitment is complete. This study is registered with Chictr.org.cn, ChiCTR-OIC-17013586. FINDINGS: Between Aug 21, 2017, and May 31, 2019, we screened 32 patients, of whom 30 were enrolled. Median follow-up was 14·2 months (IQR 9·4-19·7). Of the 27 patients included in the per-protocol population, one patient (3·7%; 95% CI 0-11·3) achieved an objective response according to RECIST, and seven patients (25·9%; 8·3-43·6) achieved an objective response according to Choi criteria. Median progression-free survival was 18 months (95% CI 3-34) according to RECIST and 18 months (3-33) according to Choi criteria. The most common treatment-related grade 3 adverse events were hypertension (seven [24%] of 29 patients) and proteinuria (two [7%]). No treatment-related grade 4 adverse events or treatment-related deaths were observed. INTERPRETATION: To our knowledge, this is the first trial of apatinib for the treatment of advanced chordoma. Apatinib shows promising activity and manageable toxicity and thus might be an option for the treatment of advanced chordoma. FUNDING: None.

Clinical findings in families with chordoma with and without T gene duplications and in patients with sporadic chordoma reported to the Surveillance, Epidemiology, and End Results program.

OBJECTIVE: To gain insight into the role of germline genetics in the development of chordoma, the authors evaluated data from 2 sets of patients with familial chordoma, those with and without a germline duplication of the T gene (T-dup+ vs T-dup-), which was previously identified as a susceptibility mechanism in some families. The authors then compared the patients with familial tumors to patients with sporadic chordoma in the US general population reported to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program through 2015. METHODS: Evaluation of family members included review of personal and family medical history, physical and neurological examination, and pre- and postcontrast MRI of the skull base and spine. Sixteen patients from 6 white families with chordoma had a chordoma diagnosis at family referral. Screening MR images of 35 relatives revealed clival lesions in 6, 4 of which were excised and confirmed to be chordoma. Thus, data were available for 20 patients with histologically confirmed familial chordoma. There were 1759 patients with histologically confirmed chordoma in SEER whose race was known. RESULTS: The median age at chordoma diagnosis differed across the groups: it was lowest in T-dup+ familial patients (26.8 years, range 5.3-68.4 years); intermediate in T-dup- patients (46.2 years, range 11.8-60.1 years); and highest in SEER patients (57 years, range 0-98 years). There was a marked preponderance of skull base tumors in patients with familial chordoma (93% in T-dup+ and 83% in T-dup-) versus 38% in the SEER program (37% in white, 53% in black, and 48.5% in Asian/Pacific Islander/American Indian/Alaska Native patients). Furthermore, 29% of white and 16%-17% of nonwhite SEER patients had mobile-spine chordoma, versus no patients in the familial group. Several T-dup+ familial chordoma patients had putative second/multiple primary chordomas. CONCLUSIONS: The occurrence of young age at diagnosis, skull base presentation, or multiple primary chordomas should encourage careful review of family history for patients diagnosed with chordoma as well as screening of at-risk family members by MRI for early detection of chordoma. Furthermore, given genetic predisposition in some patients with familial chordoma, identification of a specific mutation in a family will permit surveillance to be limited to mutation carriers-and consideration should be given for imaging the entire neuraxis in any chordoma patient presenting at an early age or with a blood relative with chordoma. Finally, future studies should explore racial differences in age at diagnosis and presenting site in chordoma.

Descriptive epidemiology of chordomas in the United States.

PURPOSE: Chordomas account for 1% to 4% of all bone malignancies and 0.5% of all primary intracranial central nervous system tumors. Prior epidemiologic literature is based on limited population data. The purpose of this study is to provide the largest and most inclusive population based study of the descriptive epidemiology of chordomas. METHODS: The Centers for Disease Control and Prevention and National Program of Cancer Registries were queried for chordoma in all locations. Age-adjusted incidence per 100,000 persons was calculated by age, sex, race, and ethnicity. Annual percentage change was calculated using Joinpoint. RESULTS: From 2004 to 2014, a total of 3670 chordomas were diagnosed in the US. The most common location was cranial (38.7%), followed by sacral (34.3%) and spinal (27.0%). The average age-adjusted incidence rate was 0.088 per 100,000 persons per year (95% CI 0.086-0.091), with an annual percentage change of 1.29% (95% CI 0.31-2.28%). For all chordomas, the incidence peaks in the 75-84 year age group. The male-to-female incidence rate ratio is 1.54 (p < 0.001). American Indian/Alaskan Native and Black patients had a statistically lower incidence rate than White and Asian/Pacific Islander patients. CONCLUSION: Approximately 0.088 chordomas per 100,000 persons are newly diagnosed in the US each year, with cranial location being the most common, followed by sacral and spinal. Incidence increases with age, and men are at a significantly higher risk than women. This investigation represents the largest population-based epidemiologic study of chordomas in the US.

Epidemiologic and survival trends in adult primary bone tumors of the spine.

BACKGROUND CONTEXT: Malignant primary spinal tumors are rare making it difficult to perform large studies comparing epidemiologic, survival, and treatment trends. We investigated the largest registry of primary bone tumors, the National Cancer Database (NCDB), to compare epidemiologic and survival trends among these tumors. PURPOSE: To use the NCDB to describe current epidemiologic trends, treatment modalities, and overall survival rates in patients with chordomas, osteosarcomas, chondrosarcomas, and Ewing sarcomas of the mobile spine. The secondary objective was to determine prognostic factors that impact overall survival rates. STUDY DESIGN: Retrospective study. PATIENT SAMPLE: A total of 1,011 patients with primary bone tumors of the spine (377 chordomas, 223 chondrosarcomas, 278 Ewing sarcomas, and 133 osteosarcomas). OUTCOME MEASURES: Five-year survival. METHODS: We reviewed the records of 1,011 patients in the NCDB from 2004 through 2015 with histologically confirmed primary osteosarcoma, chondrosarcoma, Ewing sarcoma, or chordoma of the spine. Demographic, clinical, and outcomes data were compiled and compared using chi-squared tests and ANOVA. Long-term survival was compared using the Kaplan-Meier method with statistical comparisons based on the log-rank test. Multivariate analysis was performed to determine survival determinants. RESULTS: Surgical resection was the primary mode of treatment for chondrosarcoma (90%), chordoma (84%), and osteosarcoma (80%). The treatment for Ewing sarcoma was multimodal involving chemotherapy, radiation therapy, and surgical resection. Five-year survival rates varied significantly with chordomas and chondrosarcomas having the greatest survival (70% and 69%), osteosarcomas having the worse survival (38%), and Ewing having intermediate 5-year survival at 62% (overall log-rank p<.0001). Multivariate analysis demonstrated significantly improved 5-year survival rates with younger age at diagnosis, private insurance status, lower comorbidity score, lower tumor grade, smaller tumor size, surgical resection, and negative surgical margin. Radiation therapy only improved survival for Ewing sarcoma. CONCLUSIONS: This study provides the most comprehensive description of the epidemiologic, treatment, and survival trends of primary bone tumors of the mobile spine. Second, patient and tumor characteristics associated with improved 5-year survival were identified using a multivariate model.

Evaluating the Role of Adjuvant Radiotherapy in the Management of Sacral and Vertebral Chordoma: Results from a National Database.

BACKGROUND: Chordomas are slow-growing but locally invasive tumors. The standard of care consists of surgical resection and radiotherapy (RT) when complete resection is not possible. The reported data has reached equivocal results regarding the effect of adding RT to increase patient survival. We investigated the effect of adjuvant RT on patient survival. METHODS: The National Cancer Database was queried for patients with a diagnosis of sacral and vertebral column chordoma from 2004 to 2010. The primary outcome was overall survival, which was assessed using Kaplan-Meier plots. Cox proportional hazards were performed to evaluate the effect of each treatment modality on survival after adjusting for an array of patient demographics, facility type, and tumor characteristics. RESULTS: The data from 282 patients with chordoma were analyzed; 209 patients (74.1%) had undergone gross total resection (GTR) alone. The median follow-up period for the GTR alone and GTR plus RT groups was 63.4 and 67.6 months, respectively. The mean survival was comparable between patients receiving GTR alone and those receiving adjuvant RT, for both sacral (7.7 and 6.9 years, respectively; P = 0.56) and vertebral chordoma (8.8 and 6.2 years, respectively; P = 0.59). Using Cox proportional hazards, we found that compared with GTR alone, GTR plus adjuvant RT did not add any significant survival benefit, for patients with either sacral chordoma (hazard ratio, 0.55; P = 0.43) or vertebral chordoma (hazard ratio, 7.29; P = 0.23). CONCLUSION: Using data from a large national cancer registry, we found that the available evidence is not enough to suggest that the addition of RT offers a survival benefit for patients with sacral and spinal chordoma after GTR. Given the non-negligible complications associated with RT, the balance of benefits and risks must be considered during preoperative tailoring of the treatment decisions.

Sacral chordoma: a clinical review of 101 cases with 30-year experience in a single institution.

BACKGROUND: Local recurrence rates are high in sacral chordoma patients. Adjuvant radiotherapy may play a role in increasing local control. Patients with locally recurrent tumors continue to comprise a significant proportion of the sacral chordoma population and appear to have worse prognosis than those with primary tumors. High-quality studies comparing presentation and treatments for primary and first local recurrent sacral chordoma tumors are sparse. PURPOSE: To determine: whether there is a difference in how primary and tumors at first recurrence present; the overall survival, local relapse-free survival, and distant relapse-free survival rates and prognostic factors for patients presenting with a primary tumor; overall survival, local relapse-free survival, and distant relapse-free survival rates and prognostic factors for patients presenting with a first local relapse; if there any differences in overall survival, local relapse-free survival, and distant relapse-free survival rates between patients presenting with a primary tumor and those with a first local relapse. STUDY DESIGN: Retrospective case series. PATIENT SAMPLE: One hundred one sacral chordoma cases. OUTCOME MEASURE: Overall survival, local relapse-free survival, and distant relapse-free survival rates. METHODS: Between 1978 and 2013, 131 patients with sacral chordoma were seen. Of them, 17 patients (13%) presented with a history of more than one local recurrence. One patient (1%) presented with multiple distant metastases. Ten patients (8%) had less than 36 months of follow-up and had no event (eg, death, local recurrence, or distant metastasis). A total of 102 patients met our inclusion criteria: patients with primary or first recurrent tumors, without metastatic disease, who underwent surgery and with at least 36 months of follow-up. One patient (1%) died intraoperatively; therefore, 101 patients were included in the present analysis. Cox proportional hazards regression analysis was performed for primary and local recurrent tumor separately and to compare primary and local recurrent tumors. RESULTS: We analyzed 73 primary and 28 first time recurrent sacral chordomas. Tumor size at presentation was different for primary and recurrent tumors (primary median size: 158 cm3, interquartile range [IQR]: 46-634; recurrent median size: 39 cm3, IQR: 14-175; p=.001). Overall survival at 5 and 10years for the primary tumors was 79% and 59%, respectively. Local relapse-free survival at 5years was 86%. For primary tumors, not receiving radiation was an independent predictor for worse local relapse-free survival (hazard ratio [HR]: 0.20; 95% confidence interval [CI]: 0.0043-0.90; p=.004) and increased tumor size was an independent predictor for both worse overall survival (HR: 1.68; 95% CI: 1.38-2.42; p=.004) and worse distant relapse-free survival (HR: 2.25; 95% CI: 1.47-3.44; p<.001). For recurrent tumors, the 5- and 10-year overall survival was 65% and 40%, respectively. Local relapse-free survival at 5years was 79% for recurrent tumors. On bivariate analysis, increased tumor size was a significant predictor for worse survival (LR median: 338 mL; IQR: 218-503 mL; no LR median: 26 mL; IQR: 9-71 mL). A trend was seen toward better distant relapse survival for tumors presenting as a primary tumor (HR: 0.51; 95% CI: 0.25-1.06; p=.072). CONCLUSION: Using a combination of surgical resection and adjuvant radiotherapy allowed us to obtain a good overall survival, local relapse-free survival, and distant relapse-free survival in patients presenting with either a primary tumor or with a first time local recurrent tumor.

Chordoma: update on disease, epidemiology, biology and medical therapies.

PURPOSE OF REVIEW: Chordoma is an exceedingly rare subtype of bone sarcoma. This review aims to provide a comprehensive insight into chordoma epidemiology, and an update on the recent advances in disease, biology and medical therapies. RECENT FINDINGS: The incidence of chordoma is approximately 0.08/100 000 and the 5-year overall age-adjusted relative survival is 72% in the United States and 61% in Europe. Over the last years, significant steps forwards have been done in the comprehension of chordoma complexity, with insights gained into the biology and morphology of this disease. New entities have been described and potentially druggable molecular targets identified. This is becoming all the more relevant today, as new potentially active agents are under development. SUMMARY: Chordoma is a complex disease because of its rarity, biological heterogeneity and peculiar clinical behaviour. Despite the progress done, the outcome in this disease remains unsatisfactory and the identification of active systemic treatments remains an urgent, unmet medical need.

Chordoma: a systematic review of the epidemiology and clinical prognostic factors predicting progression-free and overall survival.

BACKGROUND AND AIMS: The aim of this systematic review is to describe the epidemiology of chordoma and to provide a clear overview of clinical prognostic factors predicting progression-free and overall survival. METHODS: Four databases of medical literature were searched. Separate searches were performed for each of the two objectives. Reference and citation tracking was performed. Papers were processed by two independent reviewers according to a protocol that included risk of bias analysis. Disagreement was resolved by discussion. Pooled analyses were planned if homogeneity of data would allow. RESULTS: Incidence-incidence rates ranged between 0.18 and 0.84 per million persons per year and varied between countries and presumably between races. On average patients were diagnosed in their late fifties and gender data indicate clear male predominance. Two of the largest studies (n = 400 and n = 544) reported different anatomical distributions: one reporting the skull base and sacrococcygeal area affected in 32% and 29% of cases, whereas the other reporting that they were affected in 26% and 45% of cases, respectively. PROGNOSTIC FACTORS: Statistically significant adverse prognostic factors predicting progression-free and overall survival include female sex, older age, bigger tumour size, increasing extent of tumour invasion, non-total resection, presence of metastasis, local recurrence, and dedifferentiated histological subtype. CONCLUSIONS: Incidence rate and anatomical distribution vary between countries and presumably between races. Most chordomas arise in the skull base and sacrococcygeal spine, and the tumour shows clear male predominance. Multiple adverse prognostic factors predicting progression-free and overall survival were identified in subgroups of patients. These slides can be retrieved under Electronic Supplementary Material.

Surgical Treatment of Sacral Chordoma: En Bloc Resection with Negative Margins is a Determinant of the Long-Term Outcome.

STUDY DESIGN: Retrospective case series. OBJECTIVE: To report the outcome of a series of patients with sacral chordoma who were surgically treated at a single center. SUMMARY: Chordomas are low-grade malignant tumors that arise from remnants of the notochord. They are most often found in the sacrum, spine and skull-base. These tumors have a slow clinical evolution and may eventually metastasize, even after adequate treatment. Rarely, they can dedifferentiate into high-grade sarcomas. Traditionally, chordomas were considered to be resistant to chemotherapy and standard radiation therapy. However, recently, adrotherapy has been shown to be effective for local and systemic control of the disease. In this study, clinical outcomes and local and systemic recurrence were reviewed to identify prognostic factors for local and systemic control. METHODS: Thirty-three patients with sacral chordoma (19 males, 14 females; median age 61 y, range 43-80) who were surgically treated at our institution between 1994 and 2015 were reviewed. In 24 patients, resection was performed above S2. No patients received pre-operative radiotherapy (RT). Three cases received RT (carbon ion therapy) as treatment for local recurrence. Wide (R0) surgical margins were achieved in 17 patients, marginal (R1) margins in 14 patients and intralesional (R2) margins in 2 patients. RESULTS: At a median follow-up of 53 months (range 0-198), 19 patients were continuously disease-free, 6 were disease-free after local recurrence (5) or metastases (1), 3 were alive with disease (2 local recurrence and 1 metastasis), 4 were dead of disease (1 patient died intraoperatively) and 1 was dead of another cause. Local recurrence was observed in 9 cases (27%); all 9 were treated surgically and 3 received carbon ion therapy after surgical intralesional excision. Overall survival at 10 years was 86.6%. Local recurrence-free survival at 10 years was 51%. A statistical analysis confirmed the importance of negative surgical margins (R0) to achieve local control of the disease (p = 0.0007). High resections (above S2) were associated with lower survival and higher risk of local recurrence. CONCLUSION: Surgical en bloc resection is the primary treatment for sacral chordoma. Carbon ion therapy is used when it is difficult to obtain wide surgical margins. Due to morbidity and the disabling sequelae of surgery, adrotherapy may be considered an alternative to high (above S2-S3) sacral chordoma resections.

Variables affecting functional improvement in chordoma patients admitted to an inpatient rehabilitation facility: A retrospective review.

STUDY DESIGN: Retrospective chart review of patients after surgical resection of chordoma admitted to an inpatient rehabilitation facility. OBJECTIVE: To evaluate the characteristics associated with improving two or more functional levels and therefore classifying as a substantial responder after an inpatient rehabilitation facility stay in post-resection chordoma patients. SETTING: Acute inpatient rehabilitation facility in the United States. METHODS: A total of 40 patients were admitted to an inpatient rehabilitation facility from 2010-2015 after chordoma resection. Demographics, tumor management information, lengths of stay and functional independence measures on admission and discharge were collected. Substantial responders were identified as individuals who improved two or more functional levels based on total FIM score change. Logistic regression was used to analyze the available data for association of quantitative and categorical variables with being a substantial responder. RESULTS: The categorical variables analyzed in this study (sex, readmission to an acute hospital, Charlson Comorbidity Index, tumor level, nerve sacrifice, recurrent tumor and metatases) were not associated with being a substantial responder. The quantitative variables age and length of stay at the inpatient rehabilitation facility were individually associated with being a substantial responder, while length of stay at the acute hospital was not. CONCLUSIONS: Patients who were younger were more likely to be classified as substantial responders. Patients with longer lengths of stay at the inpatient rehabilitation facility were also more likely to be classified as substantial responders.

Long-Term Results Following Surgical Resection of Chordomas in the Craniocervical Junction and the Upper Cervical Spine: Review of 12 Consecutive Cases.

BACKGROUND: Since chordoma is refractory to chemotherapy and conventional radiotherapy, radical surgical resection is mandatory. However, it is surgically demanding in the craniocervical junction (CCJ) and upper cervical spine. OBJECTIVE: To analyze long-term surgical results of cervical chordomas. METHODS: We retrospectively reviewed 12 consecutive patients who underwent surgical treatment for CCJ or upper cervical chordomas from 2001 to 2009 in 2 academic institutions. We analyzed the progression-free survival and overall survival and compared the results between gross total resection (GTR) cases and partial resection (PR). Complications were analyzed by comparing primary and recurrent tumor. We also delineated the type of radiotherapy. RESULTS: Of the 12 patients, 5 underwent GTR and 7 underwent PR. GTR of the tumor was achieved by intralesional piecemeal removal. No recurrence occurred in the GTR group. PR group had 6 cases of regrowth (85.7%). Ten patients (83.3%) underwent any kind of radiation therapy. There were 3 (60%) patients in the GTR group and 7 (100%) in the PR group. Compared to PR, GTR revealed a better 3-yr progression-free survival rate (100% vs 14.3%) as well as a better 3-yr overall survival rate (100% vs 71.4%). Surgical complication rate (40% for GTR vs 42.9% for PR) was not significantly different between the groups. The surgical complication rates of primary and revision surgery were 25% and 75%, respectively. Complication associated with radiation occurred in 2 patients. CONCLUSION: Gross total intralesional piecemeal resection with perioperative radiation therapy is an acceptable strategy for CCJ and the upper cervical chordoma management.

Iatrogenic seeding of skull base chordoma following endoscopic endonasal surgery.

OBJECTIVE: Iatrogenic tumor seeding after open surgery for chordoma has been well described in the literature. The incidence and particularities related to endoscopic endonasal surgery (EES) have not been defined. METHODS: The authors retrospectively reviewed their experience with EES for clival chordoma, focusing on cases with iatrogenic seeding. The clinical, radiographic, pathological, and molecular characterization data were reviewed. RESULTS: Among 173 EESs performed for clival chordomas at the authors' institution between April 2003 and May 2016, 2 cases complicated by iatrogenic seeding (incidence 1.15%) were identified. The first case was a 10-year-old boy, who presented 21 months after an EES for a multiply recurrent clival chordoma with a recurrence along the left inferior turbinate, distinct from a right petrous apex recurrence. Both appeared as a T2-hypertintense, T1-isointense, and heterogeneously enhancing lesion on MRI. Resection of the inferior turbinate recurrence and debulking of the petrous recurrence were both performed via a purely endoscopic endonasal approach. Unfortunately, the child died 2 years later due progression of disease at the primary site, but with no sign of progression at the seeded site. The second patient was a 79-year-old man with an MRI-incompatible pacemaker who presented 19 months after EES for his clival chordoma with a mass involving the floor of the left nasal cavity that was causing an oro-antral fistula. On CT imaging, this appeared as a homogeneously contrast-enhancing mass eroding the hard palate inferiorly, the nasal septum superiorly, and the nasal process of the maxilla, with extension into the subcutaneous tissue. This was also treated endoscopically (combined transnasal-transoral approach) with resection of the mass, and repair of the fistula by using a palatal and left lateral wall rotational flap. Adjuvant hypofractionated stereotactic CyberKnife radiotherapy was administered using 35 Gy in 5 fractions. No recurrence was appreciated endoscopically or on imaging at the patient's last follow-up, 12 months after this last procedure. In both cases, pathological investigation of the original tumors revealed a fairly aggressive biology with 1p36 deletions, and high Ki-67 levels (10%-15%, and > 20%, respectively). The procedures were performed by a team of right-handed surgeons (otolaryngology and neurosurgery), using a 4-handed technique (in which the endoscope and suction are typically passed through the right nostril, and other instruments are passed through the left nostril without visualization). CONCLUSIONS: Although uncommon, iatrogenic seeding occurs during EES for clival chordomas, probably because of decreased visualization during tumor removal combined with mucosal trauma and exposure of subepithelial elements (either inadvertently or because of mucosal flaps). In addition, tumors with more aggressive biology (1p36 deletions, elevated Ki-67, or both) are probably at a higher risk and require increased vigilance on surveillance imaging and endoscopy. Further prospective studies are warranted to evaluate the authors' proposed strategies for decreasing the incidence of iatrogenic seeding after EES for chordomas.