Single-cell sequencing reveals VEGFR as a potential target for CAR-T cell therapy in chordoma.

BACKGROUND: Chordomas are rare osseous neoplasms with a dismal prognosis when they recur. Here we identified cell surface proteins that could potentially serve as novel immunotherapeutic targets in patients with chordoma. METHODS: Fourteen chordoma samples from patients attending Xuanwu Hospital Capital Medical University were subjected to single-cell RNA sequencing. Target molecules were identified on chordoma cells and cancer metastasis-related signalling pathways characterised. VEGFR-targeting CAR-T cells and VEGFR CAR-T cells with an additional TGF-ß scFv were synthesised and their in vitro antitumor activities were evaluated, including in a primary chordoma organoid model. RESULTS: Single-cell transcriptome sequencing identified the chordoma-specific antigen VEGFR and TGF-ß as therapeutic targets. VRGFR CAR-T cells and VEGFR/TGF-ß scFv CAR-T cells recognised antigen-positive cells and exhibited significant antitumor effects through CAR-T cell activation and cytokine secretion. Furthermore, VEGFR/TGF-ß scFv CAR-T cells showed enhanced and sustained cytotoxicity of chordoma cell lines in vitro compared with VRGFR CAR-T cells. CONCLUSIONS: This study provides a comprehensive single-cell landscape of human chordoma and highlights its heterogeneity and the role played by TGF-ß in chordoma progression. Our findings substantiate the potential of VEGFR as a target for CAR-T cell therapies in chordoma which, together with modulated TGF-ß signalling, may augment the efficacy of CAR-T cells.

Unraveling molecular advancements in chordoma tumorigenesis and treatment response: a review of scientific discoveries and clinical implications.

Chordomas are tumors thought to originate from notochordal remnants that occur in midline structures from the cloves of the skull base to the sacrum. In adults, the most common location is the sacrum, followed by the clivus and then mobile spine, while in children a clival origin is most common. Most chordomas are slow growing. Clinical presentation of chordomas tend to occur late, with local invasion and large size often complicating surgical intervention. Radiation therapy with protons has been proven to be an effective adjuvant therapy. Unfortunately, few adjuvant systemic treatments have demonstrated significant effectiveness, and chordomas tend to recur despite intensive multimodal care. However, insight into the molecular underpinnings of chordomas may guide novel therapeutic approaches including selection for immune and molecular therapies, individualized prognostication of outcomes, and real-time noninvasive assessment of disease burden and evolution. At the genomic level, elevated levels of brachyury stemming from duplications and mutations resulting in altered transcriptional regulation may introduce druggable targets for new surgical adjuncts. Transcriptome and epigenome profiling have revealed promoter- and enhancer-dependent mechanisms of protein regulation, which may influence therapeutic response and long-term disease history. Continued scientific and clinical advancements may offer further opportunities for treatment of chordomas. Single-cell transcriptome profiling has further provided insight into the heterogeneous molecular pathways contributing to chordoma propagation. New technologies such as spatial transcriptomics and emerging biochemical analytes such as cell-free DNA have further augmented the surgeon-clinician's armamentarium by facilitating detailed characterization of intra- and intertumoral biology while also demonstrating promise for point-of-care tumor quantitation and assessment. Recent and ongoing clinical trials highlight accelerating interest to translate laboratory breakthroughs in chordoma biology and immunology into clinical care. In this review, the authors dissect the landmark studies exploring the molecular pathogenesis of chordoma. Incorporating this into an outline of ongoing clinical trials and discussion of emerging technologies, the authors aimed to summarize recent advancements in understanding chordoma pathogenesis and how neurosurgical care of chordomas may be augmented by improvements in adjunctive treatments.

The role of systemic therapy in advanced skull base chordomas: overview of the current state and the MD Anderson protocol.

The role of systemic therapy in primary or advanced and metastatic chordoma has been traditionally limited because of the inherent resistance to cytotoxic therapies and lack of specific or effective therapeutic targets. Despite resection and adjuvant radiation therapy, local recurrence rates in clival chordoma remain high and the risk of systemic metastases is not trivial, leading to significant morbidity and mortality. Recently, molecular targeted therapies (MTTs) and immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic avenues in chordoma. In recent years, preclinical studies have identified potential targets based on intrinsic genetic dependencies, epigenetic modulators, or newly identified tumor-associated cell populations driving treatment resistance and recurrence. Nonetheless, the role of systemic therapies in the neoadjuvant or adjuvant setting for primary, locally progressive, and distant metastatic chordomas is still being investigated. Herein, an overview of current and emerging systemic treatment strategies in advanced clival chordoma is provided. Furthermore, several molecular biomarkers have been recently uncovered as potential predictors of the response to specific molecular therapeutics. The authors describe the recently discovered role of 1p36 and 9p21 deletions as biomarkers capable of guiding drug selection. Then they discuss completed and ongoing clinical trials of MTTs, including several tyrosine kinase inhibitors used as monotherapy or in combination, such as imatinib, sorafenib, dasatinib, and lapatinib, among others, as well as mammalian target of rapamycin inhibitors such as everolimus and rapamycin. They present their experience and other recent studies demonstrating vast benefits in advanced chordoma from ICIs. Additionally, they provide a brief overview of novel systemic strategies such as adoptive cell transfer (CAR-T and NK cells), oncolytic viruses, epigenetic targeting (KDM6, HDAC, and EZH2 inhibitors), and several promising preclinical studies with high translational potential. Finally, the authors present their institutional multidisciplinary protocol for the incorporation of systemic therapy for both newly diagnosed and recurrent chordomas based on molecular studies including upfront enrollment in MTT trials in patients with epidermal growth factor receptor upregulation or INI-1 deficiency or enrollment in ICI clinical trials for patients with high tumor mutational burden or high PD-L1 expression on tumor cells or in the tumor microenvironment.

Chordoma: Genetics and Contemporary Management.

Chordomas, arising from notochord remnants, are rare neoplasms with aggressive growth patterns despite their histologically low-grade nature. This review explores their embryological origins, molecular markers like brachyury, and genetic alterations driving pathogenesis. Diagnosis relies on advanced imaging and biopsy confirmation due to overlapping features with chondrosarcoma. The WHO classification distinguishes conventional, dedifferentiated, and poorly differentiated chordomas, each with distinct prognostic implications. Recent genomic analyses uncovered recurrent mutations in PI3K signaling pathways and chromatin remodeling genes, informing prognostic models. Surgery remains the cornerstone of treatment, though adjuvant radiation complements surgical resection. Although chordomas are generally considered refractory to medical therapy, emerging targeted molecular strategies show potential promise in ongoing trials. This review aims to provide a concise yet comprehensive overview of chordomas, guiding clinicians in diagnosis, treatment, and prognostication for improved patient outcomes.

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.

Economics of the Management of Craniospinal Chordoma and Chondrosarcoma and the feasibility of the bundled payment model.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) created a new reimbursement model "Bundled Payment for Care Improvement (BPCI)" which reimburses providers a predetermined payment in advance to cover all possible services rendered within a certain time window. Chordoma and Chondrosarcoma are locally aggressive malignant primary bony tumors. Treatment includes surgical resection and radiotherapy with substantial risk for recurrence which necessitates monitoring and further treatment. We assessed the feasibility of the BPCI model in these neurosurgical diseases. METHODS: We selected patients with chordoma/chondrosarcoma from inpatient admission table using the International Classification of Disease, 9th (ICD-9), and 10th (ICD-10) revision codes. We collected the patients' demographics and insurance type at the index hospitalization. We recorded the following outcomes length of stay, total payment, discharge disposition, and complications for the index hospitalization. For post-discharge, we collected the 30 days and 3/6/12 months inpatient admission, outpatient service, and medication refills. Continuous variables were summarized by means with standard deviations, median with interquartile and full ranges (minimum-maximum); Continuous outcomes were compared by nonparametric Wilcoxson rank-sum test. All tests were 2-sided with a significance level of 0.05. Statistical data analysis was performed in SAS 9.4 (SAS Institute, Inc, Cary, NC). RESULTS: The population size was 2041 patients which included 1412 patients with cranial (group1), 343 patients with a mobile spine (group 2), and 286 patients with sacrococcygeal (group 3) chordoma and chondrosarcoma. For index hospitalization, the median length of stay (days) was 4, 6, and 7 for groups 1, 2, and 3 respectively (P<.001). The mean payments were ($58,130), ($84,854), and ($82,440), for groups 1, 2, and 3 respectively (P=.02). The complication rates were 30%, 35%, and 43% for groups 1, 2, and 3 respectively (P<.001). Twelve months post-discharge, the hospital readmission rates were 44%, 53%, and 65% for groups 1, 2, and 3, respectively (P<.001). The median payments for this period were ($72,294), ($76,827), and ($101,474), for groups 1, 2, and 3, respectively (P <.001). CONCLUSION: The management of craniospinal chordoma and chondrosarcoma is costly and may extend over a prolonged period. The success of BPCI requires a joint effort between insurers and hospitals. Also, it should consider patients' comorbidities, the complexity of the disease. Finally, the adoptionof quality improvement programs by hospitals can help with cost reduction.

Chemoradiotherapy for Unresectable INI1-negative Chordoma in a Child.

The characteristics of chordomas in children are distinct from those in adults. In particular, the prognosis of patients with INI1-negative chordoma is dismal. The standard treatment for localized chordoma, complete surgical resection with a wide margin, is seldom feasible for chordomas arising at the clivus in children, mainly due to associated complications. Therefore, other treatments for unresectable chordomas in children, including chemoradiotherapy, must be explored. Here, we report a 7-year-old girl with an INI1-negative chordoma of the clivus, who responded to conventional chemotherapy plus radiotherapy. Without surgical resection, she remains alive after 1 year and 7 months of the initial diagnosis.

[Chordoma: is there a molecular basis for diagnosis and treatment?] / Chordome: Gibt es eine molekulargenetische Grundlage für Diagnostik und Therapie?

Chordomas are malignant bone tumours with a reported annual incidence of 0.08 per 100,000 cases. They show a notochordal differentiation and are characterised by their nuclear expression of brachyury (TBXT). Chordomas are localised in the axial skeleton, where they occur from the clivus to the sacrococcygeal region. They are slow growing, locally destructive tumours, and are often not diagnosed until they have reached an advanced stage. Putative precursor-lesions are benign notochordal cell lesions, which are microscopically small and intraosseous. Different histological chordoma subtypes exist, which differ in their prognosis. To date, there are no known recurrent genetic drivers for this disease. Brachyury seems to play a key role in the pathogenesis of chordoma, though the detailed mechanism still needs to be elucidated. Surgical en bloc resection with negative margins is the only curative treatment for this disease. High-dose irradiation, particularly with protons and carbon ions, is a therapeutic alternative in cases of inoperable tumours. Currently, there is no approved medical treatment for chordoma. Clinical trials exploring additional therapeutic modalities are ongoing.

[Interpretation of 2020 NCCN Clinical Practice Guidelines in Oncology-Bone Cancer].

The specialty of bone cancer has developed rapidly in China in recent years, but because of the low incidence of these diseases and the unbalanced development of different regions, the malpractice problem of diagnosis and treatment is still outstanding.The NCCN clinical practice guide for bone cancer in the United States has been updated for several years and is now more mature and has been recognized worldwide.It can provide reference for medical professionals in related fields in China, it covers the most common bone tumors such as osteosarcoma, Ewing's sarcoma, chondrosarcoma, giant cell tumor of bone and chordoma.This article describes and interprets the core diagnostic and therapeutic contents of NCCN clinical practice guide for bone cancers.

Y-box binding protein-1 promotes tumorigenesis and progression via the epidermal growth factor receptor/AKT pathway in spinal chordoma.

Chordomas are rare bone tumors with a poor prognosis and no approved targeted therapy. Y-box binding protein-1 (YBX1) promotes tumor growth, invasion and drug resistance. However, the role of YBX1 in chordoma is unclear. In this study, we examined the expression of YBX1 using immunohistochemistry and found that YBX1 was significantly upregulated in 32 chordoma tissues compared to distant normal tissues. In addition, YBX1 upregulation was associated with surrounding tissue invasion, recurrence and poor prognosis. Biological function studies demonstrated that YBX1 promoted cell proliferation and invasion, accelerated G1/S phase transition, and inhibited apoptosis. Further investigation revealed that YBX1 enhanced epidermal growth factor receptor (EGFR) transcription by directly binding to its promoter in chordoma cells. YBX1 regulated protein expression of p-EGFR, p-AKT and its downstream target genes that influenced cell apoptosis, cell cycle transition and cell invasion. YBX1 activated the EGFR/AKT pathway in chordoma and YBX1-induced elevated expression of key molecules in the EGFR/AKT pathway were downregulated by EGFR and AKT pathway inhibitors. These in vitro results were further confirmed by in vivo data. These data showed that YBX1 promoted tumorigenesis and progression in spinal chordoma via the EGFR/AKT pathway. YBX1 might serve as a prognostic and predictive biomarker, as well as a rational therapeutic target, for chordoma.

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.

Survival analysis of patients with spinal chordomas.

This study was aimed to analyze the survival of patients with spinal chordomas. Patients' data in the Surveillance, Epidemiology, and End Results (SEER) database were retrieved and analyzed statistically. There were 765 patients with spinal chordomas between 1974 and 2013. The overall survival did not improve significantly over decades for patients receiving surgery and radiotherapy (SR) (P = 0.221). There were significant differences in overall survival among subgroups of patients receiving surgery (S), radiotherapy (R), and neither S nor R (NSR) (P = 0.031, 0.037, and 0.031, respectively). Cancer-specific survival did not change significantly among subgroups of patients receiving R (P = 0.411), while it increased steadily among subgroups of patients receiving S, SR, and NSR (P < 0.001, 0.001, and 0.049, respectively). In the multivariate Cox regression model, younger onset age (hazard ratio [HR] 1.052, P < 0.001), surgery (HR 0.291, P = 0.001), and tumor location of the sacrum (HR 0.401, P = 0.002) were associated with a better overall survival. Similarly, younger onset age (HR 1.036, P = 0.029), surgery (HR 0.221, P = 0.009), and tumor location of the sacrum (HR 0.287, P = 0.002) were also associated with a higher cancer-specific survival. The changes in overall and cancer-specific survival over time differ among different treatment groups. Younger onset age, surgical strategy, and tumor location of the sacrum may be correlated with a higher overall and cancer-specific survival.

Clinicopathologic characteristics of poorly differentiated chordoma.

Chordoma is a rare malignant tumor of bone with high morbidity and mortality. Recently, aggressive pediatric poorly differentiated chordoma with SMARCB1 loss has been described. This study summarizes the clinicopathologic features of poorly differentiated chordoma with SMARCB1 loss in the largest series to date. A search of records between 1990-2017 at MGH identified 19 patients with poorly differentiated chordoma. Immunohistochemical stains were evaluated. Kaplan-Meier survival statistics and log-rank (Mantel Cox) tests compared survival with other subtypes. The patients (n = 19) were diagnosed at a median age of 11 years (range: 1-29). Tumors arose in the skull base and clivus (n = 10/19; 53%); cervical spine (n = 6/19; 32%); and sacrum or coccyx (n = 3/19; 16%). The clinical stage of these patients (AJCC 7e) was stage 2A (n = 7/16; 44%); stage 2B (n = 6/16; 38%); stage 4A (n = 1/16; 6%); and stage 4B (n = 2/16; 13%). The tumors were composed of sheets of epithelioid cells with nuclear pleomorphism, abundant eosinophilic cytoplasm, and increased mitoses. Tumors were positive for cytokeratin (n = 18/18; 100%) and brachyury (n = 18/18; 100%). Patients were treated with a combination of excision, radiation therapy, and chemotherapy. No difference in overall survival, progression free survival, local control time, and metastasis free survival was identified between poorly differentiated chordoma of the skull base and of the spine. Compared to other chordoma subtypes, poorly differentiated chordoma has a significantly decreased mean overall survival after stratification by site (p = 0.037). Pediatric poorly differentiated chordoma has a distinct clinical and immunohistochemical profile, with characteristic SMARCB1 loss and decreased survival compared to conventional/chondroid chordoma. Recognition of this subtype is important because these malignancies should be treated aggressively with multimodality therapy.

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.

Impact of early access to multidisciplinary care on treatment outcomes in patients with skull base chordoma.

OBJECTIVE: To determine if early access to multidisciplinary surgical care affects outcomes in patients with skull base chordoma. METHOD: A retrospective chart review of prospectively collected data was performed on 51 patients treated from 1993 to 2014. The cohort was divided into those presenting (1) for initial management (ID, n = 21) or (2) with persistent/progressive disease after prior biopsy/surgery (PD, n = 30) outside of a multidisciplinary setting. The impact of initial surgical management in a multidisciplinary center on progression-free survival (PFS) was assessed with Kaplan-Meier and log-rank analyses. RESULTS: Mean follow-up, median PFS, median overall survival (OS), and 10-year OS for the entire cohort was 70 months, 47 months, 159 months, and 19%, respectively. Initial management in a multidisciplinary center resulted in a significant improvement in PFS versus initial surgery with or without radiotherapy (XRT) outside of this setting (64 vs 25 months, p = 0.035). Initial surgical resection outside of a multidisciplinary setting increased the risk of recurrence/progression on univariate (HR, 2.276; p = 0.022) and multivariate analysis (HR, 2.831; p = 0.006), respectively. CONCLUSIONS: The results from this study emphasize the impact that coordinated multidisciplinary surgical care has on patient outcomes for chordomas of the clivus. Biopsy followed by attempted radical resection at a dedicated center does not affect PFS and, therefore, represents a reasonable first step in management for patients presenting outside of multidisciplinary setting.

[Chordoma cutis, an unusual clinical presentation of a rare neoplasm: Chordoma]. / Chordoma cutis, un tableau clinique rare d'une tumeur inhabituelle : le chordome.

Chordoma cutis represents an unusual clinical presentation of a rare neoplasm. The involvement of skin or sub-cutaneous soft tissues can be the consequence of local infiltration or metastasis; the latter may occur several years following the initial diagnosis of chordoma and therefore, may pose a diagnosis challenge when the clinical history of the patient is unknown. The clinical forms, morphology, immuno-histochemical profile and the main differential diagnoses of chordoma cutis are presented here through an anatomoclinical case.

Best practices for the management of local-regional recurrent chordoma: a position paper by the Chordoma Global Consensus Group.

Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.

Chordoma arising from benign multifocal notochordal tumors.

This case reports a 25-year-old woman initially diagnosed with adjacent benign notochordal cell tumors (BNCTs) of L3 and L4 based on needle biopsy of L3 and stable imaging over a 3-year period who was ultimately found to have a chordoma arising from a BNCT at L3. It illustrates the potential relationship between benign and malignant notochordal tumors and the difficulty in distinguishing them by clinical, radiological, and even histopathological means.

Multidisciplinary management of clival chordomas; long-term clinical outcome in a single-institution consecutive series.

OBJECTIVE: Chordomas of the skull base have high recurrence rates even after radical resection and adjuvant radiotherapy. We evaluate the long-term clinical outcome using multidisciplinary management in the treatment of clival chordomas. METHODS: Between 1984 and 2015, 22 patients diagnosed with an intracranial chordoma were treated at the Karolinska University Hospital, Stockholm, Sweden. Sixteen of 22 were treated with Gamma Knife radiosurgery (GKRS) for tumour residual or progression during the disease course. Seven of 22 received adjuvant fractionated radiotherapy and 5 of these also received proton beam radiotherapy. RESULTS: Fifteen of 22 (68%) patients were alive at follow-up after a median of 80 months (range 22-370 months) from the time of diagnosis. Six were considered disease free after >10-year follow-up. The median tumour volume at the time of GKRS was 4.7 cm3, range 0.8-24.3 cm3. Median prescription dose was 16 Gy, range 12-20 Gy to the 40-50% isodose curve. Five patients received a second treatment with GKRS while one received three treatments. After GKRS patients were followed with serial imaging for a median of 34 months (range 6-180 months). Four of 16 patients treated with GKRS were in need of a salvage microsurgical procedure compared to 5/7 treated with conventional or proton therapy. CONCLUSION: After surgery, 7/22 patients received conventional and/or photon therapy, while 15/22 were treated with GKRS for tumour residual or followed with serial imaging with GKRS as needed upon tumour progression. With this multidisciplinary management, 5- and 10-year survivals of 82% and 50% were achieved, respectively.

Maximum surgical resection and adjuvant intensity-modulated radiotherapy with simultaneous integrated boost for skull base chordoma.

BACKGROUND: Local recurrence is common after surgical resection of clivus chordoma. We report the results of maximum surgical resection followed by intensity-modulated radiotherapy with simultaneous integrated boost (IMRT-SIB). METHODS: We reviewed 14 consecutive clivus chordoma cases undergoing postoperative IMRT-SIB using the institutional protocol between 2005 and 2013. Total and near-total resections were achieved in 11 patients (78.6 %), partial in 2 patients (14.3 %), and 1 patient (7.1 %) received RT for recurrent tumor after total resection. Gross residual or the high-risk area defined the planning target volume (PTV)1; PTV2 was the postoperative tumor bed plus a 3-5-mm margin, and PTV3 was PTV2 plus a 5-10 mm margin. A moderate hypofractionation schedule was used: doses to PTV1, PTV2 and PTV3 were 3.9 Gy, 3.15 Gy and 2.8 Gy through 15 fractions for the first two patients, and the rest received 2.5 Gy, 2.2 Gy and 1.8 Gy through 25 fractions. The biologically equivalent dose in 2-Gy fractions (EQD2) was 65-68 Gy for PTV1, 52-56 Gy for PTV2, and 44.3-44.8 Gy for PTV3. RESULTS: Median follow-up was 41 months. Eight patients were free of disease for median 42.5 months (range 23-91 months), four patients had stable disease for median 60.5 months (range 39-113 months), and 1 patient showed partial response for 38 months after RT. Local progression was seen in one patient who received EQD2 67.8 Gy after partial resection. Estimated 5-year progression-free and overall survival rates were 92.9 %. Surgery improved the neurologic deficit in six patients, and IMRT-SIB was well tolerated without lasting toxicity. CONCLUSION: Our experience suggests that maximum resection and high-dose IMRT-SIB can achieve local control without significant morbidities.