Cutting edge and traditional

Research agent report, 4 September 2026. Sources: PubMed (E-utilities queries run today), ClinicalTrials.gov API v2 (registry status queried today, 4 Sep 2026), Chordoma Foundation, Cancer Research UK, NHS England, Cochrane, NICE, and published trials. Gaps marked. No prognosis or survival figures. Where a statement is inference or clinical judgement rather than citation it is labelled as such. No em dashes.

Patient context: 34-year-old woman in the UK, 3.8 cm invasive clival mass with partial basilar artery encasement and right third and fourth nerve involvement, working diagnosis chordoma (chondrosarcoma the main lookalike), biopsy pending, expected pathway endoscopic surgery then proton beam therapy. Weight 51 kg and falling, continuous right trigeminal-distribution pain, likely on an opioid, a nerve-pain drug and possibly dexamethasone. Partner very wary of sedation and cognitive side effects. Referral to the National Chordoma and Chondrosarcoma Skull Base MDT (Manchester, since April 2026) is being requested. The request from the family's friend: think outside the box, cutting edge, especially anything grounded in ancient knowledge.

0. The short version

1. For the disease itself, the cutting edge in September 2026 is still surgery plus high-dose particle radiotherapy, and the UK already offers the version with the best evidence. Nothing in Track A beats maximal safe endoscopic resection followed by proton therapy at the Christie or UCLH for a newly diagnosed skull base chordoma. Every drug in Track A was tested in advanced, progressing or recurrent chordoma, after surgery and radiotherapy had been used, and the best of them stabilise disease in a minority of people rather than shrink it. None is licensed for chordoma anywhere.

2. The real "outside the box" moves for a new diagnosis are three things the family can influence now: (a) make sure fresh frozen tumour is banked at biopsy or surgery so that NHS whole genome sequencing and immunohistochemistry for brachyury, INI1/SMARCB1, p16/CDKN2A, IDH1/2 and PD-L1 are done, because every later option depends on that; (b) get the case to the national skull base chordoma MDT and a proton centre before surgery, not after, so that surgical margins and radiotherapy planning are designed together; (c) register with the Chordoma Foundation's patient navigation service and Chordoma UK, which is how UK patients reach the trials that exist.

3. Carbon ions are not better than protons for skull base chordoma on the only randomised evidence (Shanghai phase 2, 2025: no difference in local control or toxicity), and carbon ion therapy is not commissioned by the NHS. Travelling to Heidelberg or Pavia would be self-funded and would not be buying better evidence.

4. Trials open today that a UK patient with chordoma could in principle reach are few and almost all in the USA, for progressing disease after standard treatment. The most interesting biology (SHP2 inhibition with ERAS-601) has closed to new chordoma patients. In the UK the practical routes are DETERMINE (CRUK's precision-medicine platform, needs a matching mutation), the CHONQUER phase 3 (only if histology is IDH1-mutant chondrosarcoma) and off-label imatinib or afatinib through a sarcoma centre if the disease ever progresses. Section A14 lists them with registry numbers.

5. From ancient medicine, three things have modern randomised evidence and are relevant to her comfort, not to the tumour: acupuncture for cancer pain and opioid sparing (JAMA Oncology 2020 meta-analysis; 360-patient PEACE trial 2021), music before and after surgery (73-trial Lancet meta-analysis), and mind-body practice for sleep, fatigue and anxiety (Cochrane). One plant product, frankincense (Boswellia serrata), has a placebo-controlled trial showing it reduces brain oedema during radiotherapy and a 94-patient series showing steroid-sparing effect after radiosurgery; it is the one supplement worth a specific conversation with the proton centre, and only then. Psilocybin has genuine randomised evidence for cancer-related distress but is illegal outside trials in the UK, has no UK cancer trial open that I could confirm, and an untreated intracranial mass is a standard exclusion. Hyperthermia is the most convincing "fever therapy" descendant, with randomised sarcoma and head and neck evidence, but no device can heat the clivus and no UK centre offers it.

6. Things that sound cutting edge or ancient and should be left alone: ketogenic diets and fasting (two randomised glioma trials negative, and she is losing weight), honokiol, tanshinone, TCM formula "adjuncts", raw Tripterygium, ashwagandha at supplement doses on top of opioids, and any private "hyperthermia" or "immunotherapy" clinic.

Track A: the cutting edge in chordoma and skull base chondrosarcoma, September 2026

Two framing facts first. Chordoma is treated as a bone sarcoma; the ESMO-EURACAN-GENTURIS-ERN PaedCan bone sarcoma guideline (Strauss and colleagues, Annals of Oncology 2021;32:1520-1536) and the 2015 global consensus (Stacchiotti and colleagues, Lancet Oncology 2015;16:e71-e83, PMID 25638683) give conventional chemotherapy no role in conventional chordoma and place imatinib as the default first systemic drug for advanced disease, after surgery and radiotherapy. Second, every drug trial below enrolled people with advanced, unresectable, progressing or metastatic chordoma. None was run in newly diagnosed patients before surgery. So for the patient today, Track A is a map of what would become available if the disease is incompletely controlled, and of what to ask for in tissue handling now so that those doors stay open.

Registry status quoted below is from ClinicalTrials.gov on 4 September 2026.

A1. Brachyury-directed therapy

What it is. Brachyury (gene TBXT) is the notochordal transcription factor that essentially defines chordoma; nearly all chordomas express it and about a quarter carry extra copies of the gene (Tarpey and colleagues, "The driver landscape of sporadic chordoma", Nature Communications 2017;8:890, PMID 29026114: brachyury duplication in up to 27% of 104 tumours, PI3K pathway mutations 16%, LYST 10%). Two strategies exist: vaccines that teach T cells to recognise brachyury, and small molecules that reduce brachyury production.

Vaccines: the evidence. - GI-6301 (yeast-brachyury) phase 1 and a randomised placebo-controlled phase 2 with radiotherapy (QUILT-3.011, NCT02383498): the randomised trial was negative for its primary endpoint (Chordoma Foundation summary, "Learning from results of three recent brachyury vaccine trials"). - BN-Brachyury (MVA-BN-Brachyury prime, fowlpox boost) plus radiotherapy, single-arm phase 2, NCT03595228, completed: Cote and colleagues, Cancer 2024, PMID 38985843. 29 adults with advanced chordoma; 2 of 26 evaluable had durable partial responses (7.7%), 21 stable disease, 3 progression; the trial did not meet its prespecified goal of 4 responses. The authors themselves conclude that a randomised design would be needed to show activity. Bavarian Nordic has not opened a successor trial; nothing brachyury-vaccine related is recruiting on ClinicalTrials.gov today. - Verdict: safe, immunologically active, clinically weak so far. No open trial. Not something to travel for.

Small molecules that lower brachyury: the evidence. - Transcriptional CDK inhibitors (CDK7/12/13, CDK9) lower brachyury and kill chordoma cells in the laboratory (Sharifnia and colleagues, Nature Medicine 2019, PMID 30664779). The CDK9 inhibitor KB-0742 (Kronos Bio) entered a phase 1 that included 5 chordoma patients; the only published output is in adenoid cystic carcinoma (Hanna and colleagues, Cancer Research Communications 2025, PMID 40277179) and the programme is not recruiting. No chordoma results are published. - Afatinib, an EGFR inhibitor, also degrades brachyury in chordoma cells (Magnaghi and colleagues, Molecular Cancer Therapeutics 2018, PMID 29237806); see A4. - True brachyury degraders (PROTAC-type) have been shown in cell models only (Sheppard and colleagues, "Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity", Cell Reports Medicine 2021, PMC7817874). Not in humans. - The Broad Institute CRISPR map of chordoma dependencies (Sharifnia and colleagues, Nature Communications 2023, PMID 37024492) confirmed brachyury and found PTPN11 (SHP2), CDK6, EGFR and others; it is what led to ERAS-601 (A11). - Verdict: the most chordoma-specific biology, still preclinical or in dormant phase 1. Applies only after histology confirms brachyury-positive chordoma, and only if disease progresses.

A2. CDK4/6 inhibitors (palbociclib, abemaciclib, ribociclib)

Rationale. Loss of CDKN2A (p16) is one of the commonest alterations in chordoma, which makes the tumour theoretically dependent on CDK4/6.

Evidence. The only completed trial is German: NCT PMO-1601, palbociclib, single-arm phase 2, NCT03110744 (Heidelberg, completed). Teleanu and colleagues, ESMO Open 2025, PMID 40627883: 42 screened, 28 treated (all with p16 or CDKN2A loss and retained RB1); disease control rate 39% (11 of 28, all stable disease), no objective responses, median progression-free survival 5.6 months; treatment-related adverse events in 96%, grade 3 neutropenia in 28.5%, one fatal neutropenic sepsis. The trial met its own modest statistical bar; the authors call the activity "modest" and recommend combinations.

Open trials. Abemaciclib for bone and soft tissue sarcoma with CDK pathway alteration, NCT04040205, phase 2, Medical College of Wisconsin, USA, recruiting, chordoma explicitly eligible with no prior-therapy requirement, but requires metastatic or unresectable disease. In France, MegaMOST (NCT04116541, Centre Leon Berard, Lyon, recruiting) has a ribociclib plus HDM201 cohort for CDKN2A homozygous deletion or CDK4/6 amplification with wild-type p53, open to any advanced solid tumour on molecular-board recommendation.

Access from the UK. Palbociclib and abemaciclib are licensed in the UK for breast cancer only; off-label use for chordoma would need an individual funding request through a sarcoma centre and would be hard to justify on the above data. Verdict: proven safe-ish, weak activity as a single drug; only relevant if the sequenced tumour shows CDKN2A loss and the disease is progressing; not a reason to travel.

A3. EZH2 inhibition (tazemetostat) for INI1/SMARCB1-deficient poorly differentiated chordoma

Rationale. A rare subtype, poorly differentiated chordoma (mostly children and young adults, mostly skull base and cervical spine, aggressive), has lost the SMARCB1/INI1 protein; that makes it dependent on EZH2, which tazemetostat blocks. Conventional chordoma does not have this feature, so this section applies only if histology shows INI1 loss.

Evidence. Gounder and colleagues, Nature Communications 2026;17:7120, PMID 41882006 (phase 2 basket NCT02601950, completed, sites included the UK): poorly differentiated chordoma cohort n = 18, one partial response (6%), below the trial's threshold for activity. One well-documented exceptional case: a patient with metastatic INI1-negative poorly differentiated chordoma had a durable response after tazemetostat then radiotherapy, with a distant "abscopal" effect (Clinical Cancer Research 2019;25:2064). CONFIRMED 6 Oct 2026: Ipsen withdrew tazemetostat from all markets and indications in March 2026 after SYMPHONY-1 showed haematological second cancers (MDS, AML) in 5.7% of treated patients vs none in controls (Alumkal and Ellis, Clin Cancer Res 2026, PMID 42599162, abstract read). Trials and compassionate access stopped. (On 6 Oct I told her partner it "applies on both branches" from memory, without reading this section; corrected in the room the same day.) See research 37.

Open trial. Tazemetostat plus nivolumab and ipilimumab in INI1-negative or SMARCA4-deficient tumours, NCT05407441, phase 1/2, Dana-Farber/Boston Children's, USA, poorly differentiated or dedifferentiated chordoma explicitly eligible, currently active but not recruiting.

Access. None in the UK. Verdict: only relevant in the unlikely event of INI1-loss histology; ask the pathologist to do INI1 immunohistochemistry regardless, because it changes the whole treatment conversation (chemotherapy enters, see file 11 section 12).

A4. EGFR inhibitors (afatinib, erlotinib, lapatinib)

Rationale. EGFR is active in most chordomas and afatinib additionally lowers brachyury (A1).

Evidence. The Chordoma Foundation-supported European phase 2 of afatinib, NCT03083678 (Leiden sponsor; sites in the Netherlands, Italy and the UK; completed) was presented at ASCO 2024 (Journal of Clinical Oncology 2024;42(16 suppl):11517). First-line cohort of 30: 12-month progression-free rate 40%, 4 partial responses (13%); later-line cohort: 9-month progression-free rate 38.5%. The trial met its endpoint. A full paper is not on PubMed as of today. Earlier: lapatinib phase 2 (Stacchiotti and colleagues, Annals of Oncology 2013; 18 EGFR-positive patients; responses by Choi criteria but none by RECIST) and a Gustave Roussy retrospective series of erlotinib in 31 patients. Verdict: afatinib is now the best-evidenced targeted drug in chordoma on published numbers, comparable with or better than imatinib, but it is still a drug for progressing disease that stabilises rather than cures.

Access. Afatinib is licensed in the UK for lung cancer. Off-label use for chordoma is possible through a sarcoma centre (UCLH/Royal National Orthopaedic Hospital, the Christie, Royal Marsden, Birmingham) via an individual funding request; the UK trial site is the obvious place to ask. The Chordoma Foundation has stated an urgent need for a biomarker of response; none exists yet.

A5. Other tyrosine kinase inhibitors (imatinib, sorafenib, nilotinib with radiotherapy, apatinib)

• Imatinib: Stacchiotti and colleagues, Journal of Clinical Oncology 2012, PMID 22331945: 56 PDGFRB-positive patients, 1 partial response (2%), 70% stable disease, median progression-free survival 9 months. Imatinib plus everolimus (Stacchiotti, Cancer 2018, PMID 30216418) added modest activity with more toxicity. Imatinib remains the ESMO-listed first systemic option for advanced chordoma and is available off-label in the UK through sarcoma centres.
• Sorafenib: French Sarcoma Group phase 2, Bompas and colleagues, Annals of Oncology 2015, PMID 26202596: 27 patients (3 clival), one partial response, most patients progression-free at 9 months. Available off-label in principle; rarely used.
• Nilotinib plus radiotherapy: Massachusetts General phase 1 (NCT01407198, completed; PMID 30077789): 200 mg daily with radiotherapy was tolerable, 200 mg twice daily was not. The only trial of a targeted drug given with definitive radiotherapy for high-risk chordoma. Not taken forward into phase 2; no successor open. Ask the proton centre whether they would ever consider a radiosensitiser; the honest answer today is that no radiosensitiser has evidence in chordoma.
• Apatinib: single-centre Chinese phase 2, Lancet Oncology 2020, PMID 32888455, 30 patients, low response rate but long disease control; not licensed in Europe.
• Verdict for the family: these are the "salvage" drugs; imatinib and afatinib are the two a UK sarcoma oncologist would actually reach for, and only on progression after surgery and protons.

A6. Immune checkpoint inhibitors, alone or with radiotherapy

Rationale. Chordoma has a low mutation burden (inference from Tarpey 2017) but some tumours express PD-L1 and are infiltrated by T cells; radiotherapy may release antigens.

Evidence. - Nivolumab plus relatlimab (anti-LAG-3), NCT03623854, UCLA, completed: 1 partial response in 9 patients, 4 stable at one year (Chordoma Foundation ASCO 2024 report). - Nivolumab with or without stereotactic radiosurgery, NCT02989636, Johns Hopkins, phase 1, active not recruiting; no results published as of today. - Pembrolizumab plus pemetrexed for progressive chordoma, NCT06794645, Saint John's Cancer Institute (California), phase 2, recruiting since January 2025, single US site; requires progression within 6 months. - Case reports: response to nivolumab in an INI1-deficient paediatric chordoma correlated with brachyury-specific immunity (npj Precision Oncology 2021). - Verdict: a real signal in a minority; nothing licensed; the radiotherapy combination is unproven. Not applicable at diagnosis.

UK access. Pembrolizumab and nivolumab are not funded for chordoma. DETERMINE arm 02 (atezolizumab) needs TMB-high, MSI-high or constitutional mismatch repair deficiency; a conventional chordoma essentially never meets that bar (inference from its low mutation burden). NICE has not adopted the FDA's TMB-high tumour-agnostic pembrolizumab indication; NTRK-fusion drugs (larotrectinib, entrectinib) are NICE-approved tumour-agnostically but NTRK fusions are not a chordoma feature.

A7. Carbon ion radiotherapy versus protons, and UK access

The evidence. - The only randomised comparison: Shanghai Proton and Heavy Ion Center phase 2, protons 64 to 70 GyRBE versus carbon 63 to 70 GyRBE for skull base chordoma and chondrosarcoma, presented as abstract 656O, Annals of Oncology 2025: no significant difference in local progression-free survival, progression-free survival, overall survival or toxicity. The German HIT-1 randomised phase 3 (Nikoghosyan and colleagues, BMC Cancer 2010, PMC2988755) began in 2010 and has not reported. - The largest carbon series: Uhl and colleagues, Cancer 2014, PMID 24948519, 155 skull base chordomas treated at GSI Darmstadt, median 60 GyRBE in 20 fractions; local control 72% at 5 years and 54% at 10 years, no excess late toxicity. Modern Heidelberg data (147 patients, Radiation Oncology 2023, PMC9876873) and CNAO series are in the same range as high-dose proton series. - Meta-analyses (TRP-Chordoma 2024, PMC11274426; Radiotherapy and Oncology 2024 meta-regression) find particle therapy better than photons and no clear difference between carbon and protons. - UK proton doses at the Christie: 73.8 GyRBE for chordoma, 70.2 for chondrosarcoma (Potter and colleagues, Radiographics 2024, PMID 39298353), which is at the top of the international dose range.

UK access. NHS England commissions proton therapy at the Christie (Manchester) and UCLH (London) for skull base chordoma and chondrosarcoma; referral is by the treating oncologist to the national proton panel. Carbon ion therapy is not available in the UK and is not NHS-commissioned; the NHS Proton Overseas Programme funded protons abroad only, and ended when the UK centres opened. Carbon centres nearest the UK: HIT Heidelberg, MIT Marburg, CNAO Pavia, MedAustron (Austria); also Japan (QST Chiba, Gunma, Osaka) and Shanghai. Costs are self-funded, typically tens of thousands of pounds, plus travel and 4 to 7 weeks away with a toddler at home. The French ETOILE randomised trial of carbon versus standard radiotherapy (NCT02838602, Lyon, recruiting) explicitly excludes skull base chordoma and chondrosarcoma.

Verdict. Protons at the Christie or UCLH are the evidence-based choice. Carbon ions are a legitimate alternative, not a superior one; the case to travel would be a specific dosimetric problem the UK centre cannot solve (for example brainstem constraints that force under-dosing), and that is a question to put to the proton physicist, not a default.

A8. Proton dose escalation and hypofractionation

• Standard is 70 to 74 GyRBE in 1.8 to 2 Gy fractions over 7 to 8 weeks; the Christie already uses 73.8 GyRBE. Dose escalation beyond this is limited by brainstem, optic apparatus and temporal lobe tolerance, and with partial basilar encasement and cranial nerve involvement those constraints will be the planning issue for the patient (inference).
• Hypofractionation: a Madrid prospective series of 5-fraction proton therapy for skull base chordoma and chondrosarcoma (Sallabanda and colleagues, Cancers 2023, PMID 38067283) and a Spanish trial of 5 versus 25 fractions (NCT05861245, Quironsalud, recruiting) exist; a randomised hypofractionated proton versus carbon trial (ISAC, Radiotherapy and Oncology 2024) is sacral only. Early results, small numbers, no long-term safety for lesions abutting the brainstem.
• Verdict: do not seek hypofractionation for a 3.8 cm clival lesion touching the basilar artery outside a trial; conventional fractionation is safer for the normal tissue she most needs to protect (clinical judgement).

A9. Intraoperative innovations

• 5-ALA fluorescence: a multicentre retrospective study of endoscopic endonasal surgery found limited utility overall; chordoma fluoresced in 1 of 2 cases (Journal of Neurosurgery 2020, PMID 33126212). Not a reason to choose a surgeon.
• Intraoperative MRI: Gulsuna and colleagues, Frontiers in Oncology 2021, PMID 35083136: 42 endoscopic clival chordoma resections with intraoperative MRI; gross total resection 52% overall, and in 13 patients where the first scan showed removable residue a second look achieved total resection in 7. This is the one intraoperative technology with chordoma-specific evidence that it changes what the surgeon does. Ask whichever unit operates whether they have intraoperative MRI or CT for endonasal work, and if not, what their protocol is for early postoperative MRI and planned second-look surgery.
• Augmented reality endoscopic navigation: feasibility studies only (PLoS One 2016; automatic registration systems 2025); one Chinese trial recruiting (NCT06282224). Not a discriminator.
• Robotics: no established role in endonasal clival surgery.
• Intraoperative ultrasound: case report level.
• Verdict: the surgeon's volume and the unit's habit of second-look surgery matter more than any gadget (see file 09).

A10. Molecular profiling: what to ask for, and why it is the family's single most useful lever

• NHS Genomic Medicine Service whole genome sequencing is commissioned for sarcomas under the National Genomic Test Directory (the South West Genomic Laboratory Hub, which covers Cornwall and Plymouth, runs a sarcoma WGS service). WGS needs fresh frozen tumour plus a blood sample, collected at biopsy or surgery; formalin-fixed tissue is not enough. This must be arranged before the procedure. It is the single request that keeps every later option (DETERMINE, CDK4/6, IDH, SMARCB1, PI3K) open.
• Immunohistochemistry to request explicitly: brachyury (diagnostic), INI1/SMARCB1 (poorly differentiated subtype), p16 (CDKN2A), IDH1 R132H plus IDH1/2 sequencing if chondrosarcoma is possible (skull base chondrosarcomas have a distinctive IDH profile; Tallegas and colleagues, Human Pathology 2019, PMID 30296521), PD-L1, EGFR, and Ki-67.
• 100,000 Genomes Project closed to recruitment in 2018; its cancer analyses are published (PMC10803271) and it is the reason WGS is now routine, but it is not a route for the patient.
• Chordoma Foundation: offers a free Patient Navigation Service (help finding experts and trials), a tumour and biospecimen donation programme and a tumour-model programme; it does not itself run a tumour board for individual NHS patients, but its navigators can arrange expert second opinions. Chordoma UK is the UK charity.
• DETERMINE (CRUK, section A14) accepts referrals only when standard-of-care profiling has found an actionable alteration; this is why the WGS matters.

A11. First-in-human and phase 1 to 2 chordoma trials, 2025 to 2026

• ERAS-601 (SHP2 inhibitor), NCT06957327, phase 1b/2, Memorial Sloan Kettering with 7 US sites, opened April 2025, now active, not recruiting (closed to new patients as of today). Basis: the phase 1 basket in which 13 chordoma patients received ERAS-601 with or without cetuximab: 1 partial response, 11 stable disease, 10 with some shrinkage (Chordoma Foundation report; presented by Gounder). Excludes poorly differentiated and dedifferentiated subtypes; requires 20% growth within 9 months. This is the most promising new mechanism and it is currently closed; the Chordoma Foundation should be asked whether an expansion or a European site is planned.
• Pembrolizumab plus pemetrexed, NCT06794645, phase 2, USA, recruiting (A6).
• Abemaciclib, NCT04040205, phase 2, USA, recruiting (A2).
• Tazemetostat plus nivolumab and ipilimumab, NCT05407441, USA, INI1-loss only, not recruiting (A3).
• ctDNA biomarker study during neoadjuvant radiotherapy, NCT06463262, Johns Hopkins, observational, includes skull base chordoma; interesting because it studies radiotherapy before surgery, which some US centres do for spinal chordoma; not standard for the clivus.
• NCI natural history study of chordoma, NCT03910465, USA, recruiting: enrolment gives access to NIH expert review and germline testing (relevant because she is 34; familial chordoma is rare but real).
• Chondrosarcoma, in case that is the histology: ozekibart (INBRX-109, a DR5 agonist antibody), ChonDRAgon, NCT04950075, randomised placebo-controlled phase 2 with UK sites, positive: median progression-free survival 5.52 versus 2.66 months, hazard ratio 0.48 (Inhibrx press release October 2025; ASCO 2026 abstract 11504); FDA decision due April 2027; not licensed in the UK; expanded-access enquiry would go through the sponsor via a UK sarcoma centre. Ivosidenib for IDH1-mutant conventional chondrosarcoma: CHONQUER phase 3, NCT06127407, recruiting, UK sites, placebo-controlled, for locally advanced or metastatic disease (A14). Enasidenib for IDH2-mutant sinonasal and skull base tumours including chondrosarcoma, NCT06176989, NCI, USA, recruiting.
• Nothing on the Chordoma Foundation trial list or ClinicalTrials.gov today is a chordoma drug trial with a UK or European site.

A12. What applies when

A13. Honest counter-case for Track A

Every systemic option above produced disease control, not shrinkage, in most people who benefited; the numbers are small, single-arm and in heavily pretreated patients, and none has been tested against best supportive care. A family that spends the next months chasing drug trials will be spending energy that would be better spent on the surgical plan, the tissue handling, and the proton referral. The disease-directed cutting edge for the patient is a well-executed standard pathway with molecular profiling done properly, so that if anything goes wrong later the options are already mapped.

A14. Trials of related tumour types that a chordoma or chondrosarcoma patient might enter

Chordoma is rare enough that most of what a UK patient could actually join is defined by a molecular feature or by "sarcoma" rather than by "chordoma". Status from ClinicalTrials.gov, 4 September 2026. "Eligible" means the registry eligibility text names the diagnosis; "possible" means the criteria are tumour-agnostic and a chordoma would qualify if the molecular condition is met.

UK

Not found in the UK today: any sarcoma trial that names chordoma as an eligible histology; any UK skull base radiotherapy or radiosensitiser trial for chordoma; any UK hyperthermia trial for deep tumours; any UK-based DRUP equivalent beyond DETERMINE (the Dutch DRUP model, van der Velden and colleagues, Nature 2019, is what DETERMINE copies; the US equivalents are TAPUR (ASCO) and NCI-MATCH successors, which are US-only).

Europe

USA

Entering a US trial means self-funding travel and living costs, being fit enough to travel (ECOG 0 to 1 is a near-universal requirement), and having progressing disease measurable by RECIST. The trial drug is normally free. The Chordoma Foundation's navigators are the practical route.

Molecular features a sequenced chordoma might match, and where they lead - CDKN2A loss: abemaciclib trial (USA), MegaMOST ribociclib cohort (France); palbociclib data show limited single-agent activity. - PDGFR/PDGFRB expression or amplification: imatinib (off-label UK), MegaMOST regorafenib cohort. - EGFR expression: afatinib (off-label UK, UK trial site experience). - PI3K pathway mutation (16% of chordomas): no dedicated arm; PIK3CA inhibitors exist in breast cancer; MegaMOST or phase 1 units. - SMARCB1/INI1 loss: tazemetostat combinations (USA), chemotherapy discussion. - PBRM1 loss (a recurrent chordoma alteration): preclinical EZH2 sensitivity only (Cancers 2022, doi 10.3390/cancers14061486); no trial. - High TMB or MSI: DETERMINE atezolizumab arm; almost never in chordoma. - IDH1 or IDH2 mutation: only in chondrosarcoma; CHONQUER (UK sites) or enasidenib (USA). - NTRK fusion: NICE-funded larotrectinib or entrectinib; essentially never in chordoma or chondrosarcoma. - Brachyury expression: no open trial today.

Track B: treatments with roots in traditional or ancient medicine that have reached modern clinical evidence

Assessed for a woman with a skull base tumour about to have endoscopic surgery and proton therapy, with pain, weight loss and a partner who wants her mind clear.

B1. Hyperthermia: from Hippocratic fever to Coley to regional hyperthermia with radiotherapy

Origin. Fever as a cure is in the Hippocratic corpus; Busch (1866) and Coley (from 1891) reported sarcoma regressions after erysipelas and after injected streptococcal and Serratia toxins (Coley's toxins, used commercially until the 1950s; reviews in PMC1888599 and PMC11726767). Modern hyperthermia heats the tumour to 40 to 43 degrees C for an hour with radiofrequency or microwave applicators to sensitise it to radiotherapy or chemotherapy.

Modern evidence. - Soft tissue sarcoma: EORTC 62961-ESHO 95, Issels and colleagues, Lancet Oncology 2010 and JAMA Oncology 2018 (PMID 29450452): 341 patients with localised high-risk soft tissue sarcoma randomised to neoadjuvant chemotherapy with or without regional hyperthermia; at a median 11.3 years, local progression-free survival was significantly better with hyperthermia (hazard ratio 0.65) and overall survival was also significantly better. This is level 1 evidence, in a different sarcoma, with chemotherapy not radiotherapy. - Head and neck cancer with radiotherapy: Datta and colleagues, International Journal of Hyperthermia 2016, PMID 26928474: six controlled trials (five randomised), 451 patients, complete response 62.5% with hyperthermia plus radiotherapy versus 39.6% with radiotherapy alone (odds ratio 2.92), no excess toxicity. Tumours invading the skull base were excluded from those trials. - Chordoma specifically: Paul Scherrer Institute treated 5 large inoperable sacral chordomas with protons plus weekly hyperthermia (Tran and colleagues, British Journal of Radiology 2020, PMID 30943055): feasible, all shrank, one late fracture. In the laboratory, hyperthermia before proton irradiation increased chordoma cell kill and reduced brachyury (Singh and colleagues, International Journal of Radiation Biology 2021, PMID 34495790). That is the entire chordoma literature. - Skull base: no clinical application exists. Deep head and neck applicators (the Erasmus HYPERcollar) heat the neck and oropharynx; nobody has a validated way to heat the clivus without heating the brainstem (Radiation Oncology 2016, PMC4751675 reviews the technology). Inference: it is physically the wrong site.

Safety and interactions. Pain at the site, burns, and in deep pelvic use bone fracture. Not sedating.

UK access. There is no NHS deep regional hyperthermia service. UK private "oncothermia" or "hyperthermia" clinics use low-power devices that are not what was tested in the trials above and should be treated as unproven.

Verdict. The most honest example of an ancient idea validated by randomised trials. It does not apply to a clival tumour, is not available in the UK, and is not worth the family's time for the patient. If the disease ever recurs in the sacrum or spine, PSI's proton plus hyperthermia programme would be worth asking about.

B2. Therapeutic fasting and ketogenic diets

Origin. Fasting as therapy is in Hippocrates and in most religious traditions; the ketogenic diet was formalised in the 1920s for epilepsy; the modern cancer rationale is Warburg's observation that tumours use glucose.

Modern evidence. In glioma: ERGO pilot (Rieger and colleagues, International Journal of Oncology 2014, PMID 24728273): 20 recurrent glioblastoma patients, diet feasible, no clinical activity as a single agent. ERGO2 (Voss and colleagues, International Journal of Radiation Oncology Biology Physics 2020, PMID 32619561): 50 patients randomised to re-irradiation with or without a calorie-restricted ketogenic diet plus fasting; no benefit in progression-free or overall survival, despite ketosis in most. UK KEATING feasibility trial (Liverpool, protocol PMC5704454) tested acceptability only; a 2025 phase 1 (Amaral, Scientific Reports, PMID 40595067) and the US DIET2TREAT phase 2 are ongoing. For chordoma: nothing, in the dish or in people.

Relevance to her. Chordoma is a slow, notochordal tumour, not a glycolytic high-grade glioma; the rationale is weaker still (inference). She weighs 51 kg and is losing weight with a 7-week course of radiotherapy ahead. ESPEN's practical oncology nutrition guideline (Muscaritoli and colleagues, Clinical Nutrition 2021) states there is no evidence to recommend ketogenic or fasting diets in cancer patients and warns of malnutrition risk.

Safety. Weight loss, muscle loss, hypoglycaemia, constipation on opioids, kidney stones; fasting around anaesthesia interferes with glycaemic management. Ketosis can cause fatigue and cognitive slowing early on, which is the opposite of what the partner wants.

Verdict. No. The evidence-based diet for her is the reverse: a dietitian, protein and energy supplementation, and treating the nausea and pain that stop her eating.

B3. Traditional Chinese medicine compounds with modern trials

• Homoharringtonine / omacetaxine (Cephalotaxus, plum yew): a genuine drug, FDA-approved in 2012 for chronic myeloid leukaemia after two tyrosine kinase inhibitors, after a 40-year development (Journal of Clinical Oncology 2013 review, PMID 23790799). Works by blocking protein synthesis. No solid tumour indication, no chordoma data. Not available in the UK for anything relevant. Verdict: history, not an option.
• Triptolide / Minnelide (Tripterygium wilfordii, thunder god vine): Minnelide is a water-soluble prodrug in phase 1 to 2 for pancreatic and gastrointestinal cancers (Borazanci, Oncologist 2024, PMID 38169017; Skorupan, Future Oncology 2022, PMID 35535581): tolerable dose found, some activity in refractory pancreatic cancer, but grade 3 or worse toxicity in 69% and two cases of severe cerebellar toxicity at higher drug levels. Raw Tripterygium is hepatotoxic, nephrotoxic and causes infertility. No chordoma trial, no European trial. Verdict: interesting drug, wrong cancer, neurotoxic; keep away from the plant.
• Berberine (Coptis, Berberis; also in goldenseal): the one TCM small molecule with a large modern randomised trial: Chen and colleagues, Lancet Gastroenterology and Hepatology 2020, PMID 31926918: about 1,100 Chinese patients after polypectomy, 0.3 g twice daily, adenoma recurrence 36% versus 47% (relative risk 0.77); a 6-year follow-up (2025) supports it. This is chemoprevention of colorectal polyps, not treatment of any tumour. Berberine inhibits CYP2D6, CYP3A4 and P-glycoprotein, so it would raise levels of codeine-type opioids, oxycodone, dexamethasone and possibly carbamazepine (LiverTox and MSKCC monographs). Verdict: no relevance to chordoma; interaction risk with her likely medicines; not while on opioids or steroids.
• Tanshinones (Salvia miltiorrhiza, danshen): sodium tanshinone IIA sulfonate is a licensed cardiovascular injection in China; cancer work is laboratory and nanoparticle formulation (2021 to 2026 papers) with no quality randomised cancer trial found today. Danshen has antiplatelet and warfarin-interaction effects, which is relevant before skull base surgery. Verdict: no.
• Arsenic trioxide: the strongest TCM-to-drug story: Shanghai group, Shen and colleagues, Blood 1997, PMID 9129042, led to a licensed, curative drug for acute promyelocytic leukaemia. It proves the point that traditional pharmacopoeias contain real drugs; it has no relevance to chordoma.
• TCM formula "adjunct" trials (Chinese herbal decoctions alongside radiotherapy for nasopharyngeal or other cancers): hundreds of Chinese trials exist; systematic reviews consistently rate them at high risk of bias with unblinded designs, unvalidated outcome measures and near-universal positive results; Cochrane reviews in this area rate the certainty very low. Individual formulae contain 8 to 15 plants with unknown interactions, and hepatotoxicity from imported TCM products is documented in the UK by the MHRA. Verdict: not evidence-based, not safe to layer onto anaesthesia, opioids and radiotherapy.

B4. Ayurvedic-origin compounds

• Withaferin A / ashwagandha (Withania somnifera): withaferin A has one phase 1 trial, oral, in advanced osteosarcoma (Pires and colleagues, Journal of Ayurveda and Integrative Medicine 2020, PMID 30904387): safety and pharmacokinetics only, no efficacy claim. Ashwagandha root for fatigue: Biswal and colleagues, Integrative Cancer Therapies 2013, PMID 23142798: 100 breast cancer patients, open-label and non-randomised, less fatigue with 2 g three times daily during chemotherapy. Safety: LiverTox documents ashwagandha-associated liver injury; it raises thyroid hormone; it is sedative and is marketed for sleep, which is additive with opioids and diazepam. Verdict: weak evidence, sedative, liver signal, no chordoma relevance; not on top of her current drugs.
• Boswellic acids / frankincense (Boswellia serrata, Ayurvedic "salai guggal"): the one supplement in this file with a placebo-controlled brain trial. Kirste and colleagues, Cancer 2011;117:3788-3795, PMID 21287538: 44 patients with brain tumours (mostly metastases, some glioblastoma) having radiotherapy, randomised double-blind to 4,200 mg per day Boswellia serrata or placebo; more than 75% reduction in cerebral oedema on MRI in 60% versus 26% (p = 0.023); the difference was gone 4 weeks after radiotherapy ended. Upadhyay and colleagues, International Journal of Radiation Oncology Biology Physics 2025, PMID 39993542: 94 patients with radiation necrosis after radiosurgery, 4,050 to 4,500 mg per day for at least 2 months, objective oedema response 59.6%, median response duration 13.9 months, mild gastrointestinal upset in 16%; most had stable or reducing steroid needs. A 2025 meta-narrative review (Dejonckheere, Advances in Radiation Oncology, PMID 40092573) confirms the small evidence base and calls for a randomised steroid-sparing trial. Mechanism: 5-lipoxygenase inhibition and reduced vascular leak. Relevance to her: if she needs dexamethasone for oedema or cranial nerve swelling during or after proton therapy, this is a documented steroid-sparing adjunct, and steroid side effects (insomnia, mood, muscle loss, weight gain in the wrong places, glucose) are exactly what a 51 kg patient with a worried partner would want to avoid. A clival chordoma is outside the brain, so the oedema it causes is less than with an intra-axial tumour, which limits how much there is to treat (inference). Safety and interactions: gastrointestinal upset; in vitro inhibition of several CYP enzymes (clinical significance unknown); theoretical antiplatelet effect, so stop 2 weeks before surgery; product quality varies, look for standardised AKBA content (for example the H15 preparation used in Kirste's trial). UK access: over the counter, roughly 20 to 40 pounds a month at trial doses; not prescribable on the NHS. Verdict: the only supplement in this file with a randomised trial on a relevant outcome; worth asking the proton centre oncologist specifically whether they would support it during and after radiotherapy if steroids are needed; not before biopsy or surgery.

B5. Honokiol (magnolia bark)

Used in Chinese and Japanese medicine (houpo) for anxiety and gut symptoms. Laboratory work shows it kills glioma cells and crosses the blood-brain barrier (Preclinical work, Phytomedicine 2016, PMID 27064011; liposomal honokiol in glioblastoma models, PMC8667111). Reviews mention a Chinese phase 1 of liposomal honokiol in glioma, but I could not find a trial publication on PubMed today; the human literature is case reports (Integrative Cancer Therapies 2020; a 2023 glioblastoma case report). It is a GABA-A modulator and sedative. Verdict: preclinical; sedating; no.

B6. Psilocybin and psychedelic-assisted therapy for cancer-related distress

Origin. Psilocybe mushrooms in Mesoamerican ritual use for at least two thousand years; the modern trials use synthetic psilocybin with structured psychological support.

Modern evidence. Griffiths and colleagues, Journal of Psychopharmacology 2016, PMID 27909165: 51 patients with life-threatening cancer and anxiety or depression, randomised double-blind crossover of high versus very low dose; large sustained reductions in depression and anxiety at 6 months. Ross and colleagues, same journal and year, PMID 27909164: 29 patients, psilocybin versus niacin, rapid and sustained benefit. Long-term follow-up (Agin-Liebes and colleagues, 2020, PMID 31916890) at about 4.5 years found most participants still improved. A 2025 open-label study reported 2-year durability in cancer patients with major depression (Wiley press release, June 2025). Meta-analysis of adverse events across classic psychedelic trials (Hinkle and colleagues, JAMA Psychiatry 2024, PMID 39230883) found serious adverse events rare in screened participants, with transient blood pressure rises, headache, nausea and anxiety common.

UK position, 2026. Psilocybin is Schedule 1 and can be used only in licensed research. The UK's first publicly funded randomised trial (King's College London, Nature Medicine 2026) was in treatment-resistant depression, not cancer. I could not confirm any UK cancer-distress psilocybin trial open today; the active trials are in the USA (TRIPS at MD Anderson, NCT06801041; NCT05847686; a Canadian palliative microdose trial NCT07063862). Compass Pathways' phase 3 programme is for depression and could lead to a licensed product by 2027 to 2028, which would still not be a cancer-distress licence.

Cognitive and interaction issues, and why it is not for her now. Trial screening excludes people with seizure risk, uncontrolled hypertension and intracranial lesions; a session raises blood pressure and heart rate for hours; SSRIs and some other antidepressants blunt or complicate it; lithium is dangerous with it; the session itself is 6 to 8 hours of altered cognition. For a woman with an untreated mass encasing the basilar artery, this is a contraindication by any trial's rules (inference from standard exclusion criteria). Verdict: a real example of ancient use meeting modern trials, with better evidence than most of Track B; not legal, not available, and not safe for her at this stage. If, after treatment, she has persistent existential distress, ask about UK trials then.

B7. Acupuncture for cancer pain and opioid sparing

Origin. Chinese, at least 2,000 years; electroacupuncture is a 20th-century modification.

Modern evidence. He and colleagues, JAMA Oncology 2020, PMID 31855257: 17 randomised trials, 1,111 patients; acupuncture or acupressure reduced pain intensity with moderate-certainty evidence and reduced analgesic use; the 7 sham-controlled trials at low risk of bias still favoured real acupuncture. Mao and colleagues, PEACE trial, JAMA Oncology 2021, PMID 33734288: 360 cancer survivors with chronic musculoskeletal pain, randomised to 10 weekly sessions of electroacupuncture, auricular acupuncture or usual care; both acupuncture arms reduced pain more than usual care (roughly 1.9 and 1.6 points on a 0 to 10 scale), auricular had more adverse events. The Cochrane review (Paley and colleagues, 2015, CD007753) found the evidence insufficient at that time; the trials above postdate it. NICE NG193 (2021) recommends considering a course of acupuncture for chronic primary pain; hers is secondary (tumour-related) pain, so the recommendation does not formally cover her, though the mechanism arguments and the He 2020 data do.

Relevance. Her pain is trigeminal neuropathic pain from tumour; acupuncture evidence in trigeminal neuralgia is small and low quality. The best-supported gain is modest pain reduction and a small reduction in opioid need, which matters to a partner worried about sedation.

Safety. Very safe in trained hands; avoid needling over the tumour region (not relevant for a clival lesion); avoid during neutropenia (not expected); no cognitive effect; no drug interactions.

UK access. Some NHS pain clinics and hospices offer it; Macmillan centres sometimes fund it; private 40 to 70 pounds a session; the British Acupuncture Council and British Medical Acupuncture Society registers list practitioners. In Cornwall, ask the hospital pain team and Cornwall Hospice Care.

Verdict. Reasonable, safe, modestly evidenced adjunct that fits the family's priorities exactly. Start after biopsy, alongside proper pharmacological pain control, not instead of it.

B8. Mind-body approaches: mindfulness, yoga, tai chi and qigong, CBT for insomnia

• Mindfulness-based stress reduction: Cochrane (Schell and colleagues, 2019, PMID 30916356; 14 trials, mostly breast cancer): probably reduces anxiety and depression and probably improves sleep quality, with effects lasting up to 6 months; fatigue improved only short-term.
• Yoga (Indian, at least 2,500 years): Cochrane (Cramer and colleagues, 2017, CD010802; 24 trials, breast cancer) found moderate-quality evidence for quality of life, fatigue and sleep; a 2024 to 2025 Cochrane review (CD015520) finds yoga probably reduces short-term cancer-related fatigue.
• Tai chi and qigong (Chinese): Wayne and colleagues, Journal of Cancer Survivorship 2018, PMID 29222705: 15 randomised trials, 1,283 participants; improved fatigue (effect size -0.53), sleep difficulty (-0.49), depression (-0.27) and quality of life; pain trend not significant.
• Cognitive behavioural therapy for insomnia: not ancient, but the best-evidenced non-drug sleep treatment in cancer; NICE-recommended digital CBT-I (Sleepio) is available free through many NHS regions. Relevant because sleep is where the partner is most likely to be offered sedatives.

Relevance and safety. Physical practices must be gentle: no inversions, no straining (raised intracranial pressure and a skull base lesion), and not in the first weeks after endonasal surgery, when nose-blowing, bending and Valsalva are forbidden. Breath-based and seated practices are fine throughout. No drug interactions, no sedation.

UK access. Macmillan, Maggie's centres (nearest to Cornwall is not close; online programmes exist), Penny Brohn UK (Bristol, free residential and online courses for people with cancer), NHS Talking Therapies, Sleepio via NHS.

Verdict. Low cost, genuinely evidenced for sleep, fatigue and anxiety, and precisely the non-sedating route the partner is looking for.

B9. Music

Origin. Music for healing is in Egyptian papyri, Greek medicine and every culture since.

Modern evidence. Hole and colleagues, Lancet 2015, PMID 26277246: 73 randomised trials of music around surgery; reduced postoperative pain (standardised mean difference -0.77), anxiety (-0.68) and analgesic use (-0.37), even when played under general anaesthesia; trials of head, neck and central nervous system surgery were excluded, so the transfer to endonasal skull base surgery is inference. Bradt and colleagues, Cochrane 2021, PMID 34637527: 81 trials, 5,576 people with cancer; music interventions probably reduce anxiety and may reduce depression, pain and fatigue and improve quality of life; evidence low to moderate certainty.

Relevance. Cheap, safe, no interactions, no sedation, and the proton centres allow patients to bring music for the daily 20 to 30 minute sessions over 7 weeks. Ask the anaesthetist whether she can have headphones in the anaesthetic room.

Verdict. Yes. Nothing to lose.

B10. Other traditional-origin measures with modern trials

• Opium to morphine, willow bark to aspirin, chili to capsaicin: she is already on the descendants; the 8% capsaicin patch (NICE CG173) is for peripheral neuropathic pain and cannot be used on the face.
• Ginger for nausea: multiple randomised trials in chemotherapy nausea (for example Ryan and colleagues, Supportive Care in Cancer 2012, 576 patients) show modest benefit; safe as food; useful if opioid nausea is a problem. Culinary doses only before surgery (antiplatelet effect at high doses).
• Melatonin (pineal hormone, but marketed as a "natural" sleep aid): Cochrane (Hansen and colleagues, 2015, CD009861) found it reduces preoperative anxiety comparably to midazolam without cognitive impairment; sleep benefit in cancer is modest. Prescription-only in the UK; non-sedating in the morning; ask the anaesthetist. This is the one "sleep" option that answers the partner's concern about sedatives directly.
• Hypnosis: randomised evidence for procedural and surgical anxiety and pain (Montgomery and colleagues, Anesthesia and Analgesia 2002 meta-analysis; Tefikow and colleagues, Clinical Psychology Review 2013). Useful for the daily mask immobilisation of proton therapy if she finds it claustrophobic; the proton centres have psychology support.
• American ginseng for fatigue: Barton and colleagues, JNCI 2013, 364 patients, modest benefit at 8 weeks; interaction with warfarin and enzyme effects; not worth adding on top of everything else.
• Mistletoe, turmeric, black seed, artemisinin, cannabinoids: covered in files 10 and 11; verdicts unchanged.

B11. Honest counter-case for Track B

Track B contains nothing that treats chordoma. The best of it (acupuncture, music, mind-body practice, CBT-I) changes pain scores by a point or two, sleep and anxiety by modest amounts, and analgesic use by a fraction. That is worth having. The risk is displacement: time, money and hope spent on supplements and diets instead of on the biopsy decision, the surgical unit choice and the proton referral, which are the things that decide the outcome.

Synthesis

1. Disease-directed options: what exists now or via trial, all gated on histology and the specialist teams

Ranked by what could actually change her outcome.

1. Get the tissue right. Fresh frozen tumour and blood at biopsy or surgery for NHS whole genome sequencing (sarcoma pathway); immunohistochemistry for brachyury, INI1/SMARCB1, p16, IDH1 R132H, PD-L1; IDH1/2 sequencing if chondrosarcoma is possible. This is the only item on the list that is entirely within the family's power to request today and it determines everything below.
2. Maximal safe endoscopic resection at a high-volume unit with a second-look habit, planned jointly with the proton centre. Intraoperative MRI is the one gadget with chordoma evidence (A9). The national skull base chordoma MDT exists precisely to make this joint plan; insist that the referral goes in before surgery.
3. Protons at the Christie or UCLH to 73.8 GyRBE. This is already the top of the international dose range. Carbon ions are equivalent on the only randomised data and are not commissioned; only a specific dosimetric problem would justify self-funded travel to Heidelberg or Pavia.
4. If histology is chondrosarcoma: IDH testing opens CHONQUER (UK sites, ivosidenib phase 3, advanced disease) and, when licensed, ozekibart. These are the only related-type trials with UK access and a positive randomised signal.
5. If the disease ever progresses: afatinib (best published numbers) or imatinib off-label through a UK sarcoma centre; DETERMINE or MegaMOST if WGS shows a matching alteration; US trials (abemaciclib, pembrolizumab plus pemetrexed, any reopened ERAS-601 cohort) via the Chordoma Foundation navigators. None is a cure; each is a chance of months of stability.
6. If histology shows INI1 loss (unlikely): tazemetostat combinations and chemotherapy enter the conversation; the national MDT will know.
7. Brachyury vaccines, degraders, CDK9 inhibitors, checkpoint inhibitors with radiotherapy, radiosensitisers, hyperthermia with protons: real science, no open trial she can join today; worth a standing question to the Chordoma Foundation every 6 months.

2. Symptom and wellbeing options with real evidence that she could use soon

1. Acupuncture for pain and opioid sparing (moderate evidence; safe; after biopsy; via pain clinic, hospice or private).
2. Music before, during and after surgery and during proton sessions (73-trial meta-analysis; free).
3. Mind-body practice: seated or breath-based mindfulness or gentle yoga now; tai chi or qigong when recovered from surgery; CBT-I (Sleepio) for sleep rather than a hypnotic. All non-sedating, all with Cochrane-level evidence for sleep, fatigue and anxiety.
4. Melatonin (prescription) as the pre-operative anxiolytic and sleep aid that does not cloud thinking; ask the anaesthetist.
5. Boswellia serrata at 4,200 mg per day as a steroid-sparing agent during and after proton therapy, only if the oncologist agrees and only if oedema or steroids become an issue. Stop 2 weeks before any surgery. The one supplement with a randomised brain trial on a relevant outcome.
6. Dietitian, not diet. Energy and protein support for a 51 kg patient facing 7 weeks of radiotherapy; ginger for opioid nausea.
7. Hypnosis or psychology support for mask immobilisation if needed; the proton centres provide it.

3. Things that sound cutting edge or ancient and should be left alone

• Ketogenic diets and fasting (two randomised glioma trials negative; she is losing weight).
• Carbon ion "medical tourism" as a default (equivalent on randomised data; unfunded; disruptive).
• Private hyperthermia, "oncothermia", immunotherapy or "dendritic cell" clinics (not the trialled technology; skull base is not heatable; no chordoma data).
• Honokiol, tanshinone, raw Tripterygium, TCM formula decoctions, ashwagandha at supplement doses, berberine while on opioids or steroids, graviola (file 11).
• Psilocybin outside a trial (illegal, and an intracranial mass is an exclusion); revisit only after treatment if distress persists and a UK trial opens.
• Brachyury vaccine or "personalised vaccine" offers from private clinics: the real vaccine failed its trial endpoint; anything else is untested.
• Any offer to "sequence and treat" privately before the NHS WGS result: the NHS test is comprehensive and free; a private panel adds nothing and may consume the tissue.

What the family should ask the national chordoma MDT

1. Will you take the case before surgery, and will the surgical plan and the proton plan be made together (margins, residual tumour left deliberately at the brainstem or basilar, timing of protons)?
2. Will fresh frozen tissue and blood be taken at biopsy or surgery for NHS whole genome sequencing, and who is responsible for requesting it?
3. Which immunohistochemistry will be done: brachyury, INI1/SMARCB1, p16, IDH1, PD-L1?
4. Does the operating unit have intraoperative MRI or CT, and what is the protocol for early postoperative MRI and second-look surgery?
5. Is there any trial in the UK or Europe, chordoma-specific or basket, that she could enter now or at progression, and who tracks that for her? Is she registered with the Chordoma Foundation and Chordoma UK?
6. If histology is chondrosarcoma: IDH status, and CHONQUER eligibility.
7. If histology is poorly differentiated: INI1 status and what changes.
8. Who is her named sarcoma medical oncologist, so that afatinib or imatinib can be considered quickly if ever needed?

What to ask the proton centre

1. What dose will you give, and does the basilar artery or brainstem force any compromise? If so, would carbon ions abroad or a different technique change that, honestly?
2. Do you allow music in the gantry, and what psychology support is there for the mask?
3. What is your policy on supplements during radiotherapy, and specifically would you support Boswellia serrata if dexamethasone is needed for oedema?
4. What are your rules on acupuncture, yoga and exercise during the 7 weeks?
5. Do you have or know of any radiosensitiser or immunotherapy-plus-radiotherapy trial for chordoma?
6. Will you bank the planning data and scans in case of a future trial or re-irradiation?

Exactly where to look for trials

• Chordoma Foundation drug and trial finder: https://www.chordomafoundation.org/drug-therapy-options/?tab=trials and the Patient Navigation Service at https://www.chordomafoundation.org/patient-navigation/
• ClinicalTrials.gov: https://clinicaltrials.gov/search?cond=chordoma&aggFilters=status:rec%20not (also search "chondrosarcoma", "sarcoma" with location United Kingdom, and "solid tumor" with a mutation name)
• EU Clinical Trials Information System (CTIS): https://euclinicaltrials.eu/search-for-clinical-trials/ (search chordoma, chondrosarcoma, sarcoma)
• NIHR Be Part of Research: https://bepartofresearch.nihr.ac.uk/ (UK trials)
• Cancer Research UK trial finder: https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial (search chordoma, sarcoma, DETERMINE)
• DETERMINE: https://www.cancerresearchuk.org/for-researchers/how-we-deliver-research/our-research-infrastructure/centre-for-drug-development/determine-precision-medicine-trial (patient and clinician pages; referral via any listed site including Southampton)
• Sarcoma UK clinical trials hub: https://sarcoma.org.uk/ (trials section)
• Chordoma UK: https://chordoma-uk.org/
• EORTC sarcoma trials: https://www.eortc.org/research_field/sarcoma/
• SARC (US sarcoma trial consortium): https://sarctrials.org/
• ChonDRAgon and ozekibart expanded access: via a UK sarcoma centre to Inhibrx Biosciences
• NHS Genomic Medicine Service test directory (sarcoma WGS): https://www.england.nhs.uk/genomics/ and the South West Genomic Laboratory Hub at North Bristol NHS Trust

Sources

Track A - Stacchiotti S, Sommer J, Chordoma Global Consensus Group. Building a global consensus approach to chordoma. Lancet Oncology 2015;16:e71-e83. PMID 25638683. - Strauss SJ et al. Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan clinical practice guideline. Annals of Oncology 2021;32:1520-1536. - Tarpey PS et al. The driver landscape of sporadic chordoma. Nature Communications 2017;8:890. PMID 29026114. - Sharifnia T et al. Small-molecule targeting of brachyury transcription factor addiction in chordoma. Nature Medicine 2019. PMID 30664779. - Sharifnia T et al. Mapping the landscape of genetic dependencies in chordoma. Nature Communications 2023. PMID 37024492. - Sheppard HE et al. Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity. Cell Reports Medicine 2021. PMC7817874. - Cote GM et al. A phase 2 study of a brachyury-targeting vaccine in combination with radiation therapy for the treatment of advanced chordoma. Cancer 2024. PMID 38985843. NCT03595228. - Chordoma Foundation. Learning from results of three recent brachyury vaccine trials. https://www.chordomafoundation.org/latest-updates/learning-from-results-of-three-recent-brachyury-vaccine-trials/ - QUILT-3.011 yeast-brachyury vaccine, NCT02383498. - Hanna GJ et al. Safety and efficacy of a selective CDK9 inhibitor (KB-0742) in adenoid cystic carcinoma. Cancer Research Communications 2025. PMID 40277179. - Teleanu MV et al. CDK4/6 inhibition in advanced chordoma: final results of the NCT PMO-1601 trial. ESMO Open 2025. PMID 40627883. NCT03110744. - Abemaciclib for sarcoma with CDK pathway alteration, NCT04040205. - Gounder M et al. Tazemetostat, an EZH2 inhibitor, in solid tumors harboring SWI/SNF alterations: a phase II basket study. Nature Communications 2026;17:7120. PMID 41882006. NCT02601950. - Immunologic correlates of the abscopal effect in a SMARCB1/INI1-negative poorly differentiated chordoma after EZH2 inhibition and radiotherapy. Clinical Cancer Research 2019;25:2064. - Tazemetostat plus nivolumab/ipilimumab in INI1-negative tumours, NCT05407441. - Magnaghi P et al. Afatinib is a new therapeutic approach in chordoma with a unique ability to target EGFR and brachyury. Molecular Cancer Therapeutics 2018;17:603. PMID 29237806. - Afatinib phase 2 in advanced chordoma, NCT03083678; ASCO 2024 abstract, Journal of Clinical Oncology 2024;42(16 suppl):11517; Chordoma Foundation summary https://www.chordomafoundation.org/latest-updates/afatinib-results-and-other-asco-advances/ - Stacchiotti S et al. Phase II study of imatinib in advanced chordoma. Journal of Clinical Oncology 2012. PMID 22331945. - Stacchiotti S et al. Imatinib and everolimus in patients with progressing advanced chordoma. Cancer 2018. PMID 30216418. - Bompas E et al. Sorafenib in patients with locally advanced and metastatic chordomas: a phase II trial of the French Sarcoma Group. Annals of Oncology 2015. PMID 26202596. - Nilotinib plus radiation in high-risk chordoma, phase 1. PMID 30077789. NCT01407198. - Liu C et al. Apatinib in patients with advanced chordoma. Lancet Oncology 2020. PMID 32888455. - Nivolumab and relatlimab in advanced chordoma, NCT03623854. Nivolumab with or without SRS, NCT02989636. Pembrolizumab and pemetrexed, NCT06794645. - Clinical response to nivolumab in an INI1-deficient pediatric chordoma. npj Precision Oncology 2021. - Shanghai Proton and Heavy Ion Center. Proton versus carbon ion radiotherapy in skull base chordoma and chondrosarcoma: initial outcomes from a phase II randomized trial. Annals of Oncology 2025, abstract 656O. - Nikoghosyan AV et al. Randomised trial of proton vs carbon ion radiation therapy in patients with chordoma of the skull base (HIT-1). BMC Cancer 2010. PMC2988755. - Uhl M et al. Highly effective treatment of skull base chordoma with carbon ion irradiation using a raster scan technique in 155 patients. Cancer 2014. PMID 24948519. - Proton and carbon ion beam treatment in 147 patients with skull base chordoma at HIT. Radiation Oncology 2023. PMC9876873. - TRP-Chordoma 2024 systematic review and meta-analysis of particle versus photon therapy. PMC11274426. - Potter GM et al. Skull base chordoma and chondrosarcoma: neuroradiologist's guide. Radiographics 2024. PMID 39298353. - Sallabanda M et al. Five-fraction proton therapy for skull base chordomas and chondrosarcomas. Cancers 2023. PMID 38067283. NCT05861245. - ISAC hypofractionated proton and carbon ion radiotherapy for sacrococcygeal chordoma. Radiotherapy and Oncology 2024. - ETOILE carbon ion trial, NCT02838602. - Limited utility of 5-ALA fluorescence in endoscopic endonasal skull base surgery. Journal of Neurosurgery 2020. PMID 33126212. - Gulsuna B et al. Intraoperative MRI assisted endoscopic endonasal resection of clival chordomas. Frontiers in Oncology 2021. PMID 35083136. - Augmented reality neuronavigation in transnasal endoscopic skull base surgery, NCT06282224. - Chordoma Foundation. New clinical trial opens testing ERAS-601; Promising results emerge from clinical trial testing ERAS-601. NCT06957327. - Ivosidenib CHONQUER, NCT06127407; phase 1 ivosidenib in chondrosarcoma, Clinical Cancer Research 2025. PMC12130799. - Ozekibart (INBRX-109) ChonDRAgon, NCT04950075; Inhibrx press release 23 October 2025; ASCO 2026 abstract 11504; Subbiah V et al. Clinical Cancer Research 2023. PMID 37265425. - Enasidenib in IDH2-mutated sinonasal and skull base tumours, NCT06176989. - Tallegas M et al. IDH mutation status in 88 head and neck chondrosarcomas. Human Pathology 2019. PMID 30296521. - DETERMINE trial: Cancer Research UK clinician and patient pages; Annals of Oncology 2023 abstract 716TiP. - MegaMOST, NCT04116541. Bergonie Institut Profiling, NCT02534649. - van der Velden DL et al. The Drug Rediscovery Protocol (DRUP). Nature 2019. - NHS England Genomic Medicine Service; South West Genomic Laboratory Hub sarcoma WGS page; 100,000 Genomes cancer programme analysis, PMC10803271. - Chordoma UK, proton beam therapy page. https://chordoma-uk.org/proton-beam-therapy

Track B - Coley's toxins history: PMC1888599; PMC11726767. - Issels RD et al. Neoadjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma. Lancet Oncology 2010;11:561. Long-term: JAMA Oncology 2018. PMID 29450452. - Datta NR et al. Hyperthermia and radiotherapy in head and neck cancers: systematic review and meta-analysis. International Journal of Hyperthermia 2016. PMID 26928474. - Tran S et al. Proton therapy with concomitant hyperthermia in large inoperable sacral chordomas. British Journal of Radiology 2020. PMID 30943055. - Singh P et al. Hyperthermia and proton beam radiation in chordoma cells. International Journal of Radiation Biology 2021. PMID 34495790. - Status quo and directions in deep head and neck hyperthermia. Radiation Oncology 2016. PMC4751675. - Rieger J et al. ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. International Journal of Oncology 2014. PMID 24728273. - Voss M et al. ERGO2: randomized trial of calorie-restricted ketogenic diet and fasting plus reirradiation for malignant glioma. IJROBP 2020. PMID 32619561. - KEATING protocol, PMC5704454. Amaral LJ et al. Scientific Reports 2025. PMID 40595067. DIET2TREAT, Journal of Clinical Oncology 2024 TPS2103. - Muscaritoli M et al. ESPEN practical guideline: clinical nutrition in cancer. Clinical Nutrition 2021. - Homoharringtonine/omacetaxine: the long road to FDA approval. PMID 23790799. - Borazanci E et al. First-in-human phase I of Minnelide. Oncologist 2024. PMID 38169017. Skorupan N et al. Future Oncology 2022. PMID 35535581. - Chen YX et al. Berberine versus placebo for prevention of recurrence of colorectal adenoma. Lancet Gastroenterology and Hepatology 2020. PMID 31926918. - Shen ZX et al. Arsenic trioxide in acute promyelocytic leukemia. Blood 1997. PMID 9129042. - Pires N et al. Safety and pharmacokinetics of withaferin-A in advanced high grade osteosarcoma: phase I. Journal of Ayurveda and Integrative Medicine 2020. PMID 30904387. - Biswal BM et al. Withania somnifera and chemotherapy-induced fatigue in breast cancer. Integrative Cancer Therapies 2013. PMID 23142798. - Kirste S et al. Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: randomized placebo-controlled double-blind pilot trial. Cancer 2011;117:3788. PMID 21287538. - Upadhyay R et al. Boswellia serrata for cerebral radiation necrosis after radiosurgery for brain metastases. IJROBP 2025. PMID 39993542. - Dejonckheere CS et al. Boswellia serrata for radiation-induced cerebral edema and necrosis: meta-narrative review. Advances in Radiation Oncology 2025. PMID 40092573. - Honokiol in glioblastoma: Phytomedicine 2016, PMID 27064011; liposomal honokiol, PMC8667111. - Griffiths RR et al. Psilocybin in patients with life-threatening cancer: randomized double-blind trial. Journal of Psychopharmacology 2016. PMID 27909165. - Ross S et al. Psilocybin for anxiety and depression in life-threatening cancer: randomized controlled trial. Journal of Psychopharmacology 2016. PMID 27909164. - Agin-Liebes GI et al. Long-term follow-up of psilocybin-assisted psychotherapy in cancer. Journal of Psychopharmacology 2020. PMID 31916890. - Hinkle JT et al. Adverse events in studies of classic psychedelics: systematic review and meta-analysis. JAMA Psychiatry 2024. PMID 39230883. - King's College London psilocybin trial, Nature Medicine 2026; TRIPS NCT06801041; NCT05847686; NCT07063862. - He Y et al. Acupuncture and acupressure for cancer pain: systematic review and meta-analysis. JAMA Oncology 2020. PMID 31855257. - Mao JJ et al. PEACE randomized clinical trial. JAMA Oncology 2021;7:720. PMID 33734288. - Paley CA et al. Acupuncture for cancer pain in adults. Cochrane 2015. CD007753. - NICE NG193 Chronic pain in over 16s, 2021. - Schell LK et al. Mindfulness-based stress reduction for women diagnosed with breast cancer. Cochrane 2019. PMID 30916356. - Cramer H et al. Yoga for breast cancer. Cochrane 2017. CD010802. Cochrane CD015520 yoga and cancer-related fatigue. - Wayne PM et al. Tai chi and qigong for cancer-related symptoms and quality of life. Journal of Cancer Survivorship 2018. PMID 29222705. - Hole J et al. Music as an aid for postoperative recovery in adults. Lancet 2015. PMID 26277246. - Bradt J et al. Music interventions in people with cancer. Cochrane 2021. PMID 34637527. - Hansen MV et al. Melatonin for pre- and postoperative anxiety in adults. Cochrane 2015. CD009861. - Ryan JL et al. Ginger for chemotherapy-related nausea. Supportive Care in Cancer 2012. - Barton DL et al. American ginseng for cancer-related fatigue. JNCI 2013. - Montgomery GH et al. Hypnosis and surgical patients, meta-analysis. Anesthesia and Analgesia 2002. Tefikow S et al. Clinical Psychology Review 2013. - LiverTox (NIH) and Memorial Sloan Kettering About Herbs monographs for ashwagandha, berberine, boswellia.

Addendum 25 Sep 2026: cetuximab single-agent phase 2

NCT05041127 (MD Anderson, sponsor; Chordoma Foundation supported). Single arm, weekly IV cetuximab, EGFR-expressing unresectable or metastatic chordoma, n=29. Active, not recruiting; completion estimated 2028-09. No results found on PubMed, ASCO or the CF site as of 25 Sep 2026. Prior human signal is case reports only, both with gefitinib: spinal cord compression regressed (PMID 18752082); partial response over 9 months of a local recurrence plus lung metastases in an EGFR-positive sacral chordoma (PMID 17202828). I first told her partner "stabilised" for the second; corrected in the message after reading the abstract. Relevance: disease after surgery and protons only; reinforces EGFR IHC on the biopsy.