What evidence‑based systemic therapies are available for metastatic sacral chordoma?

Systemic Therapy for Metastatic Sacral Chordoma

There is no standard of care systemic therapy for metastatic sacral chordoma, but imatinib and sorafenib represent the most evidence-based palliative options to slow disease progression, though neither is curative. 1

Primary Therapeutic Options with Evidence

Imatinib (Most Established Agent)

• Imatinib is the most commonly used systemic agent, though evidence remains limited and access varies significantly by healthcare system 1
• A phase II trial of 56 patients demonstrated 70% achieved stable disease, with a clinical benefit rate of 64% and median progression-free survival of 9 months 1
• Tumor liquefaction on CT imaging may occur after prolonged treatment (≥1 year), with earlier changes visible on MRI (decreased contrast enhancement) and PET (decreased glucose uptake) 2
• Mechanism of action: targets platelet-derived growth factor receptor-beta (PDGFRB), which is phosphorylated/expressed in chordoma tumors 2
• Critical limitation: Not uniformly available within some healthcare systems (e.g., NHS) as it is not commissioned for this indication 1

Sorafenib (Second Most Established)

• Sorafenib has the second-greatest evidence of efficacy alongside imatinib and represents a reasonable palliative treatment option 1
• Primarily stabilizes disease rather than producing objective tumor shrinkage 3

EGFR Inhibitors (Emerging Evidence)

• EGFR inhibitors show potential benefit in small retrospective series: erlotinib, gefitinib, and cetuximab 1
• May be available through compassionate-access schemes, but additional evidence is required for standard of care acceptance 1
• Afatinib is currently under investigation in the first prospective international trial, with results eagerly awaited 1
• Case reports demonstrate activity in patients with advanced chordoma resistant to prior imatinib therapy 1

Immune Checkpoint Inhibitors (Promising but Investigational)

• Show promise in retrospective single-center series, but prospective studies are warranted to evaluate efficacy 1
• May be considered for patients with high tumor mutational burden or high PD-L1 expression 4

Agents with Limited or Anecdotal Evidence

Other Targeted Therapies

• Sunitinib: Case reports note activity 1
• mTOR inhibitors (everolimus, rapamycin): Under investigation 4
• Combination regimens: Imatinib plus cisplatin or sirolimus has shown effectiveness in small series of imatinib-resistant patients 1

Cytotoxic Chemotherapy

• Cytotoxic chemotherapy is generally inactive and not recommended 1
• Exception: Anecdotal responses reported in high-grade dedifferentiated chordoma and some pediatric cases 1

Clinical Response Patterns and Expectations

Response Assessment Challenges

• Best objective response with targeted therapies is disease stabilization in 52-69% of cases, not tumor shrinkage 3
• Stable disease occurred in 58.1% of cases, partial responses in 28.2%, and disease progression in 13.7% despite targeted therapy 5
• Response patterns evolve slowly compared to other malignancies, similar to gastrointestinal stromal tumors but more gradual 2

Common Adverse Events

• Fatigue (47.1%), skin reactions (32.4%), hypertension (23.5%), diarrhea (17.6%), and thyroid abnormalities (5.9%) 5

Treatment Algorithm for Metastatic Sacral Chordoma

Step 1: Assess for Oligometastatic Disease

• If oligometastatic: Consider local treatments (surgery, radiofrequency ablation, cryotherapy, or stereotactic radiotherapy) before systemic therapy 1

Step 2: Determine Disease Tempo

• If asymptomatic with slow progression: Active surveillance may be appropriate, as the naturally indolent course means systemic therapy may not alter outcomes 1
• If symptomatic or progressive: Proceed to systemic therapy 1

Step 3: Select Systemic Agent

• First-line: Imatinib 800 mg daily (if accessible) 1, 2
• Alternative first-line: Sorafenib 1
• Second-line (after imatinib failure): EGFR inhibitors (erlotinib, gefitinib, cetuximab) through compassionate access 1
• Consider molecular profiling to guide experimental therapy selection, particularly for INI1 loss (may predict EZH2 inhibitor sensitivity) 1

Step 4: Clinical Trial Enrollment

• Patients should be recruited to clinical trials wherever possible, as this is the only pathway to improving outcomes 1

Critical Pitfalls to Avoid

Unrealistic Expectations

• Do not present systemic therapy as curative: The goal is palliative disease stabilization and symptom control, not cure 1
• Metastatic chordoma has extremely poor survival rates and local control is rarely achievable 1

Response Assessment Errors

• Do not rely solely on RECIST criteria: Tumor liquefaction and metabolic changes on PET may precede dimensional changes by months 2
• Monitor with serial MRI and PET imaging in addition to CT to detect early treatment effects 2

Treatment Selection Mistakes

• Do not use cytotoxic chemotherapy except in rare dedifferentiated variants 1
• Do not delay palliative care integration: Given poor prognosis, supportive care should be incorporated from the beginning 1

Quality of Life Considerations

Symptom Management Priority

• Pain control is paramount: Most patients suffer from somatic and neuropathic pain requiring specialized management 1
• Balance treatment morbidity against expected disease control: Systemic therapy toxicity must be weighed against modest benefits 1

Palliative Care Integration

• Early palliative care referral is essential for difficult symptom control and end-of-life planning 1
• Treatment decisions should address goals of care, including when to forego or stop antineoplastic treatment 1