Chordoma
Chordoma is a slow-growing bone cancer of the skull base and spine that arises from leftover embryonic notochord cells. Complete surgery followed by high-dose proton or carbon-ion radiotherapy controls most tumours, and the whole disease depends on a single transcription factor, brachyury, which vaccines and degraders are now trying to hit.
Overview
Chordoma arises from notochordal remnants along the axial skeleton (clivus, mobile spine, sacrum). Nearly all tumours express the T-box transcription factor brachyury (TBXT), a lineage dependency rather than a mutation: a common germline TBXT variant raises risk, and germline TBXT duplication causes familial chordoma. Conventional and chondroid chordomas are indolent but locally destructive; dedifferentiated and poorly differentiated chordomas are aggressive. Poorly differentiated chordoma, seen mainly in children, is defined by SMARCB1 (INI1) loss, placing it in the SWI/SNF-deficient family with epithelioid sarcoma and ATRT.
Curative treatment is en bloc resection with negative margins where anatomy permits, followed by high-dose radiotherapy, because the tumour is radioresistant at conventional doses and sits against the brainstem, cranial nerves or sacral roots. Proton and carbon-ion therapy deliver 70 Gy-equivalent or more while sparing neural tissue, and definitive particle therapy is used when resection is impossible. Systemic options are limited: imatinib (PDGFRB-expressing disease, phase 2 Stacchiotti 2012) and afatinib (EGFR) give disease stabilisation more often than shrinkage, and are not approved. Tazemetostat is being studied in INI1-negative poorly differentiated chordoma on the basis of its epithelioid sarcoma activity.
The frontier is brachyury itself: a yeast-based brachyury vaccine (GI-6301) and adenoviral brachyury vaccines have been tested with radiotherapy, and brachyury degraders and CDK7/9 inhibitors that lower TBXT expression are in preclinical or early clinical development. The Chordoma Foundation coordinates a global registry, biobank and drug-screening pipeline, a model for how a rare cancer community can run its own research programme.
State of the art today
- Particle therapy after maximal surgery has made long-term local control the expected outcome for skull-base chordoma, with less neurological injury than photon plans.
- Brachyury is now recognised as the lineage dependency of the disease: TBXT knockdown is lethal to chordoma cells, and vaccines plus degraders that target it are the main mechanistic bets.
- SMARCB1-deficient poorly differentiated chordoma in children is being treated with EZH2 inhibition borrowed from epithelioid sarcoma, an example of biology-based rather than histology-based drug repurposing.
- Patient-led infrastructure (the Chordoma Foundation's registry, cell-line bank and prize-driven drug screens) has produced most of the field's preclinical models.
Where it starts and where it drains
Bone sarcomas favour the fast-growing ends of long bones (osteosarcoma) or the shaft (Ewing), soft tissue sarcomas the deep muscle compartments; spread is through the blood to the lungs, rarely via lymph nodes.
- Metaphysis, near the growth plate (osteosarcoma)Conventional chordoma
- Shaft (Ewing sarcoma)
- Deep soft tissue compartmentConventional chordoma · Chondroid chordoma · Dedifferentiated chordoma · Poorly differentiated chordoma (SMARCB1/INI1-deficient, mostly paediatric skull base)
- Skeletal muscle (rhabdomyosarcoma)
- Neurovascular bundle (limb salvage decision)
Lymph node spread is rare (except epithelioid, synovial, clear cell and rhabdomyosarcoma); sarcomas go through the blood to the lungs.
Same organ: Sarcomas (soft tissue, bone, GIST), Osteosarcoma, Ewing sarcoma, Rhabdomyosarcoma, Desmoid tumour, Tenosynovial giant cell tumour (TGCT), Epithelioid sarcoma, Vascular tumours (angiosarcoma, epithelioid haemangioendothelioma, kaposiform haemangioendothelioma)
About one case per million people per year, at any age; skull-base tumours are more common in children, sacral tumours in older adults.
- AI in radiologyEstablished
- cfDNA fragmentomicsEstablished
- Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)Standard of care
- DNA methylation profilingEstablished
- HCC surveillance in cirrhosis (ultrasound + AFP)Standard of care
- High-risk pancreatic surveillance (CAPS / PRECEDE)Established
- A 28-day national pathway for people with a positive multi-cancer blood test
- A breath test to rule out cancer in people with vague symptoms
- A cancer blood test for older people arriving at A&E with unexplained symptoms
- A legislated, publicly reported 28-day standard from urgent referral to diagnosis
- A live national dashboard of stage at diagnosis as the scorecard for early detection
- A single 'cancer check at 60' appointment bundling all screening tests
Background: Alpha-fetoprotein (AFP), Barrett's oesophagus, CA 19-9, Early detection, Faecal immunochemical test (FIT). Also on OnCo: Symptoms and red flags · Early detection roadmap.
Where the cases are
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
En bloc resection with negative margins by a spine or skull-base team, followed by high-dose proton or carbon-ion radiotherapy; intralesional surgery is associated with early recurrence.
Definitive particle therapy (proton or carbon-ion) to 70 Gy-equivalent or higher; stereotactic photon radiosurgery where particles are unavailable.
Clinical trial preferred. Imatinib (PDGFRB-positive), afatinib or other EGFR inhibitors, or sorafenib give mainly disease stabilisation; tazemetostat for INI1-negative poorly differentiated chordoma.
Subtypes & biomarkers
top- Conventional chordoma
- Chondroid chordoma
- Dedifferentiated chordoma
- Poorly differentiated chordoma (SMARCB1/INI1-deficient, mostly paediatric skull base)
- Brachyury (TBXT) nuclear immunostaining (diagnostic)
- SMARCB1/INI1 loss (poorly differentiated subtype)
- PDGFRB and EGFR expression (drug selection in trials)
- Germline TBXT duplication (familial chordoma)
- Surgical margin status and location (skull base vs sacrum)
Target prevalence in this cancer
- 1857Virchow describes chordoma
First description of the notochord-derived tumour.
- 2006Brachyury identified as a chordoma marker
Vujovic and colleagues show near-universal nuclear brachyury expression.
- 2009Germline TBXT duplication in familial chordoma
Yang and colleagues (Nat Genet).
- 2012Imatinib phase 2 in advanced chordoma
Stacchiotti and colleagues: disease stabilisation in most patients, few objective responses.
- 2015Chordoma Global Consensus Group
First international recommendations on surgery, radiotherapy and systemic therapy (Lancet Oncol).
- 2020Poorly differentiated chordoma recognised as SMARCB1-deficient entity
WHO classification of soft tissue and bone tumours, fifth edition.
- 2021Brachyury vaccine plus radiotherapy tested
Phase 2 of GI-6301 yeast-brachyury vaccine with radiation (NCT02383498).
Open problems, and what is being done about each
No approved systemic therapy: trials of brachyury-directed vaccines, degraders and EGFR inhibitors are the response.
Recurrent skull-base disease after full-dose radiotherapy: re-irradiation with particles and salvage surgery are being studied.
and how the field plans to fix it →What is being done about thisRecurrence and residual diseaseAvailable now- Liquid biopsy (ctDNA)Standard of care
- MRD / molecular residual disease testingEstablished
- Multiparameter flow cytometry MRDStandard of care
- NGS-based MRD (clonoSEQ and molecular MRD)Standard of care
- SignateraEstablished
- Structured exercise programmes after curative treatmentEstablished
In trials- ADAURAPositive
- CAMBRIA-1 & CAMBRIA-2Recruiting
- CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)Active
- ctDNA monitoring in lymphoma (PhasED-seq, clonoSEQ)Emerging
- DYNAMICPositive
- IMvigor011Positive
Ideas and roadmaps- A blood test for the pre-metastatic niche
- A bone marrow niche on a chip to study human dormancy
- A dedicated clinic for people whose blood test says the cancer is back
- A drug screen that only rewards killing sleeping cancer cells
- A national platform trial that every ctDNA-positive patient can join
- A national residual-disease weather service: serial blood tests for every curatively treated patient, pooled
Background: Circulating tumour DNA (ctDNA), Disseminated tumour cells (DTCs), Late recurrence, Minimal / molecular residual disease (MRD), MRD negativity (myeloma, 10⁻⁵ / 10⁻⁶). Also on OnCo: Treatment journeys · Survivorship planner.
Paediatric poorly differentiated chordoma: tazemetostat and SWI/SNF-directed trials.
Access to particle therapy, which remains concentrated in a few countries.
and how the field plans to fix it →What is being done about thisCost and accessAvailable now- ImatinibApproved
- HPV & HBV vaccinationStandard of care
- Trastuzumab biosimilarsApproved
In trials- Gefitinib vs gefitinib plus pemetrexed-carboplatin in EGFR-mutant lung cancer (Tata Memorial)Positive
- IARC India HPV vaccine dose study (one, two or three doses)Positive
- IMAGINE (varnimcabtagene autoleucel, Immuneel)Positive
- Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial)Positive
- Low-dose olanzapine for cancer anorexia (Tata Memorial)Positive
- METRO PLUS (Tata Memorial Centre, Varanasi)Positive
Ideas and roadmaps- 90-day reliance approval for cancer drugs cleared by two stringent regulators
- A cheap old tablet to restore appetite
- A combination pricing rule so two-drug regimens are not priced as two monopolies
- A coordinated reserve and shared schedule for the world's medical isotope reactors
- A dedicated global financing window for cancer, modelled on the Global Fund
- A delinked market-entry reward paid by payers when a repurposed generic wins approval
Background: Accelerated approval, Biosimilar, Real-world evidence. Also on OnCo: Financial help and assistance navigator · Coverage by country · HTA decisions.
Trials
topRecruiting now (live from ClinicalTrials.gov)
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Expert centres
topCentres linked to this cancer in OnCo
- via Proton therapy
- via Carbon-ion therapy, Proton therapy
- via Proton therapy, Small-molecule kinase inhibitors
- via Carbon-ion therapy
- via Proton therapy
- via Carbon-ion therapy
- via Proton therapy
- via SBRT / SABR (stereotactic radiotherapy)
- European Society for Radiotherapy and OncologyBrussels, BEvia Carbon-ion therapy, Proton therapy, IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- Aarhus University HospitalAarhus, DKvia Proton therapy, IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- American Society for Radiation OncologyArlington, VA, USvia Proton therapy, IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- Hokkaido University HospitalSapporo, JPvia Proton therapy, IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- National Taiwan University HospitalTaipei, TWvia Proton therapy, Afatinib, Small-molecule kinase inhibitors
- via Proton therapy, IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- Apollo Hospitals (Apollo Cancer Centres)Chennai, INvia Proton therapy, SBRT / SABR (stereotactic radiotherapy)
- Centre Antoine LacassagneNice, FRvia Proton therapy, IMRT / IGRT (modern external beam)
- Centre Oscar LambretLille, FRvia IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- Comprehensive Cancer Center Freiburg (CCCF)Freiburg im Breisgau, DEvia IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- via Carbon-ion therapy, Proton therapy
- GIMEMARome, ITvia Imatinib, Small-molecule kinase inhibitors
- Hacettepe University Cancer InstituteAnkara, TRvia IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- Hunan Cancer HospitalChangsha, CNvia IMRT / IGRT (modern external beam), Small-molecule kinase inhibitors
- IRCCS Humanitas Research HospitalRozzano (Milan), ITvia IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- via Proton therapy, IMRT / IGRT (modern external beam)
- via Carbon-ion therapy, Proton therapy
- via Proton therapy, IMRT / IGRT (modern external beam)
- via Imatinib, Small-molecule kinase inhibitors
- Rajiv Gandhi Cancer Institute and Research CentreNew Delhi, INvia IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- Royal Adelaide HospitalAdelaide, AUvia Proton therapy, IMRT / IGRT (modern external beam)
- TROG Cancer ResearchNewcastle, NSW, AUvia IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- UMC Utrecht Cancer CenterUtrecht, NLvia IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterBaltimore, MD, USNCI comprehensivevia Proton therapy, SBRT / SABR (stereotactic radiotherapy)
- Velindre Cancer CentreCardiff, GBvia IMRT / IGRT (modern external beam), SBRT / SABR (stereotactic radiotherapy)
- Zhejiang Cancer HospitalHangzhou, CNvia Proton therapy, IMRT / IGRT (modern external beam)
- via Proton therapy
- via SBRT / SABR (stereotactic radiotherapy)
- via Small-molecule kinase inhibitors
- Canadian Cancer Trials Group (CCTG)Kingston, ON, CAvia SBRT / SABR (stereotactic radiotherapy)
- via Proton therapy
- via Proton therapy
- Central Drugs Standard Control OrganizationNew Delhi, INvia Imatinib
- Centre François BaclesseCaen, FRvia Proton therapy
- Centre Léon BérardLyon, FRvia Small-molecule kinase inhibitors
- via SBRT / SABR (stereotactic radiotherapy)
- Chang Gung Memorial HospitalTaoyuan, TWvia Proton therapy
- via IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- Children's Hospital of PhiladelphiaPhiladelphia, PA, USvia Proton therapy
- Cleveland Clinic Abu DhabiAbu Dhabi, AEvia Proton therapy
- Erasmus MC Cancer InstituteRotterdam, NLvia Proton therapy
- Fundación Arturo López PérezSantiago, CLvia SBRT / SABR (stereotactic radiotherapy)
- Geneva University Hospitals (HUG)Geneva, CHvia IMRT / IGRT (modern external beam)
- via Small-molecule kinase inhibitors
- Groote Schuur Hospital / University of Cape TownCape Town, ZAvia IMRT / IGRT (modern external beam)
- Guangdong Provincial People's HospitalGuangzhou, CNvia Small-molecule kinase inhibitors
- Gunma University Heavy Ion Medical CenterMaebashi, JPvia Carbon-ion therapy
- via IMRT / IGRT (modern external beam)
- Hadassah Medical CenterJerusalem, ILvia SBRT / SABR (stereotactic radiotherapy)
- via IMRT / IGRT (modern external beam)
- via SBRT / SABR (stereotactic radiotherapy)
- HealthCare Global EnterprisesBengaluru, INvia SBRT / SABR (stereotactic radiotherapy)
- Ho Chi Minh City Oncology HospitalHo Chi Minh City, VNvia IMRT / IGRT (modern external beam)
- Hospital Clínic de Barcelona / IDIBAPSBarcelona, ESvia Small-molecule kinase inhibitors
- Hospital Universitari i Politècnic La FeValencia, ESvia SBRT / SABR (stereotactic radiotherapy)
- Institut BergoniéBordeaux, FRvia IMRT / IGRT (modern external beam)
- Institut National d'Oncologie, RabatRabat, MAvia IMRT / IGRT (modern external beam)
- Institut Salah AzaïezTunis, TNvia IMRT / IGRT (modern external beam)
- Institute of Oncology LjubljanaLjubljana, SIvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- via Small-molecule kinase inhibitors
- International Association for the Study of Lung CancerDenver, CO, USvia Small-molecule kinase inhibitors
- via IMRT / IGRT (modern external beam)
- International Extranodal Lymphoma Study GroupBellinzona, CHvia IMRT / IGRT (modern external beam)
- Istanbul University Institute of OncologyIstanbul, TRvia IMRT / IGRT (modern external beam)
- Istituto di Candiolo IRCCS – FPOCandiolo, ITvia Small-molecule kinase inhibitors
- via IMRT / IGRT (modern external beam)
- Juravinski Cancer Centre / Escarpment Cancer Research InstituteHamilton, ON, CAvia IMRT / IGRT (modern external beam)
- Kenyatta National HospitalNairobi, KEvia IMRT / IGRT (modern external beam)
- via Proton therapy
- Koo Foundation Sun Yat-Sen Cancer CenterTaipei, TWvia SBRT / SABR (stereotactic radiotherapy)
- Korean Cancer Study GroupSeoul, KRvia Small-molecule kinase inhibitors
- Korle Bu Teaching HospitalAccra, GHvia IMRT / IGRT (modern external beam)
- Lagos University Teaching HospitalLagos, NGvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- Leiden University Medical CenterLeiden, NLvia Proton therapy
- Maastricht UMC+ Comprehensive Cancer CenterMaastricht, NLvia Proton therapy
- via IMRT / IGRT (modern external beam)
- via Proton therapy
- via Proton therapy
- National Cancer Center Hospital EastKashiwa, Chiba, JPvia Proton therapy
- National Cancer Center KoreaGoyang, KRvia Proton therapy
- National Cancer Centre SingaporeSingapore, SGvia Proton therapy
- via IMRT / IGRT (modern external beam)
- National Institute of Oncology, HungaryBudapest, HUvia IMRT / IGRT (modern external beam)
- via Proton therapy
- Ocean Road Cancer InstituteDar es Salaam, TZvia IMRT / IGRT (modern external beam)
- via Proton therapy
- via IMRT / IGRT (modern external beam)
- via Proton therapy
- via Carbon-ion therapy
- Rambam Health Care CampusHaifa, ILvia IMRT / IGRT (modern external beam)
- Rigshospitalet – Copenhagen University HospitalCopenhagen, DKvia IMRT / IGRT (modern external beam)
- Ruijin Hospital, Shanghai Jiao Tong UniversityShanghai, CNvia Proton therapy
- via Small-molecule kinase inhibitors
- Seoul St. Mary's HospitalSeoul, KRvia Imatinib
- Shanghai Chest HospitalShanghai, CNvia Small-molecule kinase inhibitors
- Shanghai Pulmonary HospitalShanghai, CNvia Small-molecule kinase inhibitors
- Shizuoka Cancer CenterNagaizumi, Shizuoka, JPvia Proton therapy
- Siriraj Hospital, Mahidol UniversityBangkok, THvia IMRT / IGRT (modern external beam)
- via Proton therapy
- Sunnybrook Odette Cancer CentreToronto, ON, CAvia SBRT / SABR (stereotactic radiotherapy)
- via Proton therapy
- Taipei Veterans General HospitalTaipei, TWvia Carbon-ion therapy
- Tata Medical Center, KolkataKolkata, INvia IMRT / IGRT (modern external beam)
- Tawam HospitalAl Ain, AEvia IMRT / IGRT (modern external beam)
- Tel Aviv Sourasky Medical CenterTel Aviv, ILvia IMRT / IGRT (modern external beam)
- The Clatterbridge Cancer Centre NHS Foundation TrustLiverpool, GBvia Proton therapy
- The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research InstituteColumbus, OH, USNCI comprehensivevia Small-molecule kinase inhibitors
- via IMRT / IGRT (modern external beam)
- via Proton therapy
- via Proton therapy
- via Proton therapy
- via Small-molecule kinase inhibitors
- via Proton therapy
- University of Malaya Medical CentreKuala Lumpur, MYvia IMRT / IGRT (modern external beam)
- via IMRT / IGRT (modern external beam)
- via Proton therapy
- UZ Leuven / Leuven Cancer InstituteLeuven, BEvia Proton therapy
- via SBRT / SABR (stereotactic radiotherapy)
- via IMRT / IGRT (modern external beam)
- via Proton therapy
- West Japan Oncology GroupOsaka, JPvia Small-molecule kinase inhibitors
Questions to ask
topQuestions to ask your oncologist about Chordoma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example Brachyurynuclear immunostaining, SMARCB1/INI1 loss, PDGFRB and EGFR expression, Germline TBXT duplication, Surgical margin status and location), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Conventional chordoma, Chondroid chordoma, Dedifferentiated chordoma.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Resectable, any site
- For my situation (resectable, any site), which of the standard options do you recommend and why?Why: Guideline options include: En bloc resection with negative margins by a spine or skull-base team, followed by high-dose proton or carbon-ion radiotherapy; intralesional surgery is associated with early recurrence.
Unresectable or medically inoperable
- For my situation (unresectable or medically inoperable), which of the standard options do you recommend and why?Why: Guideline options include: Definitive particle therapy (proton or carbon-ion) to 70 Gy-equivalent or higher; stereotactic photon radiosurgery where particles are unavailable.
Advanced or metastatic
- For my situation (advanced or metastatic), which of the standard options do you recommend and why?Why: Guideline options include: Clinical trial preferred. Imatinib (PDGFRB-positive), afatinib or other EGFR inhibitors, or sorafenib give mainly disease stabilisation; tazemetostat for INI1-negative poorly differentiated chordoma.
- Am I a candidate for Imatinib, Afatinib, Sorafenib or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Tazemetostat, Carbon-ion therapy, Proton therapy, Afatinib?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “No approved systemic therapy: trials of brachyury-directed vaccines, degraders and EGFR inhibitors are the response”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Recurrent skull-base disease after full-dose radiotherapy: re-irradiation with particles and salvage surgery are being studied”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
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Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
7targets
7drugs
4companies
5pathways
2terms
1bottlenecks
2Latest papers
topQuery for this cancer: (TITLE:"Chordoma" OR ABSTRACT:"Chordoma" OR TITLE:"Childhood chordoma" OR ABSTRACT:"Childhood chordoma" OR TITLE:"Clival chordoma" OR ABSTRACT:"Clival chordoma" OR TITLE:"Sacral chordoma" OR ABSTRACT:"Sacral chordoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Chordoma, not a curated reading list.
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