Radiation-Induced Sarcoma

Radiation induced sarcoma is a soft tissue or bone sarcoma arising within a previously irradiated field after a latent period, with histology different from the original tumour. It is a rare late effect and is more aggressive than sporadic sarcoma.

Diagnostic criteria. Previous irradiation of the site, a latent period usually of at least 3 to 5 years (many cases arise after 10 to 15 years), tumour arising within the irradiated field, and histologically proven sarcoma that differs from the original tumour.

Epidemiology. Cumulative incidence after radiotherapy is about 0.03 to 0.8%. Risk rises with dose (usually over 20 to 30 Gy, most cases over 50 Gy) and with time. Common prior sites are breast, lymphoma, cervix, prostate and head and neck, and childhood cancers.

Types. Undifferentiated pleomorphic sarcoma, osteosarcoma, angiosarcoma (breast and chest wall), fibrosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumour and chondrosarcoma.

Prognosis. Five year survival is generally under 50% even with complete resection, and lower for angiosarcoma and unresectable disease.

Pathophysiology.

Radiation causes DNA damage and genomic instability in mesenchymal cells, with TP53 and RB1 alterations. Post-radiation angiosarcoma of the breast is characterised by MYC amplification.

Impaired local blood supply and chronic inflammation in irradiated tissue favour malignant transformation.

• A new or enlarging mass in the irradiated field, painless or painful.
• Angiosarcoma: bruise like violaceous patches or nodules in breast or chest wall skin, with swelling.
• Bone sarcoma: pain, swelling and pathological fracture.

Red flags.

• Rapid growth, ulceration or bleeding of a mass.
• New neurological deficit from a tumour near a nerve or the spine.
• Dyspnoea, cough or haemoptysis (lung metastases).

• Obtain radiotherapy records: site, dose, fractions and date.
• MRI of the site and CT of the chest; whole body staging as needed.
• Image directed core biopsy planned with the sarcoma surgeon so that the track can be excised.
• Histology with immunohistochemistry (CD31 and ERG for angiosarcoma) and MYC testing where relevant.

Differential diagnosis. Recurrence of the original cancer, radiation fibrosis, atypical vascular lesion after radiotherapy, benign soft tissue tumour, desmoid tumour, haematoma, abscess.

• Multidisciplinary review at a sarcoma centre.
• Wide surgical excision with clear margins is the main treatment, often radical because of previous radiation. Re-irradiation is limited and used in selected cases.
• Doxorubicin 60 mg/m2 intravenously every 21 days for up to 6 cycles. Maximum cumulative dose 450 to 550 mg/m2, counting any earlier anthracycline, and lower limits apply after previous chest or mediastinal radiotherapy. Monitor echocardiography before treatment and at cumulative doses over 300 mg/m2, plus blood counts. Reduce by 50% when bilirubin is 20 to 50 micromol/L, by 75% when 51 to 85 micromol/L, and avoid when over 85 micromol/L. Avoid in significant cardiac disease and pregnancy.
• Angiosarcoma: paclitaxel 80 mg/m2 intravenously over 1 hour on days 1, 8 and 15 of each 28-day cycle, until progression or intolerance, with premedication (dexamethasone 10 mg, chlorphenamine 10 mg and famotidine 20 mg intravenously). Maximum 80 mg/m2 each dose. Monitor full blood count before each dose (hold for neutrophils under 1.0 x 10^9/L or platelets under 100 x 10^9/L), neuropathy and hypersensitivity. Reduce by 25% in mild and 50% in moderate hepatic impairment and avoid in severe impairment; no renal adjustment.
• Metastatic disease: palliative systemic therapy and early palliative care involvement.

Monitoring. Examination and imaging of the site and chest every 3 to 4 months for 2 years, then every 6 months to 5 years, then yearly.

Referral and escalation. Sarcoma centre at first suspicion, before any biopsy or excision; palliative care for advanced disease; occupational physician for dose review and compensation where required.