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Soft tissue sarcomas

1. GENERAL INFORMATION

1.1 Epidemiologic data

1.1.1 Incidence

Soft tissue sarcomas are rare. The annual incidence is around 3/100,000. Overall, soft tissue sarcomas comprise less than 1% of all malignant tumours, while they account for 2% of total cancer-related mortality. The peak incidence is around 50.

1.1.2 Survival

The five-year survival rate in Europe for adult soft tissue sarcomas (excluding those of visceral origin) averages 60%, according to EUROCARE data (Storm 1998), with substantial geographical variations.

1.2 Aetiological and risk factors

1.2.1 Genetic factors

Clinical evidence of a genetic predisposition to develop soft tissue sarcoma is rare. It may be associated with uncommon syndromes, mainly neurofibromatosis and Li Fraumeni syndrome.
Neurofibromatosis. Neurofibromatoses are autosomal dominant conditions (Gutmann 1997). However, 50% of cases of neurofibromatosis are due to de novo mutations. Indeed, type 1 neurofibromatosis has a high incidence, in the range of 1:3000. Type 1 neurofibromatosis (Von Recklinghausen’s disease) carries a 5-30% lifetime probability of giving rise to a malignant tumour, including malignant peripheral nerve sheath tumours, rhabdomyosarcoma, gliomas, phaeocromocytoma, carcinomas and leukaemias. Major signs of this condition include: benign cutaneous neurofibromas, (although neurofibromas can arise also in deep sites, such as the intervertebral foramens); café au lait spots; axillary freckling; hamartomas of the iris (Lisch nodules). Minor signs may include: scoliosis; short stature; epilepsy; slight learning difficulties; hypertension. Type 1 neurofibromatosis is caused by mutations to the oncosuppressor gene NF1, which is located on chromosome 17. Genetic analysis is complex due to the wide spectrum of mutations which may occur, and therefore the diagnosis is mainly clinical. A clinical examination on an annual basis may be appropriate for these patients, while routine use of radiological examinations (brain and abdomen) is more controversial. Type 2 neurofibromatosis is typically associated with bilateral schwannomas of the acoustic nerve, though schwannomas may also arise in other cranial nerves, spinal roots and major peripheral nerves. There is a predisposition to meningiomas and gliomas. Juvenile posterior subcapsular lenticular cataract may occur. Type 2 neurofibromatosis is caused by mutations to the oncosuppressor gene NF2, which is located on chromosome 22. Regular follow-up, which is aimed at anticipating certain expected neoplasms (mainly acoustic neuromas)should start when the patient is 10-years old.
Li Fraumeni syndrome. This is a rare dominant autosomal condition which carries an approximately 50% risk of developing malignant tumours at 30 years old and a 90% risk at 60 years old (Hisada 1998). It is caused by a mutation in the oncosuppressor gene coding for p53 protein. Soft tissue sarcomas, including embryonal rhabdomyosarcoma, osteosarcoma, epithelial tumours, (including juvenile breast cancer and adrenal carcinoma), gliomas, leukaemias and other tumours can occur. Genetic analysis is possible, although its sensitivity is limited. Suggestions for follow-up are difficult, and the sensitivity to ionizing radiations needs to be considered in planning. Annual clinical examinations, breast MRI after age 25, regular brain MRI, and abdominal ultrasound up to 16 years old would constitute an intensive follow-up schedule (whose effectiveness, however, is yet to be demonstrated).
Other genetic diseases which can increase the risk of soft tissue sarcomas are basal cell nevus syndrome (Zachariades 1982), tuberous sclerosis (Gomez 1988), Werner’s syndrome (Nehlin 2000), intestinal polyposis or Gardner’s syndrome (Naylor 1980).

1.2.2 Chemical agents

Some chemical carcinogens such as phenoxy herbicides, chlorophenols (Dich 1997, Kogevinas 1995) and dioxin (Viel 2000), have been linked to the occurrence of soft tissue sarcomas, possibly with a non-uniform pattern across the different histotypes (Hoppin 1999). Also, exposure to chemotherapeutic drugs has similarly been associated with the risk of developing sarcomas.

1.2.3 Ionizing radiations

Exposure to ionizing radiation can increase the risk of soft tissue sarcomas. In fact, although a rare event, sarcomas may arise in previously irradiated fields even in the absence of a predisposing syndrome. The median time from radiation treatment is in excess of 10 years, although the interval may be much shorter (Feigen 1997, Murray 1999). Incidence increases with dose, and radiation-induced sarcomas are only rarely seen following low doses. Surgery is the mainstay of treatment in secondary sarcomas, although other treatment modalities may be needed(Lagrange 2000). The prognosis for secondary tumours may be poorer than for primary sarcomas (Murray 1999).

1.3 Screening and case finding

1.3.1 Screening and case finding

Soft tissue sarcomas are rare and no screening programme has been evaluated. Screening is therefore not recommended. Similarly, preclinical case finding has not been evaluated and so is not recommended as well. However, it is a diagnostic goal to avoid any medical delay where suspicious symptoms are present.

1.4 Referral

1.4.1 Referral

Treatment of soft tissue sarcomas is complex in virtually all stages of the disease, and is often multidisciplinary. There is evidence that the availability of multidisciplinary expertise may improve quality of care and the final outcome (Pollock 1996, Goodlad 1996) and that suboptimal care may result from lack of referral to experienced institutions (Clasby 1997). It is recommended, on a type R basis, that soft tissue sarcoma patients are referred to selected institutions with multidisciplinary skills and experience in treating the disease, and where clinical trials are likely active(Rydholm 1998). In fact, clinical research in soft tissue sarcomas is needed, but it is always difficult due to insufficient patient accrual. Even when treatment appears to be technically easy and straightforward (e.g. a small soft tissue lesion easily amenable to surgical shelling out), referral to these institutions should be encouraged. In particular, biopsy and surgery of the primary lesion, pathologic diagnosis, surgery of lung metastases, and consolidation radiotherapy are critical procedures and require experience in treating the disease. In principle, a multidisciplinary approach to clinical decision-making is essential in all stages of disease. Even when surgery, radiotherapy, and chemotherapy constitute a standard choice, their combination may need to be individually tailored. Treatment of soft tissue sarcomas has shifted from an ablative to a more conservative approach by increasing the use of combined treatment modalities. In addition, investigational and/or new treatment modalities may be appropriate on an individual basis in specialized institutions.

1.5 Selected reviews

1.5.2 Pathology

Hibshoosh H et al (1997), Fisher C (1999), Slominski A et al (1999) on pathology. Brown et al (2000) on grading systems. Sandberg (2002) on cytogenetics.

1.5.3 Imaging

Varma DG (1999), Heslin MJ et al (1999), Gandhi MR et al (2000) on radiology.

1.5.4 Surgery

Eilber FR et al (1997), Moley JF et al (2000), O’Sullivan B (1999) and Pastorino U (1997) on surgery. Clark et al about amputation. Abdalla (2002) on surgery of lung metastases. Maki (2002) on multidisciplinary treatment.

1.5.5 Radiation therapy

O’Sullivan (2003) on radiation therapy. Janjan et al (2002) on brachytherapy. Willett (2001) on intraoperative radiation therapy.

1.5.6 Chemotherapy

Spira (2002) on chemotherapy.

2. PATHOLOGY AND BIOLOGY

2.1 Biological data

2.1.1 Histogenesis

Soft tissue sarcomas arise from mesodermal tissues. However, malignant Schwannoma which has an ectodermic origin, is also classified as a soft tissue sarcoma. It should be noted that the histotype of the tumour reflects the tissue into which the tumour has differentiated; this is not necessarily the tissue from which the tumour arose (thus the tissue found in the tumour may not be of the histological type usually found at the site of origin of the tumour).

2.1.2 Cytogenetics

There are certain chromosomal translocations (Hibshoosh 1997, Slominski 1999) which are typical of some histological types of soft tissue sarcomas; these gene translocations produce specific gene fusions as a consequence. Examples are: t(2;13) for alveolar rhabdomyosarcoma; t(12;16) for myxoid liposarcoma; ring chromosome 12 for well differentiated liposarcoma; t(X;18) for synovialsarcoma; 1p- for leiomyosarcomas; ring chromosome 12 for dermatofibrosarcoma protuberans; t(12;22) for clear cell sarcoma; and t(9;22) for myxoid chondrosarcoma.

2.2 Histological types

2.2.1 Histotypes

The following histotypes are considered in this chapter and constitute the “typical” soft tissue sarcomas of adults. The ICD-O (“International Classification of Diseases for Oncology”) morphology code is provided in brackets (ICD-O 2000).
· Alveolar soft-part sarcoma (M-9581/3)
· Angiosarcoma (M-9120/3)
· Chondrosarcoma, extraskeletal c. (M-9220/3)
· Chondrosarcoma, dedifferentiated c. (M-9240/3)
· Clear-cell sarcoma (M-9044/3)
· Dermatofibrosarcoma protuberans (M-8832/3)
· Desmoplastic small cell tumour of children and young adults (ICD-O code not available)
· Epithelioid sarcoma (M-8804/3)
· Fibrosarcoma (M-8810/3)
· Granular cell tumour, malignant g.c.t. (M-9580/3)
· Hemangiopericytoma, malignant h. (M-9150/3)
· Haemangioendothelioma, malignant h. (M-9130/3)
· Haemangioendothelioma, malignant epithelioid h. (M-9133/3)
· Leiomyosarcoma (M-8890/3)
· Leiomyosarcoma, epithelioid l. (M-8891/3)
· Liposarcoma, dedifferentiated l. (M-8858/3)
· Liposarcoma, myxoid l. (M-8852/3)
· Liposarcoma, pleomorphic l. (M-8854/3)
· Liposarcoma, round cell l. (M-8853/3)
· Liposarcoma, well-differentiated l. (M-8851/3)
· Lymphangiosarcoma (M-9170/3)
· Malignant fibrous histiocytoma (M-8830/3)
· Malignant peripheral nerve sheath tumour schwannoma, malignant s., neurofibrosarcoma, (M-9540/3)
· Mesenchymoma, malignant m. (M-8990/3)
· Osteosarcoma, extraskeletal o. (M-9180/3)
· Schwannoma, malignant melanotic s. (M-9560/3)
· “synovial” sarcoma (M-9040/3)
· sarcoma, NOS (M-8800/3)
· tenosynovial giant cell tumour, malignant t.g.c.t. (M-9252/0)
Gastrointestinal mesenchymal tumours immunohistochemically positive for the product of the c-kit oncogene (CD117) are currently termed “gastrointestinal stromal tumours” (GIST) (Miettinen 1998, Miettinen 1999).Uterine sarcomas include pure homologous hystotypes (i.e., those which correspond to tissues normally represented in the organ), typically, leiomyosarcoma; pure heterologous tumours (e.g., liposarcoma, etc.); mixed tumours, including mixed mesodermal tumours “malignant mullerian mixed tumours”, or carcinosarcomas), which encompass both a mesenchymal (homologous or heterologous) and an epithelial component (Clement 1988, Clement 2000). Amongst “endometrial” sarcomas, one may distinguish high grade and low-grade tumours.

2.3 Grading

2.3.1 Clinical implications

The most frequently occurring histotypes of soft tissue sarcomas can be either low grade or high grade. Overall, high grade tumours occur much more frequently than low grade ones. Malignancy grade clearly distinguishes patients with different prognosis and natural history; cancers with the same malignancy grade basically display the same clinical behaviour, despite different histotypes, while different malignancy grades may occur within one histotype. For this reason histotype may be less useful information for the clinician than grading. In fact, treatment of soft tissue sarcomas is currently dictated much more by the malignancy grade than by the histotype. Basically, low grade soft tissue sarcomas should be distinguished from high grade ones – even if grading systems generally distinguish more than two grades. In the three-grade classification systems, grade 1 sarcomas are low grade tumours, while grade 2-3 tumours are intermediate-high grade neoplasms. A three-grade system seems able to discriminate three clearly different levels of risk. In a retrospective study, risk of distant relapse was fivefold and ninefold greater, respectively, for grade 2 and grade 3 sarcomas, than the risk associated with grade 1 sarcomas (Kandel 1999).

2.3.2 Pathologic criteria

Several grading systems are currently used. The most important are the American, by Costa et al (Costa 1984), and the European, by Trojani et al (Trojani 1984), both of which distinguish between three grades of malignancy. The former uses the histotype and the degree of tumour necrosis to define grades, while the latter is based on the degree of necrosis, the degree of morphological differentiation, and the mitotic index. Interestingly, it has been suggested that this grading system does not predict prognosis in uterine sarcomas (Pautier 2000). With regard to GIST, a risk assessment is currently available which grades tumours on the basis of size, mitotic rate and necrosis (Farnquemont 1995).

2.3.3 Grade versus histotype

It is recommended that the pathologist always reports details of the malignancy grade to the clinician. There are some histotypes which are “typically” grade 1, such as myxoid or well differentiated liposarcoma, or dermatofibrosarcoma protuberans. Myxoid fibrous histiocytoma is usually a grade 2 sarcoma. Other histotypes are “typically” grade 3, such as pleiomorphic liposarcoma, mesenchymal extraskeletal chondrosarcoma, and alveolar sarcoma. Some histotypes are always grade 2 or 3, such as synovial sarcoma, epithelioid Schwannoma, malignant fibrous histiocytoma, angiosarcoma, or epithelioid sarcoma. However, grading should always be assessed by the pathologist for each individual tumour, preferably employing some standardized criteria and possibly individual characteristics. It is recommended, on a type R basis, that the pathological report explicitly provides the clinician with both the histotype and the malignancy grade.

2.4 Accuracy and reliability of pathological diagnosis

2.4.1 Reproducibility

Diagnosis of a soft tissue sarcoma may be difficult and the rarity of these tumours adds to such difficulties. In 5-20% of cases a second pathological opinion has changed the diagnosis from sarcoma to a non-sarcoma (Presant 1986). The reproducibility rate among different pathologists with regard to the histotype averages 45-60%. The reproducibility rate with regard to the malignancy grade is higher, around 75% (Coindre 1986). It is therefore recommended, on a type R basis, that the histopathological evaluation is performed by a pathologist who is experienced with soft tissue sarcomas.

2.4.2 Assessments

Cytogenetics and electron microscopy may allow the identification of the histotype in some cases in which it otherwise could not be identified, or may solve a problem of differential diagnosis.

2.5 Peculiar histotypes

2.5.1 Rhabdomyosarcoma and the Ewing family of tumours

Rhabdomyosarcoma, extraskeletal Ewing’s sarcoma and peripheral neuroepithelioma (peripheral neuroectodermic tumour) are aggressive tumours which are typical of childhood and are very responsive to chemotherapy and radiotherapy. The approach is basically the same in children and in adults, and differs widely from the treatment of “typical” soft tissue sarcomas. They are therefore considered in separate chapters “Rhabdomyosarcoma” and “Ewing’s Family of Tumours”). This chapter does not apply to these tumours.

2.5.2 Sarcomas in childhood

Paediatric non-rhabdomyosarcoma sarcomas are rare paediatric tumours belonging to the “typical” histotypes seen in adults. They have a natural history which is similar to the natural history in adults and so should be basically dealt with in the same way as in adults (principles provided in this chapter may thus apply). However, some problems related to the clinical approach to a soft tissue tumour in a child (in particular with regard to surgery and radiotherapy) will be found in the chapter “Rhabdomyosarcoma”.

2.5.3 Intra-abdominal desmoplastic small round cell tumour

Intra-abdominal desmoplastic small round cell tumour is a recently described rare tumour, arising in the young (males more than females) (Leuschner 1996). This tumour carries a typical chromosomal translocation t(11;22)(p13;q12) resulting in fusion of the EWS1 and WT1 genes. It tends to involve the peritoneum diffusely, giving rise to huge abdominal masses, and runs aggressively, although it does show some responsiveness to multidrug chemotherapy, within multimodality treatments as used for paediatric sarcomas (Kushner 1996).

2.5.4 Gastrointestinal stromal tumours (GIST)

Gastrointestinal mesenchymal tumours immunohistochemically positive for the product of the c-kit oncogene (CD117) are currently termed “gastrointestinal stromal tumours” (GIST) (Miettinen 1998, Miettinen 1999). Their natural history is peculiar, and also the therapeutic options are different from other adult soft tissue sarcomas, due to the effectiveness of the anti-tyrosinekinase STI571 (gleevec). GIST are not covered in this chapter.

2.5.5 Clear-cell sarcoma

Clear-cell sarcoma (Deenik 1999) has a natural history which may resemble that of malignant melanoma, particularly in its lymphotropism. It is possible, although not proven, that some therapeutic principles which apply to malignant melanoma are also of value for clear-cell sarcoma.

2.5.6 Desmoid tumour

Aggressive fibromatosis, or desmoid tumour, is a locally aggressive tumour, that does not display the potential for metastatic spread. It has a different natural history from soft tissue sarcomas, even from low grade fibrosarcomas, and is therefore considered in a different chapter.

3. DIAGNOSIS

3.1 Signs and symptoms

3.1.1 Sites of origin

Most often, soft tissue sarcomas arise in the soft parts of limbs and trunk. Non-visceral sarcomas are seen most frequently in lower extremities (approximately 40%), then in upper extremities and trunk (15-20%), followed by head and neck and retroperitoneum. Visceral sarcomas may affect parenchymatous organs, like uterus or liver.

3.1.2 Early diagnosis

A sarcoma should be suspected whenever a soft tissue mass becomes palpable. Swellings of soft tissues, in the absence of evident signs of infection, should be evaluated carefully, since soft tissue sarcomas are often deeply seated and may not be easily palpable. Depth, firmness and fixity are suspicious signs. Deep sarcomas, especially those arising in the trunk, may originate in widely expandable sites and are generally very large at diagnosis. In such cases the first symptoms of disease may stem from compression of adjacent nerves or visceral structures (e.g. ureters or bowel). Unexplained deep pain should prompt the physician to consider a possible soft tissue origin (in addition to a skeletal one), and skeletal X-rays are therefore not enough to exclude that there is a tumour.

3.2 Diagnostic strategy

3.2.1 Instrumental assessment

An ultrasonogram can confirm the presence of a clinically doubtful soft tissue mass. More expensive examinations are computerized tomography scan (CT) and magnetic resonance (MRI). Both have the advantage of being useful as staging presurgical examinations, while ultrasound must be followed by one of the two if a tumour is detected. Computerized tomography and magnetic resonance scans are roughly equivalent (Panicek 1997), although magnetic resonance can give coronal and sagittal views in addition to transaxial ones, and may show better contrast of muscles and vessels (De Schepper 2000, Bloem 1997). Carrying out either a computerized tomography scan or magnetic resonance imaging is recommended preoperatively, on a type C basis.

3.3 Pathological diagnosis

3.3.1 Pathologic assessment

It is recommended, on a type C basis, that virtually all soft tissue masses which have existed unchanged for some time should be biopsied.

3.3.2 Biopsy

It is recommended, on a type R basis, that biopsy is planned by a surgeon experienced in the treatment of soft tissue sarcomas. In fact, if carried out inappropriately, a biopsy can impair the feasibility of subsequent conservative surgery. In particular, the biopsy tract will have to be removed at the time of definite surgery. Haematomas should be avoided. Excisional biopsy entails the need for radical surgery after pathological diagnosis, and so is generally not done except for smallest lesions. Difficulties may arise in localizing the site of the tumour thereafter. An incisional open biopsy is generally regarded as the standard option, on a type C basis. Its downside may be the occurrence of local complications (up to 15-20%) and that it is often done inappropriately. In fact, in most cases, a Tru-cut biopsy can be sufficient to provide the clinician with the diagnosis of soft tissue sarcoma and the “minimal” malignancy grade, as well as to exclude small round cell sarcomas, which are treated differently (Ball 1990, Heslin 1997, Kissin 1986). In this context, the diagnosis of low grade sarcoma should be viewed with caution because the tumour can be heterogeneous and the specimen could be taken from an area outside the region of high malignancy. In reality, the accuracy of Tru-cut biopsies depends on the clinician’s and pathologist’s experience and on the kind of diagnostic problem, but the sensitivity and specificity for the diagnosis of sarcoma may be as high as 95%. Tumour grade may be correct in >85% of cases. For these reasons, Tru-cut biopsy can be now considered an alternative standard option on a type R basis. Fine needle aspiration biopsy may have more limitations. However, in skilled institutions, it may fit the needs of clinicians wishing to differentiate mainly small round cell sarcomas from other adult sarcomas. Therefore, it is suitable for individual non-standard clinical use on a type 3 level of evidence (Kilpatrick 1999 , Barth 1992) by institutions which have gained experience in its use. Overall accuracy may be as high as 90%. The Tru-cut biopsy as well as fine needle aspiration may be done in most instances under CT or ultrasound guidance.

3.3.3 Reproducibility

The diagnosis of a soft tissue sarcoma may be difficult and the rarity of soft tissue sarcomas adds to such difficulties. In 5-20% of cases, a second pathological opinion has changed the diagnosis from sarcoma to a non-sarcoma. It is recommended, on a type R basis, that the histopathological evaluation is performed by a pathologist experienced with soft tissue sarcomas.

3.3.4 Grading assessment

It is recommended, on a type C basis, that the pathological diagnosis provides the clinician with information on the histotype and malignancy grade of the tumour. The reproducibility rate among different pathologists with regard to the histotype averages >45-60%. The reproducibility rate with regard to the malignancy grade seems higher, around 75%. Malignancy grade is more important for the clinician than the histotype, and should be specified even when the histotype cannot be determined (“sarcoma, not otherwise specified”). Even when the histotype might be regarded as automatically implying a specific malignancy grade, the pathologist should state it explicitly in the pathological report.

3.3.5 Pathologic assessments

Cytogenetics and electron microscopy may allow the identification of the histotype in some cases in which it otherwise would not be identified.

4. STAGING

4.1 Stage classification

4.1.1 Criteria for stage classification

Several stage classification systems are available. In the UICC/AJCC 1997 stage classification (Fifth edition;AJCC, UICC), soft tissue sarcomas constitute one of the three neoplastic diseases in which the malignancy grade is incorporated within the stage. Thus localized lesions are divided into stages I to III, according to the malignancy grade, tumour diameter (they are T1 if the maximal tumour diameter is 5 cm), and to whether they are superficially or deeply sited (respectively classified as a or b). So, the stage classification takes into account the three most important prognostic factors in soft tissue sarcomas. Malignancy grade might also have a predictive value with regard to responsiveness to chemotherapy. Unfortunately, we lack a separate stage classification for local relapses, but TNM annotations can be used to describe local relapses as well.

4.1.2 TNM classification (UICC/AJCC, 1997)

TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 5.0 cm or less in greatest dimension (a: superficial; b: deep)
T2 Tumour more than 5.0 cm in greatest dimension (a: superficial; b: deep)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis

4.1.3 Stage classification (UICC/AJCC, 1997)

IA G1-2, T1a-b, N0, M0
IB G1-2, T2a, N0, M0
IIA G1-2, T2b, N0, M0
IIB G3-4, T1a-b, N0, M0
IIC G3-4, T2a, N0, M0
IIIA G3-4, T2b, N0, M0
IV any G, any T, N1, and/or M1

4.1.4 Stage classifications and clinical aspects

Since the malignancy grade, the tumour diameter and the deepness of the lesion are the main prognostic factors for the localized disease, and the presence of distant metastases suggests an overall dismal prognosis, the UICC/AJCC stage classification correlates well with prognosis (Wunder 2000). However, one should pay attention to two aspects. Firstly, some tumours are heterogenous and areas with different malignancy grades may coexist: in particular a biopsy may underestimate the tumour grade, since it may miss the highest grade areas, which obviously dictate the clinical aggressiveness of the tumour. Secondly, tumour diameter is most important for limb sarcomas. Sarcomas arising in the trunk, particularly in the retroperitoneum, tend to be large tumours which are unlikely to allow adequate surgical excision and, even if small, may be so located as to prevent adequate surgery. So, the prognosis of trunk sarcomas is generally poorer than their limb counterparts, somewhat independent of the tumour diameter. In this regard the staging system does not differentiate between different sites of disease nor between operable and inoperable lesions, while adequate surgery is crucial in determining chances of cure of soft tissue sarcomas. It would be difficult for a stage classification to separate operable from inoperable lesions in a ubiquitous disease like soft tissue sarcomas; in addition, operability criteria may differ from one institution to another and change depending on the availability of radical and reconstructive surgery techniques.

4.1.5 Stage I

Overall, radically excised stage I tumours have a good cure rate, which may be >80-90%. They tend to recur locally if inadequately excised and give rise to distant metastases only late in their natural history, often after a process of dedifferentiation.

4.1.6 Stage III

Stage III sarcomas are very aggressive diseases, both locally and at distant sites. Their cure rate, if adequately treated, may fall below 40-50%. Relapses tend to occur early in their natural history, often within the first two years after surgery.

4.1.7 Stage II

The cure rate of stage II lesions should be intermediate between stage I and stage III sarcomas (averaging 50%).

4.1.8 Stage and surgical planning

Stage classification may be less meaningful for treatment planning than for prognosis. In fact, from the surgeon’s standpoint, it is the tumour localization, and the infiltration of critical anatomical structures, that dictate which intervention is needed, and thereby the potential of local control and cure. Schematically, grade 1 lesions tend not to extend outside the reactive zone, while grade 2-3 sarcomas may give rise to skip lesions outside the reactive zone. This influences surgical conduct, and the need for postoperative radiation therapy after extensive surgery for high-grade lesions.

4.1.9 Stage IV

Stage IV disease due to regional lymph nodes is rare, and its prognosis seems closer to overtly metastatic disease. Overtly metastatic disease should be divided into two categories. The first group is made up of patients with isolated lung metastases (i.e. without concurrent extrapulmonary sites of disease) which accounts for as many as 80% of patients at their first distant relapse. Complete surgical excision (metastasectomy) is feasible in 20% probability of cure. The second group comprises patients with unresectable lung metastases accounting for approximately >20% of relapsing patients.

4.2 Staging procedures

4.2.1 Local and distant assessment

The extent of the primary tumour should be assessed by the best radiological resources available depending on the site of disease. It is recommended, on a type R basis, that either computerized tomography scan or magnetic resonance be employed. Magnetic resonance can give coronal and sagittal views in addition to transaxial ones, and may provide better contrast for muscles and vessels. If considering surgery, angiography or other special evaluations may prove necessary preoperatively. Bone scans may be useful to show bone infiltration. Given the high frequency of lung metastases and the potential of treating resectable lung metastases through surgery , lung computerized tomography is recommended, on a type R basis, as a staging procedure in all patients. Computerized tomography adds to the sensitivity of chest X-ray, bringing it from >60% to >80%, while specificity, which is as high as 95% for chest X-rays, somewhat decreases. The probability of synchronous distant metastases in the sarcoma patient at first diagnosis is 20%, and lung lesions are present in most metastatic patients. In the absence of lung lesions, bone and liver lesions are relatively rare (< 20%). Bone scan and liver ultrasonography, or liver computerized tomography scan, are therefore optional in the preoperative staging of the sarcoma patient, but may add somewhat to the probability of detecting distant metastases.

5. PROGNOSIS

5.1 Natural history

5.1.1 Natural history and grading

The natural history of soft tissue sarcomas includes a local phase and a distant phase. Low grade soft tissue sarcomas entail a risk of local relapse, even after quite long time intervals (Marcus 1993). High grade soft tissue sarcomas can recur locally, but have also a high propensity to give rise to distant metastases. Since low grade sarcomas may dedifferentiate, they entail some risk of distant spread, too. Occasionally, they may metastasize even without undergoing a process of dedifferentiation.

5.1.2 Local phase

At the local level (Enneking 1981), low grade soft tissue sarcomas give rise to masses which look grossly demarcated by a pseudocapsule. Pathologically, this pseudocapsule is perforated by the tumour, and satellites of vital tumour can therefore be found beyond it. Therefore, these satellites should be excised at surgery by means of more than a marginal excision. High grade sarcomas give rise, in addition to satellites, also to “skip lesions”, outside the reactive zone near the pseudocapsule. Surgical excision should therefore be wider than for low grade soft tissue sarcomas. If an amputation or a compartmental resection is not performed, radiotherapy is a widely chosen option. Overall, sarcomas tend to spread along longitudinal planes, while fascial planes, nerves, vessels and bones represent quite effective anatomical barriers. This may limit the amount of normal tissue that needs to be excised in order to reach good-quality margins when these barriers are involved.

5.1.3 Regional phase

Lymph node metastases are rare, even if some histotypes (epithelioid sarcomas, vascular sarcomas, and others) are associated with a higher probability (>10-20%) of spreading to regional lymph nodes (Mazeron 1987). Overall, lymph node metastases are a poor prognostic factor (Ruka 1988). Gastrointestinal stromal tumours as well as retroperitoneal sarcomas may metastatise widely within the abdominal cavity (Sugarbaker 1996).

5.1.4 Distant phase

Systemically, soft tissue sarcomas, especially high grade sarcomas, tend to metastasize to the lungs in most cases, without any concurrent lesion to other sites (so called “isolated” lung metastases). In fact, the first metastases are isolated to the lungs in as many as 80% of cases (Potter 1985). After a complete excision of isolated lung metastases, further relapses may again be isolated to the lungs. Metastatic spread can also be found to the bones, liver and distant soft tissues. Central nervous system metastases are exceedingly rare (Ho 1979), but may increase with the aggressive surgical and medical treatment policies used in advanced disease.

5.2 Prognostic factors

5.2.1 Grade

The malignancy grade is the main prognostic factor in soft tissue sarcomas (Trojani 1984) The long term overall survival is expected to be >80-90% in grade 1 sarcomas, as opposed to <40-50% in grade 3 sarcomas. Grade 2 soft tissue sarcomas have an intermediate long term survival. In addition, grade 3 sarcomas tend to recur earlier, i.e. in less than 2 years in most relapsing patients, than grade 2 sarcomas. Due to the coexistence of different malignancy grades within the same histotype, and the high number of different histotypes, histotype is less reliable as a prognostic factor than malignancy grade.

5.2.2 Size

Tumour diameter is another important prognostic factor. As diameter increases, the prognosis gets worse (Coindre 1996). A conventional cut-off is generally set to 5-8 cm.

5.2.3 Depth

Depth of the lesion may be a prognostic factor. In particular, it may divide grade 2 tumours into two groups: the superficial ones, with a long term survival close to grade 1 tumours, and the deep ones, with a long term survival close to grade 3 sarcomas (Coindre 1996).

5.2.4 Location

Primary tumour site is a prognostic factor in as much as tumours arising in the trunk may easily reach greater dimensions before giving rise to clinical symptoms. These tumours are more difficult to operate on, by comparison with limb sarcomas. In fact, they are generally not compartmental and surgical margins tend to be less adequate. Thus, the main prognostic factor for retroperitoneal sarcomas is feasibility of surgery (Heslin 1997).

5.2.5 Local recurrence

The prognostic significance of local recurrence is still controversial, since no definite evidence would seem to support its causal role in distant recurrence (Gustafson 1991, Emrich 1989, Trovik 2000). Since, however, it is associated with poorer prognosis, adequate local control should be regarded as a major aim in the management of soft tissue sarcomas (Lewis 1997, Barr 1991).

5.2.6 Other factors

Other prognostic factors are currently being explored and some of them may turn out to be independent of grade, depth and dimensions, for example, tumour DNA content, Ki-67, and P glycoprotein expression (Levine 1997).

5.3 Predictive factors

5.3.1 Surgery

From the surgical point of view, malignancy grade is a predictive factor for the presence of skip lesions outside the reactive zone and thereby for inadequacy of limited surgery. At surgery, this prompts surgeons to resort either to compartmental resections or to integrated approaches incorporating radiation therapy in high grade sarcomas.

5.3.2 Chemotherapy

From the medical point of view, malignancy grade may be a predictive of response to chemotherapy (Van Haelst-Pisani 1991). High grade tumours would seem to respond better to chemotherapy than low grade ones. This may be less relevant in metastatic disease, in which, by definition, malignancy grade cannot be considered truly low (Daugaard 1993).

6. TREATMENT

6.1 Localized low grade soft tissue sarcomas

6.1.0 Overall treatment strategy

Standard treatment for low grade soft tissue sarcomas is adequate surgery, on a type C basis. If surgery has already been performed but proved inadequate, surgical radicalization should be carried out. If a radicalization is not feasible, postoperative radiotherapy becomes the standard option on a type R basis. Postoperative radiation therapy after adequate surgery is not generally felt to provide an advantage in low grade soft tissue sarcomas, although it may be suitable for individual clinical use in selected patients (ie, gross lesions with suboptimal quality of surgical margins, etc.) on a type 2 basis (Yang 1998). Adjuvant chemotherapy is not indicated in low grade sarcomas due to their low systemic potential, their lower responsiveness to chemotherapy, and the absence of positive clinical trials. Some randomized trials which did include patients with low grade sarcomas, failed to demonstrate any advantage in favour of adjuvant chemotherapy. So, adjuvant chemotherapy is currently not recommended in low grade sarcomas. Of course chemotherapy may be recommended, on a type R basis, if both surgery and radiotherapy are unfeasible.

6.1.1 Surgery

Since even low grade sarcomas may have “satellites” outside the tumour pseudocapsule, a sufficiently wide excision is the standard option on a type C basis. A wide excision is one which, conceptually, falls outside the “reactive zone”, and which, practically, includes some centimeters (1-2 centimeters) of negative tissue taken from all directions of potential tumour spread. Such a principle does not apply to resistant anatomical planes, such as muscular fasciae, periostium, serosae, perineurium, or vascular external tunica, if they are not infiltrated, since they are resistant to tumour spread. On the other hand, since skip lesions outside the reactive zone are not usually present, more extensive resections or radiation therapy are ordinarily not required in low grade sarcomas. High quality surgery, as can only be provided by experienced institutions, is critical in treating sarcomas (Flugstad 1999, Siebenrock 2000). A policy of reresection is justified in the case of doubts as to the adequacy of previous surgery (Lewis 2000).

6.1.2 Radiation therapy

If adequate surgery is unfeasible, external radiotherapy becomes standard treatment on a type R basis, either preoperatively in an attempt to allow subsequent surgery at doses of approximately 50 Gy, or as a substitute for surgery when doses of >65 Gy can be used, or after inadequate surgery when doses of 60 Gy are appropriate. Even though the efficacy of radiotherapy might be as high as 30%, according to selected series, the potential of radiotherapy given alone is definitely lower by comparison with surgery. Surgery may be particularly difficult in retroperitoneal low grade sarcomas, but radiotherapy at adequate doses will be difficult as well. Intraoperative radiation therapy is investigational or suitable for individual clinical use, on a type 3 basis, in these patients (Alektiar 2000).

6.1.3 Chemotherapy

In low grade sarcomas, chemotherapy may be given either preoperatively in an attempt to allow subsequent surgery or as a substitute for surgery. In the latter case, the aim is generally palliative. It seems reasonable to select the chemotherapy regimen according to the aim. Two active drugs are available in soft tissue sarcomas: doxorubicin and ifosfamide. Each of them is able to provide a 20% response rate in advanced disease. Many uncontrolled prospective trials have evaluated their combination, sometimes in addition to dacarbazine, which is another marginally active drug. In the Dana Farber’s series of 105 patients (Elias 1989), a 47% response rate was obtained with the MAID regimen (ifosfamide plus mesna + doxorubicin + dacarbazine). However complete responses are rare (<10%), even with most intensive regimens. Three randomized trials are available which compared doxorubicin or doxorubicin-based chemotherapy with doxorubicin plus ifosfamide. Two of them, from ECOG (Antman 1993) and SWOG/CALGB (Edmonson 1993), demonstrated a statistically significant higher response rate for the doxorubicin plus ifosfamide arm (roughly, 30% vs 20%) but no survival advantage. The third one (Santoro 1995), from EORTC, did not show either a survival or a response benefit, but the doses of ifosfamide and doxorubicin were lower than in the former two studies. There is evidence, mainly from uncontrolled studies, that the dose of the anthracycline and Ifosfamide may play a role in determining the response rate, though this is hardly confirmed by large studies on the whole population with advanced disease (LeCesne 2000). Practically, since an advantage in terms of partial responses was demonstrated with the combination of doxorubicin and ifosfamide at full doses, the medical oncologist may well suggest such an approach to the patient whenever it is felt that a partial response could be useful in terms of survival (e.g., when an inoperable patient might be converted into an operable one after chemotherapeutic cytoreduction) or quality of life (e.g., when existing lesions are directly associated with symptoms disturbing the patient’s ordinary life: pain, etc.). Therefore, monochemotherapy with doxorubicin is currently standard treatment on a type 1 level of evidence (Borden 1987, Antman 1993, Edmonson 1993, Santoro 1995), at least when a partial response is not a clinical goal. If a partial response represents a goal on clinical grounds, polychemotherapy with doxorubicin and ifosfamide may give higher response rates by comparison with monochemotherapy with doxorubicin, and therefore may be resorted to in the individual patient. Thus, regimens including doxorubicin and ifosfamide ± dacarbazine may be considered investigational or suitable for individual clinical use in selected patients on a type R basis.

6.2 High grade localized soft tissue sarcomas

6.2.0 Overall treatment strategy

Standard treatment for high grade soft tissue sarcomas, on a type C basis, is adequate surgery, to be followed, as a general rule, by adjuvant radiation therapy. If the surgical approach, though adequate (eg, a wide excision), was less than “radical”, assuming amputation and compartmental resection as “radical” interventions in sarcomas, then adjuvant radiation therapy is recomended. Uncontrolled clinical studies (Rydholm 1991, Baldini 1999) demonstrated a local recurrence rate of <10% for wide excisions without subsequent radiotherapy for tumours located either subcutaneously or intramuscularly. This may spare the patient those late sequelae of radiotherapy which are sometimes disturbing (oedema of the distal limb, etc.). Subcutaneous tumours were removed with a wide margin that included the deep fascia beneath the tumour, while intramuscular tumours were treated by myectomy (without prior incisional or Tru-cut biopsy). This approach, however, should be considered still investigational or suitable for individual clinical use on a type 3 basis (Rydholm 1991, Baldini 1999). By contrast, if surgery has already been carried out but was truly inadequate (less than “wide”, i.e., “intralesional” or “marginal”), radical srugery is recommended on a type C basis(Lewis 2000). The effectiveness of adjuvant chemotherapy in patients who had undergone adequate surgery, has been evaluated in at least 14 randomized trials which compared doxorubicin-based chemotherapy with a no-treatment arm after adequate surgery (Alvegard 1989, Antman 1990, Bramwell 1994, Chang 1988, Edmonson 1984, Eilber 1988, Omura 1985, Picci 1988, Ravaud 1990, Terjanian 1987). Only two of such studies (Picci 1988, Ravaud 1990) showed a statistically significant improvement in overall survival and disease free survival. Overall, a trend towards improved prognosis in treated patients was demonstrated by several studies. Many studies had a limited statistical power, and so they should be considered inconclusive rather than negative. A meta-analysis of data from individual patients in all available randomised trials has been carried out (Anonymous 1997), showing significant improvement in distant and local recurrences; the absolute benefit was 10% for recurrence-free survival at 10 years and 4% for overall survival. None of those trials, however, included ifosfamide, which is now recognized as one of the two most active drugs in soft tissue sarcomas. An Italian randomized trial comparing a full-dose doxorubicin plus ifosfamide arm against a no-chemotherapy arm was preliminarily reported on in 1997 (Frustaci 1997). It enrolled very high risk patients with “typical” limb soft tissue sarcomas. The trial was stopped early, due to the detection at an interim analysis of a significant advantage in favour of the treated arm in terms of disease-free and overall survival. All these data would strongly suggest that adjuvant chemotherapy may be effective, especially in high risk presentations, but, currently, there is no consensus on the adoption of adjuvant chemotherapy as standard practice in soft tissue sarcomas (Benjamin 1999, Verweij 1999). Randomized trials with a no-treatment arm are still ongoing in Europe. Adjuvant chemotherapy may thus be considered investigational or suitable for individual clinical use in selected patients, on a type 2 level of evidence, i.e. in those with poor prognostic factors (high grade, tumour diameter 5-10 cm., deep location), but treatment must be given after shared decision making between the fully informed patient and the clinician. In other circumstances, the patient should be aware that standard treatment is surgery ± radiotherapy, without chemotherapy, but that there are strong suggestions that adjuvant chemotherapy might give some reduction (higher than or equal to 5-10% in absolute terms) of the risk of relapse (which averages 50% or more in high-risk soft tissue sarcomas, depending on the presentation). Chemotherapy could also be suitable for individual clinical use, on a type R basis, in those cases in which a high risk sarcoma could not be best treated with surgery and radiotherapy. For example, a trunk high grade sarcoma which could not be treated with truly adequate surgery and full dose radiotherapy. Even in these cases no formal demonstration has been published of the effectiveness of adjuvant chemotherapy in terms of survival and disease free survival. There are some suggestions, however, from some of the published trials on adjuvant chemotherapy and the meta-analysis (Anonymous 1997), that the medical treatment might somewhat decrease the local risk of relapse.

Retroperitoneal sarcomas.
For retroperitoneal sarcomas, complete surgery is standard treatment on a type C basis, though it may be barely adequate; this underlies the high recurrence rate of these tumors. There is evidence, however, that aggressive surgery may result in tumour eradication in a fraction of patients (Lewis 1998, Karakousis 1996, Singer 1995). Radiation therapy may be attempted as a complement to surgery, though the anatomical setting makes it difficult to deliver effective doses (Clark 1996). On the basis of the effectiveness of radiation therapy in limb and trunk sarcomas, adjuvant radiotherapy may thus be considered suitable for individual clinical use, depending on its anatomical feasibility, on a type R basis. For large tumour beds, intraoperative radiotherapy might be a technical solution, as demonstrated in some clinical series, though a demonstration of effectivenss is lacking. Thus, intraoperative radiotherapy can be regarded as investigational or suitable for individual non standard clinical use on a type 3 level of evidence (Alektiar 2000, Bussieres 1996, Dubois 1995, Gunderson 1993).

Visceral sarcomas.
Soft tissue sarcomas may arise in viscera such as uterus, gastrointestinal tract, liver, and any other organ. Unless specific clinical recommendations can be given, on a type R basis it is recommended that the same basic principles are followed as for sarcomas of typical sites of origin. Therefore treatment should include adequate surgery, possibly followed by radiation therapy if feasible and indicated, depending on the quality of surgery and the anatomic site. Most visceral sarcomas may be either low grade or high grade. Currently, gastrointestinal stromal tumours (GIST) should be dealt with separately, given their peculiar natural history and prognostic factors and particularly the availability of the experimental drug STI571 (Gleevec), which in preliminarly studies has proved exceedingly active in this subset of sarcomas (Joensuu 2001, Blanke 2001, Van Oosterom 2001). Generally, case series of visceral sarcomas are limited, and so it is difficult to carry out controlled trials, as has been the case for uterine sarcomas. The clinician is then left with the task of transposing evidence gained in the most frequently occurring sarcomas to the rarest presentations. This applies in particular to the issue of adjuvant chemotherapy, which is still unsettled even in the most frequent high grade limb sarcomas. However, one may consider adjuvant chemotherapy in visceral sarcomas as suitable for individual clinical use, on a type R basis, in selected patients, i.e. those with high grade malignancies with clinical factors associated with a high risk of relapse. Such treatment should be decided upon within the context of shared decision-making with the patient, who is properly informed of the uncertainties in the available medical literature on somatic sarcomas.

6.2.1 Surgery

In high grade soft tissue limb sarcomas, adequate surgery may be regarded as amputation, compartmental resection or wide excision. Classically, “radical” interventions are amputation and compartmental resection. Amputation is done above the joint proximal to the lesion. Compartmental resection is the removal of the whole anatomical compartment in which the tumour arose. A compartmental resection sometimes carries unfavourable sequelae and only a fraction of limb soft tissue sarcomas are contained within anatomical compartments, i.e. are limited by fasciae. So, sarcomas arising in the femoral triangle, in the popliteal fossa, in the feet, hands, elbows and in most trunkal regions are extracompartmental by definition. Therefore, from the ’70s onwards, “wide” excisions, i.e. falling immediately outside the reactive zone, combined with radiotherapy, have been increasingly used with a curative intent. Overall, the combined treatment seems to provide patients with roughly the same probabilities of long term survival as the more ablative surgery. Local control may be somewhat less, though local failures do not exceed 5-15%, as compared with 0-5% for radical surgery, and survival is the same. There is only one randomized trial comparing conservative surgery versus amputation in limb sarcomas (Rosenberg 1982), but prospective and retrospective studies are available which confirm the rough equivalence between conservative treatment and surgery in terms of overall survival. By contrast, local control is not adequate after “marginal” surgery, ie falling just outside the pseudocapsule within the reactive zone, with relapses in 50% of cases. Also “contaminated” surgery, ie with possible seeding of neoplastic cells outside the tumour (eg, due to tumour rupture), carries a high risk of local relapse, given the demonstrated tendency of sarcomas to implant into tissues exposed during surgery (Hughes 2000). Local control is clearly inadequate after intralesional surgery, ie when the cut falls within the tumour (either microscopically or macroscopically). Local control is always a goal in treating soft tissue sarcomas. In fact, as long as new local relapses do occur, prognostic features may worsen. If the surgeon feels that a truly complete adequate excision is unfeasible in a conservative way, ablative surgery is the treatment of choice. Studies on quality of life in amputated patients have demonstrated that adaptative resources make it possible for these patients to maintain a quality of life which is not markedly inferior to that of limb-spared patients. On a type C basis, standard local treatment for localized high grade soft tissue sarcomas is given by the following options: i) compartmental resection, if anatomically feasible; ii) wide excision combined with pre- or postoperative radiation therapy, as an alternative to compartmental resection; iii) amputation, only if compartmental surgery or wide excision are unfeasible. Decision making may be difficult in some cases, when a complete excision is feasible (i.e. with no macroscopic or microscopic residual disease), but it is “marginal”, i.e. inadequate free margins outside the reactive zone are removed, and otherwise ablative surgery must be resorted to. In these cases, marginal excision combined with radiotherapy (postoperatively, and possibly even preoperatively), can be suitable for individual clinical use in selected patients, on a type R basis, if the patient agrees to run a higher risk of local failure with the likelihood of decreased chances of cure.Principles of surgery are not different, thoeretically, in non-limb presentations, though, of course, the true compartmental anatomy of limbs is lacking. Surgery may be particularly demanding in some anatomical locations, eg, retroperitoneal sarcomas. An attempt to perform complete surgery is worthwhile in these presentations (Lewis 1998). In visceral presentations, the aim is always one of wide surgery, according to the peculiarities of different organs. Quality of surgery is critical in sarcomas and high quality surgery may be provided in experienced institutions (Flugstad 1999, Siebenrock 2000). A policy of reresection is justified in the case of doubts as to the adequacy of previous surgery (Lewis 2000).

6.2.2 Radiation therapy

Radiotherapy, if indicated, is administered postoperatively at doses 60 Gy (for example, 50 Gy in 25 fractions over 5 weeks, with a shrinking technique at 60 Gy to the sites of likely residual microscopic disease). In some institutions, radiotherapy is given preoperatively, at doses of 50 Gy, or both preoperatively and postoperatively (Suit 1985). Preoperative treatments may make it easier for the surgeon to adequately excise the tumour, and this may be useful for gross tumours (Pollack 1998). In many cases, however, a definite judgement of operability cannot be given preoperatively, and the tumour falls in the category of “borderline” resectable lesions. In these cases some kind of preoperative treatment might be reasonable. An alternative to preoperative radiotherapy may in such cases be chemotherapy. Therefore, splitting adjuvant radiotherapy preoperatively and postoperatively, or employing preoperative chemotherapy may be suitable for individual clinical use in selected patients on a type R basis, when some surgical difficulties are expected. Hyperthermic isolated limb perfusion is investigational, and may be reserved for patients with truly inoperable lesions, or lesions which might become amenable to conservative surgery only through cytoreduction. Hyperthermic isolated limb perfusion may be combined with intravenous chemotherapy.

6.2.3 Chemotherapy
If adjuvant chemotherapy is given, it is logical to employ the most active schedules, i.e. the combinations of full dose doxorubicin and ifosfamide. Five to six courses are generally administered, on the basis of the number of cycles given by most studies on adjuvant chemotherapy. Preoperative chemotherapy should be considered investigational in operable patients, in the absence of a formal demonstration of effectiveness of chemotherapy in the classical postoperative setting. In many cases, however, a definite judgement of operability cannot be given preoperatively, and the tumour falls within the “borderline” resectable lesions. In these cases, some kind of preoperative treatment is suitable for individual clinical use on a type R basis. The probability of a partial response with preoperative full dose chemotherapy averages 40-50%, with a low risk of true progression during treatment. Chemotherapy can be given intravenously or intraarterially (Bramwell 1988), but no evidence has been produced suggesting that intraarterial chemotherapy is superior to the intravenous route of administration. Another option when cytoreduction may be the aim is preoperative radiotherapy, though it may delay surgery in the absence of a systemic coverage.

6.3 Local regional soft tissue sarcoma with regional lymph node metastases

6.3.0 Overall treatment strategy

Stage IVA disease in local regional soft tissue sarcoma is infrequent (<5% overall), even though some histotypes, such as epithelioid sarcoma, angiosarcoma, synovial sarcoma, and others are associated with a higher probability of metastasizing to regional lymph nodes (10-20%). The prognosis of these patients is definitely worse than for the localized disease without regional lymph node involvement, and in some series it was close to that of patients with distant metastases. In patients with lymph node metastases, standard treatment, on a type R basis, is surgery for the primary lesion, according to the same criteria for limited disease, lymphadenectomy, and radiotherapy where necessary. As long as adjuvant chemotherapy is effective in high-risk patients, chemotherapy in addition to surgery and radiotherapy can be considered suitable for individual clinical use on a type R basis, given the prognosis of patients with lymph node involvement.

6.4 Inoperable locally advanced disease

6.4.0 Overall treatment strategy

Inoperable lesions denote a very poor prognosis in a disease in which surgery is the mainstay of treatment. In these cases, therefore, it is reasonable to resort to any or all the available resources which can give a partial response and thereby, it is hoped, convert an inoperable disease into an operable one. Even a marginal excision can be regarded as a goal in such cases, especially if radiotherapy can follow thereafter. In some cases, especially when the malignancy grade is low, even debulking surgery may be useful to the individual patient, at least as far as his quality of life is concerned. Available therapeutic options are cytoreductive chemotherapy, irradiation, or newer locoregional approaches such as isolated limb perfusion. Radiotherapy can be combined with chemotherapy. Chemotherapy may be given intravenously or as an intraarterial infusion, where both therapeutic and toxic systemic effects will be seen. Otherwise, chemotherapy can be given as a regional intraarterial perfusion, often without major systemic effects, either in terms of therapeutic coverage nor in terms of toxicity. However, isolated regional perfusion can be combined with intravenous chemotherapy. Isolated hyperthermic limb perfusion, with tumor necrosis factor-alpha and melphalan with or without IFN-gamma, possibly followed by radiation therapy may be used (Olieman 1998, Vrouenraets 1997). No controlled evidence has been obtained so far that demonstrates superiority of any one of these approaches over the others. It could be expected that full-dose intravenous chemotherapy may achieve a response rate in excess of 30-40%. Limb perfusion techniques have been demonstrated to be relatively well tolerated. Reported complete response rates are in the range of 30%, plus partial remission rates in the range of 50% (Eggermont 1996, Gutman 1997). The limb-salvage rate may however have been increased; it is in excess of 80% in published studies (Schraffordt Koops 1998), although it is difficult to assess this benefit properly from uncontrolled studies. Overall, a combined approach with a cytoreductive treatment modality, followed by some kind of surgery, if at least marginally feasible, may be regarded as standard treatment on a type R basis. With regard to the choice of the cytoreductive treatment modality in patients with locally advanced high grade sarcomas, each of the available options, such as systemic chemotherapy, radiation therapy, limb perfusion, may be considered as suitable for individual clinical use on a type 3 level of evidence. Whether these approaches will change surgical interventions from destructive to conservative approaches remains to be assessed. More constructive approaches can be considered suitable for individual clinical use, on a type 3 basis (Eggermont 1996, Gutman 1997), if the patient accepts to undergo a theoretically higher risk of local and possibly distant relapse.

6.5 Isolated lung metastases

6.5.0 Overall treatment strategy

Operable lesions.
A conspicuous percentage of high grade sarcoma patients (as high as 80%) show isolated lung metastases as their first distant relapse (Potter 1985). If the lesions appear, to an experienced thoracic surgeon, to be completely resectable on a computerized tomography scan, an attempt to remove them surgically is standard treatment on a type C basis. A bilateral surgical exploration, by means of a median sternotomy or a bilateral thoracotomy, is useful, given the suboptimal sensitivity of computerized tomography scan for the smallest lung nodules. Patients who underwent complete removal of their lung metastases (possibly constituting 80% of all patients with isolated lung lesions) were shown in uncontrolled studies to have at least a 20% long term disease free survival, i.e. possibly a cure rate in the range of one fourth or one fifth (van Geel 1996, Casson 1991, Feldman 1972, Jablons 1989, Pastorino 1990, Robinson 1994). No prognostic factor was definitely demonstrated to be of value in selecting patients for surgery, save for feasibility of a complete excision of visible nodules. However, the number of lung nodules (e.g., more or less than four), the doubling time, or the free interval (e.g., more or less than 1-2 years) have been shown to have some prognostic value in some series, although their value in selecting patients for surgery is limited where there are no other potentially eradicative options available (Roth 1985). “Adjuvant” chemotherapy was used in some prospective uncontrolled clinical studies of surgical removal of lung metastases, but no evidence has been provided that it adds to surgery alone. Actually, many medical oncologists find it difficult not to employ chemotherapy in overt systemic disease. Indeed, risk of relapse after surgery of lung metastases is obviously high. In this context, “adjuvant” chemotherapy can be regarded as suitable for individual clinical use in selected patients, on a type R basis, providing the decision has been a joint one between the clinician and the patient. Selected patients would reasonably be those presenting with bad prognostic factors. These prognostic factors may be the tumour doubling time, the free interval after the last definitive treatment for local disease (more or less than one year), or the number of lung nodules (more or less than 4-5 nodules).

Inoperable lesions. When lung lesions are inoperable, an attempt can be made to convert them to a resectable status, but this will prove feasible in very few cases, if any. Chemotherapy is therefore standard treatment on a type R basis.

Further lung relapses.
Further lung relapses, which are isolated, and surgically removable, can be dealt with by new surgical intervention, with the aim to remove all visible nodules as well. It is difficult to state when it is most reasonable to add chemotherapy, if it has not been used before. Surgical removal of lung lesions is suitable for individual clinical use on a type 3 level of evidence as long as it is feasible, but clinical skill is needed to decide when it is no longer appropriate.

Concomitant local and lung disease.
The concurrence of local disease (either primary or relapsing) and isolated lung metastases is best treated by a combined approach following the same criteria mentioned above for each of the two conditions. Sometimes, ablative surgery can be proposed as a treatment option to an informed patient who has concurrent isolated lung metastases, in an attempt to provide him/her with some chances of cure or even a quality of life benefit (Merimsky 1997). Therefore, adequate local surgery and surgery of lung metastases are standard treatment, on a type R basis, when local disease and isolated lung metastases are present. Studies are needed to assess the clinical benefit that an aggressive approach can provide in such patients. If the chances of cure for local disease (e.g., 40%) are multiplied by chances of cure for lung disease (e.g., 20%), a 8% probability of cure might be expected. It is therefore logical not to abandon these cases to simply palliative approaches, even though the expected benefit in this population is low.

6.5.1 Chemotherapy

The clinical goal of chemotherapy must be a good response, especially when there is some chance of converting an inoperable patient to a completely resectable one; an adjuvant effect. Therefore, regimens associated with the highest predicted response rate are chosen. According to two (Antman 1993, Edmonson 1993), out of three (Santoro 1995), randomized trials, polychemotherapy with doxorubicin and ifosfamide gives higher response rates by comparison with monochemotherapy with doxorubicin, and therefore one of the regimens which include doxorubicin and ifosfamide ± dacarbazine are suitable for individual clinical use, on a type R basis, when the goal is a partial response or an adjuvant effect. Studies are needed, however, to assess effectiveness of chemotherapy both in patients with unresectable isolated lung lesions and in those who have undergone complete resection.

6.6 Extrapulmonary metastatic disease

6.6.0 Overall treatment strategy

Soft tissue sarcomas metastasize to lungs, bone, and liver, in addition to soft tissues and other organs, with decreasing frequency. Median survival for these patients is generally <12 months, although long-term survival may follow optimal response to chemotherapy in a limited percentage of patients (Wilklund 1997). Chemotherapy is widely used in these patients, basically with a palliative intent, but is clearly inadequate. Chances of partial response do not exceed 20-40%. However, no study has been initiated comparing chemotherapy to best supportive care. Indeed, many oncologists feel that best supportive care without chemotherapy may be a reasonable option at least in a subset of advanced sarcoma patients, i.e. those with poor performance status, for whom chances of response are lower and toxicity is higher; those for whom, on clinical grounds, even a partial response is likely to be useless with regard both to survival (because the disease is too advanced) and to quality of life (because no symptomatic improvement is expected). Therefore, an attempt with a first line chemotherapy regimen may be considered a standard option, on a type C basis, at least for good performance status patients and/or patients in whom some clinical benefit is reasonably expected if a partial response does occur. Indeed, best supportive care can well be suitable for individual clinical use in selected patients, on a type R basis, e.g. in patients with poor performance status, those with very advanced disease, those in whom even a partial response is not expected to improve quality of life. Palliative radiation therapy may be used as well, to improve quality of life, either in combination with chemotherapy or not.

Isolated liver metastases.
There is some evidence (Chen 1998) that surgical resection of liver metastases may parallel the benefits of surgery of lung metastases in the subpopulation of patients in whom liver may be the “first filter”.

6.6.1 Chemotherapy

There is continuing uncertainty as to the best regimen to use in patients (6.6.1) for whom one decides to resort to chemotherapy. Two active drugs are available in soft tissue sarcomas, Doxorubicin and Ifosfamide. Each of them is able to provide a 20% response rate in the advanced disease. Many uncontrolled prospective trials have evaluated their combination, sometimes in addition to dacarbazine, which is another marginally active drug. In the Dana Farber’s series of 105 patients (Elias 1989), a 47% response rate was obtained with the MAID regimen (ifosfamide plus mesna + doxorubicin + dacarbazine). However complete responses are rare (<10%), even with most intensive regimens. Three randomized trials are available which compared doxorubicin or doxorubicin-based chemotherapy with doxorubicin plus ifosfamide. Two of them, from ECOG (Antman 1993) and SWOG/CALGB (Edmonson 1993), demonstrated a statistically significant higher response rate for the doxorubicin plus ifosfamide arm (roughly, 30% vs 20%) but no survival advantage. The third study (Santoro 1995), from EORTC, did not show either a survival or a response benefit, but the doses of ifosfamide and doxorubicin were lower than in the former two studies. There is evidence, mainly from uncontrolled studies, that the dose of the anthracycline and Ifosfamide may play a role in determining the response rate, though this is hardly confirmed by large studies on the whole population with advanced disease (LeCesne 2000). Practically, since an advantage in terms of partial responses was demonstrated with the combination of doxorubicin and ifosfamide at full doses, the medical oncologist may well suggest such an approach to the patient whenever itis felt that a partial response could be useful, in terms of survival or quality of life (e.g., when existing lesions are directly associated with symptoms disturbing the patient’s ordinary life: pain, etc.). Therefore, monochemotherapy with doxorubicin is currently standard treatment on a type 1 level of evidence (Borden 1987, Antman 1993, Edmonson 1993, Santoro 1995), at least when a partial response is not a clinical goal. If a partial response represents a goal on clinical grounds, polychemotherapy with doxorubicin and Ifosfamide may give higher response rates on comparison with monochemotherapy with Doxorubicin, and therefore may be resorted to in the individual patient. Thus, regimens including doxorubicin and ifosfamide ± dacarbazine may be considered investigational or suitable for individual clinical use in selected patients on a type R basis.

6.6.2 Second line chemotherapy

Currently, there is no recognised standard second-line chemotherapy regimen. Ifosfamide at higher than standard doses (generally 14 g/sqm) achieved response rates in the 20-30% range (Le Cesne 1995, Patel 1997), although other studies have not reproduced these results (Nielsen 2000). Since the potential for a survival benefit may be difficult to predict, second line chemotherapy, with high dose Ifosfamide or investigational drugs and regimens, should be regarded as investigational or suitable for individual clinical use in selected patients on a type R basis. In fact, when a partial response is a clinical goal for palliative reasons (pain or other symptoms), secondline treatment may be chosen after shared decision making between the individual patient and the clinician. When the progression free interval has been long enough (i.e. 12 months), the clinician may revert to the same chemotherapy already used in the first line.

7. LATE SEQUELAE

7.1 Treatment late effects and sequelae

7.1.1 Local effects

Late effects and sequelae in adequately treated soft tissue sarcomas obviously depend on the site of surgery and radiation therapy. Intuitively, limb amputations carry major adverse sequelae. One should not forget, however, that even conservative surgery may be associated with adverse sequelae, such as edema and suboptimal joint function (Chang 1989, Robinson 1991). Surgical technique has improved over the last years and now conservative surgery has often a very good functional outcome. Studies on quality of life (Sugarbaker 1982, Weddington 1985) showed some years ago that the functional and psychological status of conservatively operated patients was not necessarily better than amputated patients. Now technical improvements have occurred, but the physician can still learn from those studies that quality of life of amputees may be quite satisfactory. This information can be provided to those patients to whom a demolitive approach must still be proposed. Otherwise, limb-sparing surgery is now standard practice, whenever technically feasible, with a curative intent and with a sufficiently good expected functional outcome. When radiotherapy is used, it is important to reduce normal tissue radiation as much as possible and exclude the use of circular radiation as well as radiation of joints. Therefore, radiation of these tumours should be performed by specialized radiotherapists, using advanced treatment planning systems, and closely collaborating with the surgeon who carried out the excision.

7.2 Related and secondary tumours

7.2.1 Secondary tumours

Second tumours may occasionally arise in irradiated areas.

8. FOLLOW-UP

8.1 Principles and objectives

8.1.1 Low grade sarcomas

In disease-free, adequately treated patients with low grade sarcomas, the physician will mainly have to look for signs of local relapse, and follow-up may be continued for at least ten years, given the slow natural history of these diseases.

8.1.2 High grade sarcomas

In disease-free, adequately treated patients with high grade sarcomas, the physician will have to search both for the local relapse and for a distant relapse to the lungs. In fact, isolated relapses to the lungs are often seen, and they can be rescued in >20% of completely resectable patients by means of surgery of lung metastases, while a palliative effect is likely to be achieved thereby in other patients. The risk of distant metastases will be higher in the first two to five years, depending on the tumour grade. Follow-up of high grade sarcomas could therefore be shorter than low grade sarcomas, but they should be followed for at least five years.

8.2 Suggested protocols

8.2.1 Low grade sarcomas

In asymptomatic patients treated for low grade soft tissue sarcomas, physical exam (Whooley 2000), ultrasonograms (Arya 2000, Van der Woude 1999) if physical exam is difficult, and MRI if ultrasonogram is unreliable(Davies 1998), are used to detect local relapses. It is therefore recommended, on a type R basis, that routine clinical examinations and possibly ultrasonograms are undertaken at six-month intervals or more. Chest X-rays can be done at longer intervals, given the low risk of systemic spread, and in some centers it is not included on a regular basis. Follow-up will need to be continued for a long time, say at least ten years. The patient must be informed of the risk of a local relapse.

8.2.2 High grade sarcomas

For asymptomatic patients after potentially curative treatment for high grade soft tissue sarcomas, in addition to local clinical examination and, possibly, ultrasonograms or MRI (Arya 2000, Van der Woude 1999, Davies 1998), regular chest X-rays (Whooley 1999, Bearcroft 1999) every 2-3 months for 2-3 years, and thereafter less frequently, may be recommended as routine follow-up, on a type R basis, in that lung relapse is asymptomatic and potentially curable.

9. AUTHORSHIP

This chapter results from the contribution of several people. In fact, START is a collaborative effort, which pursues a wide European consensus. Each START chapter first derives from the contribution of a few Authors of different clinical domains. The Clinical Editor in charge of the chapter has the responsibility for integrating their contributions consistently, within the framework of an evidence-based approach, in collaboration with the Statistical Editor. One or more experts then act as internal Reviewers, and their work is paralleled, independently, by Reviewers from the European cancer societies. Some Consultants directly contribute with regard to specific areas of expertise. Minor updatings and changes are made whenever it is needed, under the responsibility of the Clinical Editor, in collaboration with contributors, according to their expertise. Substantial updatings and changes are agreed upon by the Clinical Editor with the Internal Reviewer(s), while soliciting other contributors as needed. A review of each chapter is requested to all contributors on an annual basis. Formalised, independent feedback projects are carried out, to prompt external monitoring of most critical statements included within the online chapters, in collaboration with the European cancer societies. Likewise, wider feedback is solicited from the whole oncology community. Consensus development initiatives may occasionally be launched on specific items. Only this complex process of refinement should progressively let START become a true, evidence-based, European state-of-the-art instrument on the clinical approach to malignant tumours. No personal authorship can therefore be identified in so collaborative an effort. In principle, one of the contributors may even disagree on some of the statements, though the internal consensus development process should normally avoid that. This stated, it is acknowledged hereafter the effort of those experts who most directly contributed to this chapter.

Clinical Editor: Paolo G. Casali
START Programme

Author: Alessandro Gronchi
Istituto Nazionale Tumori, Milan, Italy

Author: Patrizia Olmi
Istituto Nazionale Tumori, Milan, Italy

Internal Reviewer: T. A. Alvegard
Karolinska Hospital, Stockholm, Sweden

Internal Reviewer: O. S. Nielsen
Aarhus University Hospital, Denmark

Consultant (epidemiology):Gemma Gatta
Istituto Nazionale Tumori, Milan, Italy

Consultant (medical genetics): Barbara Pasini
Istituto Nazionale Tumori, Milan, Italy

Consultant (medical oncology): Rossella Bertulli
Istituto Nazionale Tumori, Milan, Italy

Statistical Editor: Paolo Bruzzi
START Programme

INDEX

 

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Dr. Thor Alvegard (Reviewer)
University Hospital – Lund, Sweden
mail: thor.alvegard@cancerepid.lu.se

Dr. Rossella Bertulli (Consultant)
Istituto Nazionele Tumori – Milan, Italy
mail: rossella.bertulli@istitutotumori.mi.it

Dr. Paolo G. Casali (Editor)
START Clinical Editor – Istituto Nazionale Tumori – Milan, Italy
mail: paolo.casali@istitutotumori.mi.it

Dr. Maurizio Colecchia (Consultant)
Istituto Nazionale Tumori
mail: maurizio.colecchia@istitutotumori.mi.it

Dr. Judith Diement (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail:

Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: gatta@istitutotumoti.mi.it

Dr. Alessandro Gronchi (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: alessandro.gronchi@istitutotumori.mi.it

Prof. Allan T. van Oosterom (Reviewer)
UZ Ku Leuven – Leuven, Belgium
mail: allan.vanoosterom@uz.kuleuven.ac.be