These guidelines were drawn up following a consensus meeting of UK sarcoma specialists convened under the auspices of the British Sarcoma Group and are intended to provide a framework for the multidisciplinary care of patients with soft tissue sarcomas. The guidelines published by the European Society of Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) were used as the basis for discussion and adapted according to UK clinical practice and local requirements. Note was also taken of the National Institute for Health and Clinical Excellence (NICE) improving outcomes guidance (IOG) for people with sarcoma and existing technology appraisals. The guidelines are not intended to challenge NICE guidance but discrepancies may exist where current guidance does not reflect an international standard of care owing to the ever-evolving nature of cancer treatment. It is acknowledged that these guidelines will require updating on a regular basis. An appendix lists the key recommendations which are summarised below. Any patient with a suspected soft tissue sarcoma should be referred to a diagnostic centre and managed by a specialist sarcoma multidisciplinary team. Surgical excision followed by post operative radiotherapy is the standard management of high grade limb sarcomas although occasionally amputation remains the only option. Pre-operative treatment with chemotherapy or radiotherapy should be considered for patients with borderline resectable tumours. Isolated limb perfusion may permit limb salvage in some cases where amputation is the only other option. Adjuvant chemotherapy is not routinely recommended but may be considered in certain specific situations. Regular follow up is recommended to assess local control and the development of metastatic disease. Single agent doxorubicin is the standard first line therapy for metastatic disease. Ifosfamide is an alternative if anthracyclines are contraindicated. Combination therapy may be considered in individual patients. Second line agents include ifosfamide, dacarbazine, trabectedin and the combination of gemcitabine + docetaxel. Surgical resection of local recurrence and pulmonary metastases should be considered in individual patients. There is specific guidance on the management of retroperitoneal and uterine sarcomas.
Soft tissue sarcomas (STS) are a relatively uncommon group of malignancies. Although over the past few years, there have been advances in the understanding of the pathology, clinical behaviour and the treatment of this heterogeneous group of tumours, there was a concern that there was often no recognised “standard of care” for these patients in the UK. In the US, the National Comprehensive Cancer Network (NCCN) soft tissue sarcoma guidelines are highly regarded [
These guidelines are not intended to be prescriptive, but aim to improve the quality of care for patients with STS by helping identify and inform the key decisions involved in their management.
The NCCN and ESMO guidelines together with the National Institute for Health and Clinical Excellence Improving Outcomes Guidance for people with sarcoma (NICE-IOG) [
These recommendations apply principally to “adult type” soft tissue sarcomas arising from limbs and trunk and although, where appropriate, specific guidance is given according to histological subtype it is recognised that some tumours, for example, Ewing’s sarcoma and embryonal and alveolar rhabdomyosarcoma require a different approach to management, and these are excluded from this guidance [
These guidelines focus on clinical effectiveness, giving a picture of what treatments a specialist sarcoma multidisciplinary team should have access to within the UK, subject to some flexibility to allow for evolving practice, but, they do not purport to employ the same detailed analysis of cost effectiveness as NICE. These Guidelines can be considered to represent a broad consensus in 2010. They will need updating as treatment evolves.
Sarcomas are relatively uncommon tumours accounting for approximately 1% of all adult cancers [
Historically, because of the heterogeneity of this group of tumours, the true incidence has generally been under-reported. Recent estimates from the cancer networks suggest that about 3000 patients (all sarcomas) are diagnosed per annum in the UK, including sarcomas of the head and neck, gynaecological sarcomas and GIST that were either not accurately diagnosed in the past, or not captured by cancer registries.
Soft tissue sarcomas may occur at any age, and although most common in middle aged and older adults, they are relatively more common in children and young adults, accounting for 7–10% of paediatric malignancies. They are an important cause of death in the 14–29 years age group [
Approximately half of all STS patients with intermediate or high-grade tumours develop metastatic disease requiring systemic treatment [
For the vast majority of cases, the aetiology is unknown, although there are certain genetic associations, such as the 10% lifetime risk of malignant peripheral nerve sheath tumour (MPNST) in individuals with familial neurofibromatosis, caused by mutations in the
Due to the heterogeneous sites of origin of STS, it is difficult to clearly define the clinical features of the disease. However, any soft tissue lump exhibiting any of the following four clinical features should be considered to be malignant until proved otherwise [ increasing in size, size >5 cm, deep to the deep fascia, painful.
The more of these clinical features present, the greater the risk of malignancy with increasing size being the best individual indicator.
Any patient with a soft tissue mass that is increasing in size, has a size >5 cm or is deep to the deep fascia, whether or not it is painful, should be referred to a diagnostic centre with a suspected STS.
Any patient with a suspected STS should be referred to a diagnostic centre for triple assessment with clinical history, imaging and biopsy [
The standard approach to diagnosis of a suspicious mass is core needle biopsy—several cores should be taken to maximise diagnostic yield. However, an incisional biopsy may be necessary on occasion and excisional biopsy may be the most practical option for superficial lesions <5 cm diameter. The biopsy should be planned in such a way that the biopsy tract can be safely removed at the time of definitive surgery to reduce the risk of seeding and should be performed either at a diagnostic clinic or by a sarcoma surgeon or radiologist following discussion with the surgeon. Fine needle aspiration (FNA) is not recommended as a primary diagnostic modality, although it may be useful in confirming disease recurrence.
Histological diagnosis should be made according to the WHO Classification to determine the grade and stage of the tumour [
FNCLCC histological grading criteria [
Tumour differentiation | Necrosis | Mitotic count ( |
---|---|---|
1: well | 0: absent | 1: |
2: moderate | 1: <50% | 2: 10–19 |
3: poor (anaplastic) | 2: ≥50% | 3: |
The sum of the scores of the three criteria determines the grade of malignancy. Grade 1: 2, 3; Grade 2: 4, 5; Grade 3: 6, 7, 8.
Pathologic diagnosis relies on morphology and immunohistochemistry. It should be complemented, for those diagnoses characterised by a chromosomal translocation, using molecular pathology, for example, fluorescent in-situ hybridisation (FISH) or reverse transcription polymerase chain reaction (RT-PCR), in particular when the clinical pathologic presentation is unusual, or the histological diagnosis is doubtful.
The report on the resected specimen should comply with the recommendations for reporting of STS produced by the Royal College of Pathologists. The pathology report should include an appropriate description of tumour margins (i.e., whether they are intralesional, marginal, or wide, and include distance from surrounding tissues, or the presence of an anatomical barrier). The pathologic assessment of margins should be made in collaboration with the surgeon. Tumour size and grade should be documented.
Four categories of surgical margin have been described histologically: intralesional, marginal, wide and radical [
Margin runs through tumour and therefore tumour remains.
Surgical plane runs through pseudocapsule (reactive zone). The local recurrence rate is high because of tumour satellites in the reactive tissue.
Surgical plane is in normal tissue but in the same compartment as the tumour.The recurrence rate is low and is related only to skip lesions in the affected compartment.
The tumour is removed including affected compartments and there is a minimal risk of local recurrence.
If feasible, it is recommended that tumour samples should be collected and frozen both for future research and because new molecular pathological assessment techniques may become available later that could yield new information of direct value to the individual patient. Any tissue thus obtained is governed by the Human Tissue Authority; hence appropriate informed consent will need to be obtained from the patient.
If preoperative treatment (such as neo-adjuvant chemotherapy and/or pre-operative radiotherapy) was undertaken, the pathology report should include an assessment of tumour response to therapy. However, in contrast with bone sarcomas, no validated system is currently available for STS, and the percentage of residual “viable cells” is not considered to have a specific prognostic significance.
Several different staging systems may be used in STS management. The most widely accepted STS classification system produced jointly by the American Joint Committee on Cancer (AJCC)/International Union against Cancer (UICC) includes information on both the grade and stage of the tumour (Table
AJCC TNM Classification for STS [
Classification | Description |
---|---|
Primary Tumour (T) | |
TX | Primary tumour cannot be assessed |
T0 | No evidence of primary tumour |
T1 | Tumour ≤5 cm in greatest dimension |
T1a Superficial tumour | |
T1b Deep tumour | |
T2 | Tumour >5 cm in greatest dimension |
T2a Superficial tumour | |
T2b Deep tumour | |
Regional lymph nodes (N) | |
NX | Regional lymph nodes cannot be assessed |
N0 | No regional lymph node metastasis |
N1 | Regional lymph node metastasis |
Distant metastasis (M) | |
MX | Distant metastasis cannot be assessed |
M0 | No distant metastasis |
M1 | Distant metastasis |
Histologic grade (G)* | |
GX | Grade cannot be assessed |
G1 | Well-differentiated |
G2 | Moderately differentiated |
G3 | Poorly differentiated |
G4 | Poorly differentiated or undifferentiated |
Physical examination, diagnostic radiology and biopsy provide the AJCC criteria input data needed to stage STS.
The final stage grouping is thus as follows.
1A = low grade, small, superficial or deep (G1-2, T1a-b, N0, M0).
1B = low grade, large, superficial (G1-2, T2a, N0, M0).
IIA = low grade, large, deep (G1-2, T2b, N0, M0).
IIB = high grade, small, superficial or deep (G3-4, T1a-b, N0, M0).
IIC = high grade, large, superficial (G3-4, T2a, N0, M0).
High grade, large, deep (G3-4, T2b, N0, M0).
Any Metastasis (Any G, Any T, N1 or M1).
Magnetic resonance imaging (MRI) and core needle biopsy are recommended prior to definitive surgery. Imaging of the thorax by CT scan for lung metastases should be done prior to radical treatment. All patients with a suspected STS should be managed by a specialist Sarcoma MDT as specified in the NICE guidance.
Soft tissue sarcomas are a diverse group of tumours and as our understanding of the differing natural history and response to treatment improves it is increasingly possible to tailor treatment according to the individual histology. The major therapeutic goals are long-term survival, avoidance of local recurrence, maximising function and minimising morbidity.
All patients should have their care managed by a formally constituted Sarcoma MDT. Decisions about surgery, chemotherapy, radiotherapy and the timing of all these modalities should be made by the Sarcoma MDT. For site specific STS (e.g., Gynaecological, head and neck) there should be a formal relationship between the sarcoma MDT and the site-specific MDT.
Conservative surgery combined with post operative radiotherapy is standard treatment of limb and truncal tumours in the UK and achieves high rates of local control whilst maintaining optimal function. Radiotherapy may be avoided in patients with low grade tumours that have been completely resected or those with small, superficial high grade tumours resected with wide margins. Table
S uggested managment of extremity STS - adapted from ESMO guidance.
Adultsoft tissue sarcoma | Standard | Individualized | Investigational |
Extremities or superficial trunk | |||
Primary, low-grade, superficial | Surgery: wide excision | ||
Primary, low-grade, deep and | Surgery: wide excision | ||
Primary, low-grade, deep and | Surgery: wide excision | ||
Primary, high-grade, superficial | Surgery: wide excision | ||
Primary, high-grade, deep, | Surgery: wide excision | Surgery: wide excision | |
Primary, high-grade, deep, | Surgery: wide excision | Surgery: wide excision | Neoadjuvant chemotherapy |
Compartmental resection | Compartmental resection | ||
Local recurrence, low-grade | Surgery: wide excision | Surgery: wide excision | Isolated limb perfusion |
Local recurrence, high-grade | Surgery: wide excision | Surgery: wide excision | Isolated limb perfusion |
Surgery: compartmental resection | Surgery: compartmental resection |
Surgery is the standard treatment for all patients with adult-type, localised soft tissue sarcomas, and it should be performed by an appropriately trained surgeon. Evaluation of the resectability of a tumour is determined by the surgeon in consultation with the MDT, and depends on the tumour stage and the patient’s co-morbidity. The primary aim of surgery is to completely excise the tumour with a margin of normal tissue. What constitutes an acceptable margin of normal tissue is not universally agreed but is commonly accepted as 1 cm soft tissue or equivalent (e.g., a layer of fascia). However, on occasion, anatomical constraints mean that a true wide resection is not possible without the sacrifice of critical anatomical structures (such as major nerves, or blood vessels) and in this situation, it may be acceptable to leave a planned microscopic positive surgical margin, having considered the risks of recurrence and morbidity of more radical surgery and having discussed these fully with the patient [
For patients who have undergone surgery and have an unplanned positive margin, re-excision should be undertaken if adequate margins can be achieved. Macroscopic residual disease imparts a poor prognosis and local control is unlikely to be achieved even with addition of post operative radiotherapy [
Patients with tumours that, because of size or position, are considered borderline resectable should be considered for down staging treatment (neo-adjuvant) with either chemotherapy or radiotherapy depending on histology of the tumour and the performance status of the patient (see below).
In some situations amputation may be the most appropriate surgical option to obtain local control and offer the best chance of cure. It is recognised that there is a group of low grade tumours which have a low risk of local recurrence and a low risk of metastasis and it is also appropriate to treat these by planned marginal excision. (e.g., atypical lipomatous tumours).
Surgical resection of the primary tumour may be considered appropriate as a palliative procedure in patients with metastatic disease, however radiotherapy or chemotherapy may be more appropriate and the decision must take into account factors such as the patient’s symptoms (e.g., pain or fungation), co-morbidity, the expected morbidity of surgery, histological sub type and the extent of metastases and, of course, include a full discussion with the patient.
Isolated limb perfusion (ILP) is a valuable pre-operative technique for reducing the size of difficult but potentially resectable tumours in an extremity, where limb preservation may not otherwise be possible. ILP employs a locally high dose of chemotherapy (melphalan) and tumour necrosis alpha (TNF
Surgery is the standard treatment for all patients with localised STS. For those patients with resectable disease, a wide excision is the standard surgical procedure. The definition of “wide” remains unclear but most would accept that an intact fascial layer or 1cm of normal tissue would be considered adequate. Where a wide excision is not possible due to anatomical constraints, a planned marginal excision plus radiotherapy may be an appropriate means of achieving tumour control while maintaining function. Occasionally amputation is the only surgical option to achieve adequate margins For patients with borderline resectable tumours, pre-operative treatment with chemotherapy or radiotherapy should be considered dependant on individual histology. Isolated Limb Perfusion may permit limb salvage in some cases where amputation is the only conventional surgical approach.
Postoperative radiotherapy is considered to be the standard approach for nearly all intermediate or high-grade soft tissue sarcomas (see Table
The recommended postoperative radiation dose is 60–66 Gy in 1.8–2 Gy fractions [
Attention is drawn to the VORTEX clinical trial in extremity soft tissue sarcomas [
Pre-operative radiotherapy in limb sarcoma has been shown to be associated with increased postoperative complications compared to the standard postoperative treatment but less late toxicity (reflecting the lower pre-operative dose of 50 Gy compared with the postoperative dose of 66 Gy and a smaller treatment volume), with equivalent tumour control [
The role of adjuvant chemotherapy remains unproven. Although currently not regarded as standard treatment in the UK, there is conflicting evidence, and it may be considered for individual patients with potentially chemosensitive subtypes on the basis that benefit cannot be excluded, even though it has not been proven (Table
Soft tissue sarcomas grouped by chemosensitivity.
Relative chemosensitivity | Examples of soft tissue sarcomas |
---|---|
Chemotherapy integral to management | (i) Ewing’s sarcoma family tumours |
(ii) Embryonal and alveolar rhabdomyosarcoma | |
Chemosensitive | (i) Synovial sarcoma |
(ii) Myxoid/round cell liposarcoma | |
(iii) Uterine leiomyosarcoma | |
Moderately chemosensitive | (i) Pleomorphic liposarcoma |
(ii) Myxofibrosarcoma | |
(iii) Epithelioid sarcoma | |
(iv) Pleomorphic rhabdomyosarcoma | |
(v) Leiomyosarcoma | |
(vi) Malignant peripheral nerve sheath tumour | |
(vii) Angiosarcoma | |
(viii) Desmoplastic small round cell tumour | |
(ix) Scalp and face angiosarcoma | |
Relatively chemo-insensitive | (i) Dedifferentiated liposarcoma |
(ii) Clear cell sarcoma | |
(iii) Endometrial stromal sarcoma | |
Chemoinsensitive | (i) Alveolar soft part sarcoma |
(ii) Extraskeletal myxoid chondrosarcoma |
Although there are limited data, pre-operative chemotherapy may be considered for those patients with large high grade tumours that are considered borderline resectable by the MDT. The age and any comorbidity of the patient together with the histology of the tumour need to be taken into account. There is a wide variation in chemosensitivity between different histological subtypes (Table
Postoperative radiotherapy is recommended following surgical resection of the primary tumour for the majority of patients with high-grade tumours, and for selected patients with large or marginally excised, low-grade tumours. The recommended dose for postoperative radiotherapy is 60–66 Gy; in 2 Gy per fraction Pre-operative radiotherapy is advantageous in terms of long-term functional outcome with equivalent rates of disease control when compared with postoperative radiotherapy. There is however an increased risk of postoperative wound complications. The recommended dose for pre-operative radiotherapy is 50 Gy, in 2 Gy per fraction. Adjuvant chemotherapy is not routinely recommended but could be considered in situations where it may contribute to local disease control, for example, where proximity to sensitive vital structures precludes giving an adequate dose of radiotherapy or in the case of an R1 resection and a further wide excision cannot be performed.
In common with other tumour sites there are no published data supporting specific follow-up protocols for STS patients, and there is an urgent need for research. Patients may be reassured by follow up and early detection of local relapse or pulmonary metastases may improve prognosis in some patients. Follow up should be discussed with the patient and the rationale and limitations explained.
Prognosis can be estimated by well established nomograms based on grade, depth, size and diagnosis as well as patient age [
A recent survey on follow-up illustrated how varied the approach is at different centres, with no agreement on imaging, follow-up intervals or duration of follow-up [
It is recommended that standard follow up consists of: clinical history, clinical examination to focus on local recurrence, with follow up using ultrasound or MRI where indicated by clinical suspicion, chest X-ray with subsequent CT used for investigating suspicious lesions.
In certain cases, this standard follow up can be extended or adapted according to individual risk or local practice. If a patient were deemed to be unfit either for pulmonary metastectomy or systemic treatment, then diagnosing metastases when the patient is asymptomatic has no purpose, so, for example, the chest X-ray can be dispensed with.
As per the ESMO guidelines [
It is recommended that patients with intermediate or high grade sarcoma are followed up every 3-4 months for the first 2-3 years, then twice a year for up to 5 years, and annually thereafter. Patients with low-grade sarcoma should be followed up every 4–6 months for 3–5 years, then annually. Standard follow up practice should consist of: investigation of any symptoms reported by the patient, clinical examination to focus on local recurrence, with imaging follow up where indicated by clinical suspicion, routine chest X-ray to exclude pulmonary metastases.
In almost all cases the treatment intention for systemic disease is palliative. Approximately 50% of patients develop distant metastases and eventually die of disseminated disease; with a median survival of approximately 12 months from diagnosis of metastases [
The incidence of many of the individual sub-types of soft tissue sarcoma is too small to permit large-scale prospective randomised controlled trials. Accordingly data are gathered from a range of studies which include single-site and multi-site phase 2 trials, retrospective case series, sub-analyses of trials for which a range of histological subtypes are included and, for the rarer sub-types, individual case reports.
The management of advanced disease is complex; the approach to palliative treatment depends to some extent on whether or not symptoms are present. In order to achieve control of symptoms such as pain, or dyspnoea, it is necessary to achieve some degree of tumour shrinkage. An alternative approach to try and stabilise disease to delay onset of symptoms is equally acceptable.
The published response rates for chemotherapy in STS vary enormously; from 10–50% depending on the drugs used, patient selection and histological subtype (Table
As per the ESMO guidelines [
Whilst response rates may be <20% [
The standard second-line treatment is ifosfamide—which is also used first line where anthracyclines are contra-indicated, for example in patients at high risk of cardiac complications or patients pre-treated with anthracyclines. Clinical trials have indicated a dose-response relationship and a dose of 9-10 g/m2 is recommended [
Because of current uncertainty it is suggested that patients should be entered in clinical trials, for example, EORTC 62012, a trial investigating whether single agent doxorubicin 75 mg/m2 is equivalent to doxorubicin 75 mg/m2
There is no recognised “standard” therapy following failure of doxorubicin and ifosfamide. Dacarbazine has activity as do a number of newer agents—gemcitabine, taxanes and trabectedin. The evidence for gemcitabine and docetaxel is greatest for uterine leiomyosarcomas, however, subsequent studies have demonstrated activity in soft tissue leiomyosarcoma and other tumour types [
A lot of these data are based on phase II trials; the decision to offer chemotherapy and choice of agent should be based on histology and toxicity profile following full discussion with the patient.
Local recurrences are often accompanied by metastatic disease and patients should be carefully staged for this. In the absence of overt metastatic disease every attempt should be made to regain local control by further surgery with adequate margins (wide or radical) and radiotherapy (if it has not been used previously). Amputation may be needed in selected cases.
Following a diagnosis of lung or other metastases, the decision regarding metastasectomy should be based on disease-free period following primary surgery, total number of lesions per lung, tumour growth and evolution of disease [
Systemic treatments for the majority of advanced STS are not curative; median survival time is ≤12 months from diagnosis of metastases. Published chemotherapy response rates vary enormously; from 10–50% depending on the drugs used, patient selection, and tumour grade and histological subtype. Standard first-line treatment is single doxorubicin 75 mg/m2 every 3 weeks. Ifosfamide at a dose of 9–10 g/m2 may be used first line if anthracyclines are contraindicated and may be an option for second-line therapy, other options could be considered according to the histology. Although the combination of doxorubicin and ifosfamide has not been demonstrated to improve survival in comparison to single agent doxorubicin first line, response rates are higher and it may be considered in individual patients. Additional second-line agents include dacarbazine, trabectedin and the combination of gemcitabine Surgical resection of local recurrence and pulmonary metastases should be considered in individual patients although there are limited data on survival benefit.
This group includes uterine leiomyosarcomas (ULMS), endometrial stromal sarcomas (ESS), malignant mixed mullerian tumour (MMMT) and undifferentiated endometrial sarcoma. As per the ESMO guidelines, standard treatment for all localised tumours is total abdominal hysterectomy (TAH), with some differences between the tumour types as described below [
ULMS, a cancer of the smooth muscle, accounts for 35–40% of all uterine sarcomas; LMS can affect women as young as their mid-20s, although most patients will be aged 50–60 years. Standard surgical management for non-metastatic disease is TAH
Oestrogen receptor (ER) and progesterone receptor (PgR) expression is seen in approximately 50% of patients with ULMS. Some low and intermediate grade tumours may be sensitive to oestrogen deprivation, although there are very few published data on this situation. It is however reasonable to look for receptor expression in those with relatively indolent tumours for which treatment with an aromatase inhibitor or a progestogen might be appropriate. However, receptor expression does not guarantee response to oestrogen-lowering therapy, and use of oestrogen-lowering therapies should be used with particular caution in patients with high grade rapidly progressing tumours.
This is the rarest form of uterine sarcoma and is a generally indolent disease with a long natural history. It was formally known as “low grade ESS”, on the basis of a mitotic count of less than 10 mitoses per 10 high powered fields, but is now termed simply ESS, with no distinction between “grade” (mitotic count is now recognised not to be prognostic). There is a high incidence of expression of oestrogen and progesterone receptors (ER and PgR), and evidence that these tumours are hormonally responsive. Standard surgical treatment is therefore total abdominal hysterectomy, with bilateral salpingo-ophorectomy (BSO) in pre-menopausal women, and hormone replacement therapy is contraindicated post-operatively. A single small study has suggested that adjuvant progestogens after surgery may improve outcome; routine use is not indicated but could be considered in high risk patients [
This mixed tumour type is the most common of the uterine sarcomas, accounting for 50% of cases predominantly in post-menopausal women. Although the phenotype is a mixture of carcinoma and sarcoma this is now generally regarded as an epithelial tumour, rather than a biclonal malignancy, and as such is not generally treated as sarcoma and systemic treatment is similar that used for ovarian and endometrial cancers. Tumours termed adenosarcoma, in which no malignant epithelial components can be identified, may behave differently and require sarcoma therapy.
This disease entity was formally known as “high grade ESS”, but is now termed undifferentiated endometrial sarcoma. It is a highly aggressive anaplastic malignancy that does not express ER and PgR, with a poor prognosis even for early stage disease, and uncertain response to systemic treatment. Surgical management is TAH
There has been some reported success with cisplatin in treating uterine sarcomas but figures are distorted because of high numbers of carcinosarcoma/MMMT patients in the only large trial. No subset analysis has been offered, therefore this drug is not recommended.
Standard treatment for all localised uterine sarcomas is TAH. Lymphadenectomy is not routinely indicated. Oophorectomy is indicated for endometrial stromal sarcoma. These patients should not have post-operative hormone replacement therapy. Use of adjuvant anti-oestrogen therapy is not routinely indicated. Adjuvant pelvic radiotherapy has not been shown to improve local control or survival, and is not routinely indicated in FIGO stage I and II disease. However, it could be considered for selected high risk cases. Advanced/metastatic LMS and undifferentiated endometrial sarcoma are treated systemically with the same drugs as STS at other sites. Gemcitabine and docetaxel may be particularly useful for LMS. Advanced/metastatic ESS can be treated with anti-oestrogen therapy, with an aromatase inhibitor or progestogen.
Although the principles of management of retroperitoneal sarcomas are similar to those for soft tissue tumours there are some important differences. Contrast-enhanced CT may be a valuable aid to diagnosis of well-differentiated/de-differentiated liposarcoma and in helping to plan surgery. Surgical margins are often more difficult to define as transcoelomic spread with distant contamination within the abdomen may occur. The goal of ‘wide excision’ is unlikely to be achievable in most cases. Here, the objective is “planned marginal excision”, achieving appropriate margins that balance tumour control with minimising operative morbidity and retaining function. However, multi-visceral resection may be appropriate if this is necessary to permit “en bloc” resection of tumour, organs frequently sacrificed include kidney and spleen, and partial organ resection and vascular reconstructions may occasionally be required. The role of post operative radiotherapy is less well defined, and although it may be of value in individual patients, it is not considered routine as for limb sarcomas. It is often difficult to define the radiation volume and dose is limited due to the risk of small bowel and other organ toxicity. In cases where it is possible to define “high risk margins” postoperative radiotherapy to a dose of 45–50 Gy in 1.8 Gy fractions should be considered [
There is currently no evidence to support the use of neo-adjuvant or adjuvant chemotherapy in the management of retroperitoneal sarcomas. Palliative chemotherapy should be considered for the same indications as limb sarcomas but well-differentiated/de-differentiated liposarcoma is generally not very chemosensitive.
DFSP is a rare neoplasm of the dermis layer of the skin. This is best considered as a borderline malignancy that rarely metastasises but is locally aggressive, may produce significant morbidity, and occasionally proves fatal. Local recurrence following surgery is common and wide excision is essential except in situations where wide excision would result in significant morbidity or functional loss. In this instance, Mohs surgery should be considered as an option if expertise in this technique is available.
Systemic treatment is appropriate in selected cases with unresectable or metastatic disease. DFSP is driven by a t(17; 22) translocation that results in over-expression of platelet derived growth factor beta (PDGF
Radiotherapy should be considered if surgery is not possible, and can result in durable remissions.
Treatment of DFSP is wide surgical excision, Mohs surgery can also be used to reduce functional loss. Imatinib may provide effective palliation for patients with unresectable DFSP.
Fibromatosis is a benign, clonal tumour which, although it may be locally aggressive (even fatal on occasion), has not been reported to metastasise. Although usually sporadic it may occur in association with familial adenomatous polyposis (FAP) in which case it is termed Gardner’s syndrome and is linked to germline mutations in the
The standard treatment of fibromatosis is complete resection. However the behaviour of this condition is unpredictable, in that the disease may recur locally in patients with clear surgical margins but, conversely, is not inevitable in cases where the margins were involved. Radiotherapy may be effective therapy for patients with unresectable tumours or may be given as adjuvant therapy following surgery for recurrent disease, especially if further surgery would result in significant morbidity and functional deficit. A dose of 50–54 Gy is usually employed. It should be noted that fibromatosis may undergo spontaneous stabilisation and a period of observation is appropriate for patients without significant symptoms from their disease [
Systemic treatment is recommended in selected cases with unresectable disease. Hormone therapies such as tamoxifen have been reported to be beneficial but, because of the unpredictable natural history of this disease, their true value remains unproven due to the lack of appropriate clinical trial data. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to improve the response to tamoxifen. The precise choice of NSAID is uncertain and although selective COX2 inhibitors have been used, the evidence that they are superior is lacking. NSAIDS have an impact on the beta catenin signalling pathway. Nuclear localisation of beta-catenin, the active form, is an important defining histological diagnostic criterion.
Chemotherapy is usually reserved for patients with significant symptoms who have failed to respond to more benign interventions such as the use of NSAIDs and tamoxifen. Weekly administration of methotrexate and vinblastine has reasonable activity and is generally well tolerated. More recently pegylated liposomal doxorubicin (Caelyx) has been reported to have significant activity with acceptable toxicity, and currently is considered treatment of choice by many investigators [
Any patient with a soft tissue mass that is increasing in size, has a size >5cm or is deep to the deep fascia, whether or not it is painful, should be referred to a diagnostic centre with a suspected soft tissue sarcoma (STS).
Magnetic resonance imaging (MRI) and core needle biopsy are recommended prior to definitive surgery. Imaging of the thorax by CT scan for lung metastases should be done prior to radical treatment. All patients with a suspected STS should be managed by a specialist Sarcoma multidisciplinary team (MDT) as specified in the NICE guidance.
Surgery is the standard treatment for all patients with localised STS. For those patients with resectable disease, a wide excision is the standard surgical procedure. The definition of “wide’’ remains unclear but most would accept that an intact fascial layer or 1cm of normal tissue would be considered adequate. Where a wide excision is not possible due to anatomical constraints, a planned marginal excision plus radiotherapy may be an appropriate means of achieving tumour control while maintaining function. Occasionally amputation is the only surgical option to achieve adequate margins. For patients with borderline resectable tumours, pre-operative treatment with chemotherapy or radiotherapy should be considered dependant on individual histology. Isolated limb perfusion may permit limb salvage in some cases where amputation is the only other option. Post-operative radiotherapy is recommended following surgical resection of the primary tumour for the majority of patients with high-grade tumours, and for selected patients with large or marginally excised, low-grade tumours. The recommended dose for postoperative radiotherapy is 60–66 Gray (Gy); in 2 Gy per fraction. Pre-operative radiotherapy is advantageous in terms of long-term functional outcome with equivalent rates of disease control when compared with postoperative radiotherapy. There is however an increased risk of postoperative wound complications. The recommended dose for pre-operative radiotherapy is 50 Gy; in 2 Gy per fraction. Adjuvant chemotherapy is not routinely recommended but could be considered in situations where it may contribute to local disease control, for example, where proximity to sensitive vital structures precludes giving an adequate dose of radiotherapy or in the case of an R1 resection and a further wide excision cannot be performed.
It is recommended that patients with intermediate or high grade sarcoma are followed up every 3-4 months for the first 2-3 years, then twice a year for up to 5 years, and annually thereafter. Patients with low-grade sarcoma should be followed up every 4–6 months for 3–5 years, then annually. Standard follow-up practice should consist of: Investigation of any symptoms reported by the patient. Clinical examination to focus on local recurrence, with imaging follow-up where indicated by clinical suspicion. Routine chest x-ray to exclude pulmonary metastases.
Systemic treatments for the majority of advanced STS are not curative; median survival time is ≤12 months from diagnosis of metastases. Published chemotherapy response rates vary enormously; from 10–50% depending on the drugs used, patient selection, tumour grade and histological subtype. Standard first-line treatment is single agent doxorubicin 75 mg/m2 every 3 weeks. Ifosfamide at a dose of 9-10 g/m2 may be used first line if anthracyclines are contraindicated and may be an option for second line therapy, other options could be considered according to the histology. Although the combination of doxorubicin and ifosfamide has not been demonstrated to improve survival in comparison to single agent doxorubicin first line, response rates are higher and it may be considered in individual patients. Additional second-line agents include dacarbazine, trabectedin and the combination of gemcitabine + docetaxel. Reported response rates are in the range of 5–25%. Some appear more active in certain histological subtypes, particularly leiomyosarcomas and liposarcomas. The choice of agent depends on histology, toxicity profile and patient preference. Surgical resection of local recurrence and pulmonary metastases should be considered in individual patients although there are limited data on survival benefit.
Standard treatment for all localised uterine sarcomas is total abdominal hysterectomy (TAH). Lymphadenectomy is not routinely indicated. Oophorectomy is indicated for endometrial stromal sarcoma. These patients should not have post-operative hormone replacement therapy. Use of adjuvant anti-oestrogen therapy is not routinely indicated. Adjuvant pelvic radiotherapy has not been shown to improve local control or survival, and is not routinely indicated in International Federation of Gynecology and Obstetrics (FIGO) stage I and II disease. However, it could be considered for selected high risk cases. Advanced/metastatic leiomyosarcomas (LMS) and undifferentiated endometrial sarcomas are treated systemically with the same drugs as STS at other sites. Gemcitabine and docetaxel may be particularly active for LMS. Advanced/metastatic endometrial stromal sarcomas (ESS) can be treated with anti-oestrogen therapy, with an aromatase inhibitor or progestagen. Treatment of dermatofibrosarcoma protuberans (DFSP) is wide surgical excision, Mohs surgery can also be used to reduce functional loss. Imatinib may provide effective palliation for patients with unresectable DFSP.
The authors would like to thank Dr. Fiona Cowie (Consultant Clinical Oncologist, Beatson West of Scotland Cancer Centre, Glasgow), Mr. Craig Gerrand (Consultant Orthopaedic Surgeon, Freeman Hospital, Newcastle-upon-Tyne, Newcastle), Professor Bass Hassan (Consultant Medical Oncologist, Weatherall Institute of Molecular Medicine, Oxford), Dr. Helen Hatcher (Consultant Medical Oncologist, Addenbrooke’s Hospital, Cambridge), Mr. Andrew Hayes (Consultant Sarcoma Surgeon, Royal Marsden, London), Dr. David Hughes (Consultant Histopathologist, Sheffield Teaching Hospitals, Sheffield), Dr. Martin Robinson (Consultant Clinical Oncologist, Weston Park Hospital, Sheffield), Dr. Philip Robinson (Consultant Musculoskeletal Radiologist, Leeds Teaching Hospitals, Leeds), Dr. Mike Sokal (Consultant Clinical Oncologist, University Hospital, Nottingham), Dr. Owen Tilsley (Consultant Clinical Oncologist, Velindre Hospital, Cardiff) Dr. Jeremy Whelan (Consultant Medical Oncologist, UCLH, London), Professor Penella Woll (Consultant Medical Oncologist, Weston Park Hospital Sheffield, Sheffield), Dr. Pedro Santabarbara (Clinical adviser, PharmaMar), and Mr. Roger Wilson (Sarcoma UK-secretary). The authors were supported by an educational Grant from PharmaMar.