Radiotherapy in Musculoskeletal Tumours

The spectrum. Radiotherapy kills tumour cells by causing DNA damage, and tumours vary greatly in how sensitive they are. Where a tumour sits on that spectrum determines whether radiotherapy is curative in intent, an adjunct to surgery, or palliative.

Radiosensitive tumours. Ewing sarcoma, lymphoma and myeloma of bone, and metastases, which are treated palliatively. Radiotherapy has a major therapeutic role in all of them.

Radioresistant tumours. Notably osteosarcoma and chondrosarcoma. Both are managed primarily by surgery, with chemotherapy for osteosarcoma, and radiotherapy is reserved for unresectable disease or palliation.

The lethal lesion. Radiotherapy kills cells mainly by DNA double-strand breaks, generated partly through reactive oxygen species. Hence the oxygen effect: well-oxygenated cells are more radiosensitive, while hypoxic tumour regions, and the poorly vascularised, matrix-rich tissue of chondrosarcoma, are relatively radioresistant.

Intrinsic radiosensitivity. Lymphoid and Ewing cells are intrinsically sensitive. Osteosarcoma and chondrosarcoma are intrinsically resistant.

The 4 Rs of fractionation. Dividing the dose exploits four processes, and the net effect is to kill tumour while sparing normal tissue:

• Repair of sublethal damage, which normal late-responding tissue does between fractions better than tumour
• Redistribution of cells into the radiosensitive phases (mitosis and late G2)
• Repopulation, the tumour regrowing during a course, which is why prolonged gaps are avoided
• Reoxygenation, previously hypoxic cells reoxygenating and becoming more sensitive

The alpha/beta ratio. It is high, around 10 Gy, for early-responding tissue and most tumours, and low, around 3 Gy, for late-responding normal tissue and slow-growing tumours (chondrosarcoma, chordoma). Low-alpha/beta tissues are relatively spared by fractionation but benefit from a higher dose per fraction, which is the rationale for hypofractionation, SBRT and proton therapy in chordoma.

What radiotherapy buys. For high-grade, large or deep soft-tissue sarcoma, wide local excision combined with radiotherapy achieves local control comparable to amputation while preserving the limb. Radiotherapy is generally indicated for high-grade or large/deep tumours and for close or positive margins.

Before or after surgery. Local control is similar with either timing, so the choice balances early wound morbidity against late functional morbidity.

• Neoadjuvant (pre-operative) radiotherapy uses a smaller field and a lower dose, and can downsize the tumour and reduce late effects, at the cost of more acute wound-healing complications and dehiscence
• Adjuvant (post-operative) radiotherapy uses a larger field and a higher dose, with more late fibrosis, joint stiffness and oedema/lymphoedema

Putting a number on the wounds. The randomised trial that settled it allocated 190 adults with limb soft-tissue sarcoma to pre-operative radiotherapy (50 Gy in 25) or post-operative radiotherapy (66 Gy in 33). Wound complications within 120 days occurred in 35% of the pre-operative group and 17% of the post-operative group, an absolute difference of 18% (95% CI 5 to 30, p=0.01). Roughly one in three irradiated-then-operated patients has a wound problem, against one in six operated-then-irradiated.

Site and size. Tumour size and anatomical site were themselves significant predictors, so the 35% is not uniform. A large proximal thigh sarcoma with generous soft-tissue cover is a different proposition from a distal leg or foot, where the skin is thin, the coverage poor and a wound problem far harder to salvage.

The survival signal. Overall survival was slightly better in the pre-operative group (p=0.0481), which is why the higher wound rate has not driven practice to post-operative treatment. The trade-off is early wound morbidity against late fibrosis, with a possible survival signal in favour of the pre-operative arm.

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Soft-tissue sarcoma. Neoadjuvant radiotherapy is typically around 50 Gy in 25 fractions. Adjuvant radiotherapy is a higher 60 to 66 Gy over a larger field with a tumour-bed boost, and the higher dose and larger field explain the greater late fibrosis. Ultra-hypofractionated regimens, for example 30 or more Gy in 5 fractions, are under study, per the cited Fan cohort.

Palliation of bone metastases. A single 8 Gy fraction relieves pain as effectively as multifraction schedules such as 20 Gy in 5 or 30 Gy in 10 fractions, though single-fraction treatment has a higher re-treatment rate. Multifraction is often preferred for cord compression, post-operative fields or a large soft-tissue component.

SBRT. A high dose in a few fractions, for oligometastatic disease and spinal metastases, including relatively radioresistant histologies.

Ewing sarcoma. Definitive radiotherapy uses a moderate-to-high dose, integrated with chemotherapy.

Several of the late complications are determined by field design, and three planning rules are the surgeon's business because they constrain what the surgeon does.

Spare a longitudinal strip of skin and subcutaneous tissue. Circumferential irradiation of a limb destroys the lymphatic channels running along its length, and the result is intractable distal lymphoedema. Modern conformal and IMRT planning deliberately leaves an unirradiated corridor, and a limb should not be irradiated circumferentially unless there is no alternative.

Put the biopsy tract and any drain sites inside the field. They are contaminated by definition and are treated as part of the tumour. This is why a biopsy tract has to be in line with the future incision, and a drain brought out in line with it too: a transversely placed tract or a remote drain site forces the field to be enlarged, or leaves contaminated tissue outside it. The biopsy principles are in Biopsy Principles and Techniques.

Limit bone and joint dose where possible. Irradiated bone is the substrate for insufficiency fracture, and an irradiated joint stiffens.

Time the operation and plan the closure. After neoadjuvant radiotherapy, surgery is classically at around 4 to 6 weeks to limit wound complications: long enough for the acute skin reaction to settle, not so long that fibrosis sets in. Plan the closure before starting. An irradiated bed with a large defect is a plastic-surgical problem, and involving the plastic surgeons after the wound has broken down is worse than involving them before the incision.

Ewing sarcoma. Radiotherapy, integrated with chemotherapy, gives local control when surgery is not feasible or margins are inadequate.

Lymphoma and myeloma. Bone lymphoma and solitary plasmacytoma/myeloma are very radiosensitive and frequently treated with radiotherapy.

Bone metastases. Palliative radiotherapy relieves pain, is given after internal fixation of an impending or pathological fracture, and treats metastatic spinal cord compression, with or without surgery.

Modalities. Radiotherapy can be delivered as:

• External-beam radiotherapy, conventional or IMRT
• Brachytherapy
• Stereotactic body radiotherapy (SBRT)
• Proton-beam therapy, for example for chordoma and spinal tumours, to spare the spinal cord