Clinical Review - Sarcomas

By Dr Qamar Ghafoor, specialist registrar in clinical oncology and Dr Daniel Ford and Dr David Peake, consultants in clinical oncology at University Hospital Birmingham NHS Foundation Trust.

Osteosarcoma in the head of the tiba on the left (Photograph: SPL)
Osteosarcoma in the head of the tiba on the left (Photograph: SPL)

Section 1: Primary bone sarcomas
There are four main subtypes of primary bone sarcoma. Osteo- sarcoma is the commonest of these, with approximately 150 new cases per year in the UK.

Osteosarcoma occurs typically in adolescents and young adults, but can also occur in older patients, for example the secondary osteosarcoma associated with Paget's disease of the bone.

Whereas osteosarcoma is rarely seen before the pubertal growth spurt, Ewing's sarcoma may occur at any age from infancy through to adulthood, although it occurs less frequently in older adults.

Ewing's sarcoma
Ewing's sarcoma of soft tissue is considered to be the same entity and demonstrates the typical chromosome 11,22 translocation, which is diagnostic.

Spindle cell sarcoma of bone occurs in older adults and resembles osteosarcoma, except the malignant cells do not produce osteoid tissue.

Chondrosarcomas are cartilage-forming tumours and differ from other primary bone sarcomas in that they are resistant to chemotherapy and radiotherapy, and management is predominantly surgical.

Soft tissue sarcomas present as a lump, but only about one in 10 suspicious lumps will prove to be a sarcoma.1

NICE guidance
NICE guidance is that a soft tissue lump exhibiting any of four clinical features should be considered to be malignant until proven otherwise.1 These are size >5cm; an increase in size; pain; and a mass deep to the muscle fascia.

Bone sarcomas most commonly present with pain, typically at rest, although a mass may subsequently develop later in the course of the disease and, occasionally, presentation may be with a pathological fracture.

Because of the non-specific nature of symptoms and the fact these are rare tumours, delays in diagnosis are common. Early abnormalities on X-rays can be subtle, and should be interpreted by radiologists with adequate expertise.

As primary bone tumours occur in children and adolescents, they should be considered in the list of differential diagnoses.

Section 2: Investigation and staging
Biopsy is vital prior to definitive treatment, and requires special measures. Sarcomas can seed in the biopsy tract, resulting in implantation metastases, so it is necessary to excise the biopsy tract with the tumour.

It is therefore imperative that the biopsy is performed by either a specialist surgeon, or following discussion with the surgeon at a specialist sarcoma multidisciplinary team meeting.

Pre-operative staging for a soft tissue sarcoma includes an MRI of the primary tumour site and a CT of the thorax to exclude lung metastases. An isotope bone scan is a standard procedure for bone tumours. Other investigations should be as clinically indicated or are governed by specific tumour types.

Tumour, node, mestatases staging
Both soft tissue and bone sarcomas may be staged according to the tumour, node, metastases (TNM) classification (see tables below).2 Staging also takes into account the histological grade of the tumour.

Staging of sarcomas

STAGE I
1A - Low grade, small, superficial or deep (T1a-b, N0, M0) 1B
     - Low grade, large, superficial (T2a, N0, M0)

 

STAGE II
IIA - Low grade, large, deep (T2b, N0, M0); IIB – High grade, small, superficial or deep (T1a-b, N0, M0); IIC – High grade, large, superficial (T2a, N0, M0)

 

STAGE III
High grade, large, deep (T2b, N0, M0)

 

STAGE IV
Any metastasis (any G, any T, N1 or M1) 

 

Malignant bone tumours
 Stage  Description
 T1
Tumour 8cm or less in greatest dimension
 T2 Tumour more than 8cm in greatest dimension
 T3 Discontinuous tumours in the primary bone site
 N0 No regional lymph node metastasis
 N1 Regional lymph node metastasis
 M0 No distant metastasis
 M1 Distant metastasis

 

Soft tissue tumours
T1 Tumour 5cm or less in greatest dimension
T1a Superficial tumour
T1b Deep tumour
T2 Tumour more than 5cm in greatest dimension
T2a Superficial tumour
T2b Deep tumour
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M0 No distant metastasis
M1 Distant metastasis

In the UK, the Trojani classification is most commonly used. This describes three grades of tumour - G1 low grade, G2 intermediate grade and G3 high grade.

However, for staging purposes, G2 and G3 are grouped together as high grade. An alternative system describing four grades is also in use, low grade including G1 and G2 and high grade G3 and G4.

It should be noted that, unlike most cancers, lymph node and distant metastases carry the same prognostic significance and are grouped together as stage IV disease.

Correct staging determines appropriate treatment and provides information on prognosis.

Because of the rarity of these tumours it is essential that patients are managed by a specialist multidisciplinary team including surgeons, oncologists, radiologists and pathologists in order to achieve optimal outcomes.

While the treatment for most adult type soft tissue sarcomas (STS) is broadly similar, as our understanding of this heterogeneous group of tumours improves it is becoming increasingly possible to tailor treatment according to individual history.

Section 3: Treatment of soft tissue sarcomas
The mainstay of treatment of adult type STS is surgery.3 The aim must be to achieve complete tumour resection.

Amputation was often necessary in order to achieve the wide surgical margins necessary for local control. However, current practice is to use conservative surgery combined with adjuvant radiotherapy.

Provided clear surgical margins are obtained, this approach results in equivalent local control and survival but with better functional outcome when compared with more extensive surgery.4

If it is not possible to achieve clear surgical margins by conservative surgery, then amputation may still be necessary.

Radiotherapy
Adjuvant postoperative radiotherapy (typically over six weeks) is standard in the UK, unless the patient has undergone radical surgery or has had a small, low grade tumour.

Pre-operative radiotherapy has been demonstrated to improve functional outcome with equivalent rates of local control but is associated with an increase in postoperative wound complications.5

Chemotherapy
The role of adjuvant chemotherapy remains unproven. Although not regarded as standard treatment in the UK, there is conflicting evidence and it may be considered for individuals.

A meta-analysis from 1997 reported an improvement in local control and progression-free survival.6 However, although there was a trend towards an overall survival benefit this was not statistically significant.

This data has been supported by two more recent overviews.7,8 The latter included data from a large Italian trial which, when published in 2001, reported a significant survival benefit for adjuvant chemotherapy, but this has not been maintained with long-term follow up.9

The preliminary data from EORTC 62931, the largest trial of adjuvant chemotherapy for STS, has failed to demonstrate any benefit from chemotherapy in local control, progression-free survival or overall survival.10

Treatment of metastatic disease
Metastatic disease from STS is almost always fatal, and treatment is therefore generally regarded as palliative in intent.

Palliative chemotherapy may improve quality of life and prolong life, but the response rates are only 20-30 per cent at best, and benefits of treatment must be considered against potential toxicity. The median survival of patients with metastatic disease is approximately 12 months.

Section 4: Treatment of bone sarcomas
The management is governed by histological subtype. Chondrosarcoma is generally treated by surgery alone and is relatively chemoand radio-resistant.

Chemotherapy has had a major impact on the treatment of patients with osteosarcoma and Ewing's sarcoma. Before the introduction of chemotherapy, the five-year survival of patients was less than 20 per cent, with many patients dying within the first two years.

However, with modern chemotherapy regimens, the five-year survival is now approximately 60 per cent for patients without metastases at diagnosis.

Patients with osteosarcoma receive 10 weeks of chemotherapy before surgery, with approximately a further 20 weeks of post-operative chemotherapy.

The regimen for Ewing's sarcoma is more prolonged, with approximately three months pre-operative and five months post operative treatment.

Endoprosthetic implants
Historically, the only surgical option for most bone sarcoma patients was amputation, but with modern surgical techniques and the development of custom-made endoprosthetic implants, amputation is now rarely necessary.

As surgery is often on patients who have not reached skeletal maturity, endoprostheses may need lengthening to avoid a discrepancy in limb length.

Radiotherapy is commonly included in the management of Ewing's sarcoma. Radical radiotherapy is an alternative to surgery, for example in the pelvis, when surgery would result in major morbidity and a poor functional outcome, and it is also used as an adjuvant treatment after surgery.

There is no standard role for radiotherapy in the management of localised osteosarcoma, but it is considered in individual patients on occasion.

Spindle cell sarcoma of the bone is similar to osteosarcoma in behaviour and management. However, because of the age of the population affected, the chemotherapy regimens may require modification to avoid undue toxicity.

A proportion of patients with metastatic disease can be cured, and the initial approach in those presenting with metastases is chemotherapy as for localised disease. Those with isolated pulmonary metastases have a better prognosis, whereas bone metastases have a much worse outcome.

Long-term survival may be achieved by an aggressive surgical approach to the management of lung metastases from osteosarcoma, and some patients may undergo several thoracotomies.

High-dose chemotherapy with autologous peripheral stem cell transplantation is currently under investigation for patients with poor prognosis Ewing's sarcoma.

Follow up
There is no published data supporting specific follow-up protocols for patients with STS, and a recent survey has reported a varied approach at different centres throughout the UK.11

The value of follow up is to reassure patients that are well, and for recurrent disease to potentially be identified early when salvage treatment is an option.

Consensus guidelines will recommend that follow up should be every three to four months for the first two to three years, six monthly until five years and then annually thereafter.

Prognosis
About half of all patients presenting with non-metastatic, high-grade soft tissue sarcomas will subsequently die from their disease.

Prognostic factors include histological subtype, tumour size (>10 cm have a poor prognosis) and site (deep tumours have a worse prognosis).

Histological response to chemotherapy is a powerful prognostic factor in bone tumours. Less than 10 per cent viable tumour remaining after chemotherapy is associated with significantly better survival.

Resources
1. NICE. Improving Outcomes for People with Sarcoma: the manual. London, NICE. 2006.

2. Sobin LH, Wittekind C. TNM Classification of Malignant Tumours. 6th Ed. Hoboken, New Jersey, John Wiley and Sons, 2002.

3. Hoekstra HJ, Thijssens K, van Ginkel RJ. The Role of surgery as primary treatment and as intervention in the multidisciplinary treatment of soft tissue sarcoma. Ann Oncol 2004; 15 Suppl 4: 181-6.

4. Yang JC, Chang AE, Baker AR et al. Randomised prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1988; 16: 197-203.

5. O'Sullivan B, Davis AM, Turcotte R et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002; 359: 2235-41.

6. The Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: a meta-analysis of individual data. Lancet 1997; 350: 1647-54.

7. The Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised respectable soft tissue sarcoma in adults. Cochrane Database Syst Rev 2000; (4): CD001419.

8. Pervaiz N, Colterjohn N, Farrokhyar F et al. Systemic meta-analysis of randomised controlled trials of adjuvant chemotherapy for localised respectable soft tissue sarcoma. Cancer 2008; 113(3): 573-81.

9. Frustaci S, Gherlinzoni F, De Paoli A et al. Adjuvant chemotherapy for adult sarcomas of the extremities and girdles: Results of the Italian Randomised Cooperative Trial. J Clin Oncol 2001; 19(5): 1238-47.

10. Woll PJ, van Glabbeke M, Hohenberger P et al. Adjuvant chemotherapy with doxorubicin and ifosfamide in resected soft tissue sarcoma: Interim analysis of a randomised phase III trial. ASCO Annual Meeting Proceedings. J Clin Oncol 2007; 25: Suppl 18S.

11. Gerrand CH, Billingham LJ, Woll PJ et al. Follow up after treatment of soft tissue sarcoma: A survey of current practice in the United Kingdom. Sarcoma 2007; 2007: 34128.

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