Abstract. This review focuses on epidemiology, aetiology, clinical presentation, diagnosis, management, prognosis and follow-up of soft tissue sarcomas (STS) involving limbs and trunk. Any patient with a suspected STS should be referred to a specialized sarcoma centre and managed by a multidisciplinary group. The standard treatment is surgical excision followed by adjuvant radiotherapy (RT). Radiotherapy is recommended in patients with intermediate-or high-grade tumors, >5 cm of diameter or <5 cm. RT may be indicated in low grade, deep and large- size STS and/or in absence of adequate margins, after discussion within a multidisciplinary group. Neoadjuvant radiotherapy and chemotherapy should be taken into consideration for patients with borderline resectable tumors. In selected cases, amputation may be the only curative option. Isolated limb perfusion is a pre-operative treatment that may allow for amputation to be avoided. Adjuvant chemotherapy should be considered only in selected cases. Regular follow-up with clinical examination, ultrasound (US) or magnetic resonance imaging (MRI) to exclude local recurrences and chest-X- ray or chest computed tomography (CT) to exclude metastatic disease is recommended. For metastatic disease, doxorubicin is the first-line standard therapy. Second-line agents include trabectedin, ifosfamide, dacarbazine and the combination of gemcitabine-plus-docetaxel. Surgical resection of local recurrences or lung metastases should be evaluated in selected cases. Soft tissue sarcomas (STS) are a rare and heterogeneous group of tumors, ubiquitous in their site of origin. A multi- disciplinary approach (involving pathologists, radiologists, surgeons, radiation therapists, medical oncologists) is necessary in all cases. Over the past years, many advances have been made in the diagnosis and treatment of these malignancies (1- 5). In UK, clinical management guidelines have been developed under the auspices of The British Sarcoma Group (BSG) and the National Institute for Health and Care Excellence (NICE) has drawn up the “Improving Outcomes Guidance for people with sarcoma (IOG)” (3, 4). In USA, The National Comprhensive Cancer Network (NCCN) has recently published the soft tissue sarcoma guidelines (1). In Europe, the European Society of Medical Oncology (ESMO) and, in Italy, the Italian Society of Medical Oncology (AIOM) have just revised their guidelines (2, 5). According to the NCCN’s Categories of Evidence and Consensus for STS, reported in Table I, all recommendations are category 2A unless otherwise specified in the text (1). Moreover, this review is based on the BSG, NCCS and ESMO guidelines together with the National Institute for Health (NIH) and Clinical Excellence Improving Guidance for people with sarcoma (NICE-IOG) and all the most recent scientific literature related to STS is based on searches conducted in: Medline, CANCERNET PDQ, Cochrane Library Database of Systematic Reviews. Epidemiology STS are tumors of mesenchymal cell origin, arising from muscles, tendons, synovial membranes, fat and connective tissues. More than 50 different histological subtypes of sarcomas exist with a prevalence of fuso-cellular forms in adult age (1-5). Adult STS are rare (1% of all adult neoplasms) with an estimated incidence averaging 3-5/100,000/year in Europe, 5251 Correspondence to: Saveria Tropea, Melanoma and Sarcoma Unit, Veneto Institute of Oncology IOV-IRCCS Padova, Italy. Tel/Fax: +39 498212137 and +39 498218349, e-mail: [email protected] Key Words: Soft tissue sarcomas, surgery, radiotherapy, chemotherapy, limb perfusion, follow-up, metastatic disease, review. ANTICANCER RESEARCH 34: 5251-5262 (2014) Review Soft Tissue Limb and Trunk Sarcomas: Diagnosis, Treatment and Follow-up MARCO RASTRELLI 1 , SAVERIA TROPEA 1 , UMBERTO BASSO 2 , ANNA ROMA 2 , MARCO MARUZZO 2 and CARLO RICCARDO ROSSI 1 1 Melanoma and Sarcoma Unit, Veneto Institute of Oncology IOV-IRCCS Padova, Padova, Italy; 2 Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS Padova, Padova, Italy 0250-7005/2014 $2.00+.40
Soft Tissue Limb and Trunk Sarcomas: Diagnosis, Treatment and Follow-up
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17892RASTRELLI_PROTIPIARAbstract. This review focuses on epidemiology, aetiology, clinical presentation, diagnosis, management, prognosis and follow-up of soft tissue sarcomas (STS) involving limbs and trunk. Any patient with a suspected STS should be referred to a specialized sarcoma centre and managed by a multidisciplinary group. The standard treatment is surgical excision followed by adjuvant radiotherapy (RT). Radiotherapy is recommended in patients with intermediate-or high-grade tumors, >5 cm of diameter or <5 cm. RT may be indicated in low grade, deep and large- size STS and/or in absence of adequate margins, after discussion within a multidisciplinary group. Neoadjuvant radiotherapy and chemotherapy should be taken into consideration for patients with borderline resectable tumors. In selected cases, amputation may be the only curative option. Isolated limb perfusion is a pre-operative treatment that may allow for amputation to be avoided. Adjuvant chemotherapy should be considered only in selected cases. Regular follow-up with clinical examination, ultrasound (US) or magnetic resonance imaging (MRI) to exclude local recurrences and chest-X- ray or chest computed tomography (CT) to exclude metastatic disease is recommended. For metastatic disease, doxorubicin is the first-line standard therapy. Second-line agents include trabectedin, ifosfamide, dacarbazine and the combination of gemcitabine-plus-docetaxel. Surgical resection of local recurrences or lung metastases should be evaluated in selected cases.
Soft tissue sarcomas (STS) are a rare and heterogeneous group of tumors, ubiquitous in their site of origin. A multi- disciplinary approach (involving pathologists, radiologists, surgeons, radiation therapists, medical oncologists) is necessary in all cases. Over the past years, many advances have been made in the diagnosis and treatment of these malignancies (1- 5). In UK, clinical management guidelines have been developed under the auspices of The British Sarcoma Group (BSG) and the National Institute for Health and Care Excellence (NICE) has drawn up the “Improving Outcomes Guidance for people with sarcoma (IOG)” (3, 4). In USA, The National Comprhensive Cancer Network (NCCN) has recently published the soft tissue sarcoma guidelines (1). In Europe, the European Society of Medical Oncology (ESMO) and, in Italy, the Italian Society of Medical Oncology (AIOM) have just revised their guidelines (2, 5). According to the NCCN’s Categories of Evidence and Consensus for STS, reported in Table I, all recommendations are category 2A unless otherwise specified in the text (1).
Moreover, this review is based on the BSG, NCCS and ESMO guidelines together with the National Institute for Health (NIH) and Clinical Excellence Improving Guidance for people with sarcoma (NICE-IOG) and all the most recent scientific literature related to STS is based on searches conducted in: Medline, CANCERNET PDQ, Cochrane Library Database of Systematic Reviews.
Epidemiology
STS are tumors of mesenchymal cell origin, arising from muscles, tendons, synovial membranes, fat and connective tissues. More than 50 different histological subtypes of sarcomas exist with a prevalence of fuso-cellular forms in adult age (1-5).
Adult STS are rare (1% of all adult neoplasms) with an estimated incidence averaging 3-5/100,000/year in Europe,
5251
Correspondence to: Saveria Tropea, Melanoma and Sarcoma Unit, Veneto Institute of Oncology IOV-IRCCS Padova, Italy. Tel/Fax: +39 498212137 and +39 498218349, e-mail: [email protected]
Key Words: Soft tissue sarcomas, surgery, radiotherapy, chemotherapy, limb perfusion, follow-up, metastatic disease, review.
ANTICANCER RESEARCH 34: 5251-5262 (2014)
Review
Soft Tissue Limb and Trunk Sarcomas: Diagnosis, Treatment and Follow-up
MARCO RASTRELLI1, SAVERIA TROPEA1, UMBERTO BASSO2, ANNA ROMA2, MARCO MARUZZO2 and CARLO RICCARDO ROSSI1
1Melanoma and Sarcoma Unit, Veneto Institute of Oncology IOV-IRCCS Padova, Padova, Italy; 2Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS Padova, Padova, Italy
0250-7005/2014 $2.00+.40
and 8,700 new cases/year are estimated in the USA. The incidence rate of STS changes in relation to age with a first peak in paediatric age, followed by a plateau from the age of 20 until 60 years, after which it reaches its highest peak. Approximately, half of all STS patients with intermediate- or high-grade tumors develop metastatic disease, which requires systemic treatment with a 5-year overall survival (OS) of not more than 55% (1-5).
Aetiology
The vast majority of STS are not associated with an identifiable aetiology. Many risk factors are known, such as exposure to ionizing radiation or chemical agents (e.g. pesticides) but it is difficult to demonstrate a clear causal relationship (1-5).
Moreover, recent studies have demonstrated genetic associations with STS, such as the 10% lifetime risk of malignant peripheral nerve sheath tumor (MPNST) in individuals with familial neurofibromatosis by mutation in the NF1 gene or an increased risk of sarcomas in families with polyposis and Li-Fraumeni syndrome (related to mutation in the p-53 tumor suppressor gene) or a genetic alteration of regulatory gene RB-1 (familial Retinoblastoma) (6-9).
Clinical Presentation
STS may involve any anatomical area; 60% of cases develop in the limbs, 10% in the trunk and 15% in the retroperitoneum. These tumors generally occur as considerable size solid masses and they may cause pain, soreness or other dysfunctions only when they increase in size, pressing against nearby nerves and muscles (1-5).
Any soft tissue lump should be considered malignant, until proven otherwise, and patients should be referred to a diagnostic centre if their lump shows any of the following clinical features: -increasing in size (the best indicator); -size >5 cm; -deep to deep fascia; -painful. The risk of malignancy is greater when more of these clinical features are present (1-5).
Investigation
Imaging. The preferred and elective method of investigation in patients with STS is contrast-enhanced magnetic resonance imaging (MRI), but also computed tomography (CT) or ultrasound (US) with the use of contrast agents may be appropriate imaging modalities (1-5, 10-13). MRI defines as malignant a mass with an inhomogeneous signal intensity in T2-weighted images (10, 14-16). US shows sarcoma as a large
inhomogeneous and hypoechoic mass, hypervascularised, encapsulated or with a pseudocapsule (12, 13). CT has a more specific role in calcified lesions to exclude a myositis ossificans and in patients in whom MRI cannot be performed (10-12).
After histological diagnosis of STS, it is necessary to proceed with additional exams.
Patients with STS should be staged with high resolution chest CT to identify possible lung metastases and, depending on histological type and grade, a CT abdomen-pelvis, as well as an US of regional lymph nodes may also be indicated. Positron emission tomography- CT (PET- CT) may be useful to clarify eventual doubts (17).
Biopsy. The standard approach to diagnosis of a suspicious mass consists of multiple core needle biopsies (FNAB), preferably US guided and using >14-16 G needles (1-5).
An incisional biopsy may be useful if FNAB results inadequate or if abundant material is necessary to make a histological diagnosis. Excisional biopsy may be performed for <5 cm superficial lesion, but it is not recommended. The biopsy should be planned in such a way that the biopsy pathway and the scar can be removed by definitive surgery to reduce the risk of seeding (18).
Fine needle aspiration cytology (FNAC) is not recommended as a primary diagnostic modality, but it may be useful in confirming disease recurrence or metastases.
Histology. Histological diagnosis should be performed according to the World Health Organization (WHO) classification (1-5).
Malignancy grade should be provided in all cases. In Europe, the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is generally used. It distinguishes three malignancy grades based on differentiation, necrosis and mitotic rate (Table II) (19-20).
Because of tumor heterogeneity, an FNAB may not provide accurate information about grade. In addition, certain translocation-driven sarcomas have a relatively uniform cellular morphology and can be misleadingly scored as intermediate- rather than high-grade. Some sarcomas are not considered gradable (as alveolar soft tissue sarcoma, epithelioid sarcoma, clear cell sarcoma), while for other istotypes, grading has no prognostic value (as malignant tumor of the peripheral nerve sheath) (20-21). For cases characterized by a chromosomal translocation or for doubtful diagnoses or when the clinical pathological presentation is unusual, pathological diagnosis should be complemented with molecular pathology (fluorescent in situ hybridisation -FISH- or reverse transcription polymerase chain reaction -RT-PCR-) (19-21).
A pathological expert second opinion is strongly recommended in all cases when the original diagnosis is made outside a reference centre.
ANTICANCER RESEARCH 34: 5251-5262 (2014)
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According to the recommendations for STS reporting of the Royal College of Pathologists, the pathology report should include an appropriate description of tumor margins, tumour size, tumour depth and grade.
Four categories of margins have been described histologically: - Intralesional (margins run through tumor and therefore tumour remains); - Marginal (margins run through pseudocapsule and the local recurrence rate is high because of tumour satellites); - Wide surgery; - Radical (the tumor, including affected compartments, is removed and a minimal risk of local recurrence is present) (21-23).
Pathologists, in collaboration with surgeons, should make the pathological assessment of margins.
If preoperative treatment was carried out, the pathology report should include histological assessment. However, the percentage of residual vital cells has no specific prognostic significance (21-22).
The collection of tumour samples and frozen tissue is recommended both for future research and because new molecular pathology assessment could be performed at a later stage. Informed consent for tumor banking should be obtained from the patient to enable later analyses and research.
Staging
The most widely-accepted STS staging classification is the American Joint Committee on Cancer (AJCC)/International Union against Cancer (UICC) stage classification system (Table III) (1-5, 24-25).
Management
Standard treatment. Conservative surgery combined with post-operative RT is the standard treatment of STS and it permits a high local control rate, avoiding possible functional and aesthetic damage. RT is not given in case of low-grade tumors that have been completely resected or in patients with high-grade, superficial tumors < 5cm resected with wide margins (Table IV) (1-5, 26-28).
Surgery
Surgical treatment for localized disease. Surgery must be performed by a surgeon specifically trained in sarcoma treatment. Resecability evaluation should be determined by a multidisciplinary group that includes the surgeon.
The primary aim of surgery is to obtain the complete excision of the tumor with a margin of normal tissue (R0). If a wide excision with negative margins is not possible without the sacrifice of critical anatomical structures (e.g. major nerves, blood vessels), it may be acceptable to leave planned microscopic-positive margins. This possibility
Rastrelli et al: Soft Tissue Sarcoma: Diagnosis, Treatment, Follow-up (Review)
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tio .
should balance the risk of recurrence with morbidity of more radical surgery and it should be discussed with the patient (1-5, 26-28).
For patients who have undergone surgery and have unplanned positive margins (R1), re-operation should be carried-out if negative margins can be achieved without major morbidity. In case of macroscopic residual disease (R2), re-excision is mandatory if adequate margins can be obtained (1-5, 22, 26-28).
Patients with tumors that, due to their size and position, are considered borderline-resectable should be evaluated for neoadjuvant therapy with RT or CT depending on histology of the tumor and performance status of the patients (1-5, 26-8).
The surgical techniques are: - Wide local excision consists in the excision of the tumor associated with a portion of healthy contiguous muscle tissue with a thickness of at least 1 cm and fascial or adventitial tissue macroscopically unscathed. It must include all possible contaminated areas by previous surgical treatment (e.g. scars, drain holes). It is useful to check tumor margins with biopsy and to delimit the area of excision with metal clips to facilitate post-operative RT. If locoregional lymph nodes are metastatic, a lymph node dissection should be performed. Wide local excision is sufficient for small superficial sarcomas. Radical excision (compartimentectomy) involves the whole anatomic compartment (muscle, fascia, nerves and blood vessels) and is considered an appropriate treatment for high grade intracompartimental tumors instead of wide excision associated with RT. Local recurrences occur in 15% of patients. Amputation is rarely indicated after the advent of neoadjuvant treatment (hyperthermic isolated limb perfusion -HILP- or chemo-RT) but in cases of pathological fractures, tumor multifocality, recurring disease after multimodal treatment or when the limb residual functional may be insufficient, amputation may be the best surgical treatment to obtain local control and a chance for cure. The level of amputation is placed proximally to the articulation close to the tumor (1-5, 26-30).
Isolated limb perfusion. Hyperthermic isolated limb perfusion (HILP) can be performed as an alternative to amputation. HILP employs local anticancer drugs (melphalan and tumor necrosis factor-alpha (TNF-α) at 38/41C, for 60 min, administered to the affected limb, using arterial and venous cannulation and a tourniquet at the limb to prevent systemic leakage (1-5, 30-34).
When followed by local tumor excision, it permits an overall limb sparing rate of 70% and in 30% of cases a complete tumour necrosis is documented. HILP may also be considered for palliation (31-34).
Surgical treatment for advanced disease. In patients with metastatic disease, CT combined with or without RT is the most indicated treatment (category 2B). Also, surgical resection may be acceptable, taking into account patient’s symptoms (e.g. pain or fungation), co-morbidity and the morbidity after surgery, and after discussion with the patient (1-5, 30).
The decision regarding metastasectomy should be based on the disease-free period after primary surgery, total number of metastases and their respectability, tumor growth and evolution (1-5, 30).
Thus, metacronous (disease-free interval ≥ 1 year) resectable lung metastases, in the absence of extrapulmunary disease (confirmed by abdominal CT scan, bone scan or PET-CT) should be resected as standard treatment. Chemotherapy may be optionally administered after surgery, but no evidence suggests that this combined approach improves outcome; rather it is often given before surgical treatment in order to assess tumor response (1-5, 35-38).
On the other hand, in case of resectable synchronous metastases without extra-pulmunary disease, chemotherapy usually represents the first-line treatment and surgery of residual disease may be an option, especially when the tumor responds to systemic treatment (1-5). Only highly selected cases of extrapulmunary metastases are treated with chemotherapy and after multi-disciplinary evaluation; surgery of remaining metastases may be considered an
ANTICANCER RESEARCH 34: 5251-5262 (2014)
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Table II. Adjuvant chemotherapy compared to observation: meta-analyses.
Author Number of trials Chemotherapy regimen DFS (95% CI) OS (95% CI) analyzed
Tierney [101] 15 DOXO-based, various regimens NA OR 0.59 (0.45-0.78) SMAC [98] 14 DOXO-based, various regimens HR 0.75 (0.64-0.87) HR 0.91 (0.78-1.07) Pervaiz [102] 18 DOXO-based or DOXO+IFO, various regimens OR 0.67 (0.56-0.82) HR 0.77 (0.64-0.93) O’Connor [103] 18 DOXO-based or DOXO+IFO, various regimens OR 0.71 (0.54-0.85) OR 0.79 (0.58-0.85) Afonso [104] 18 DOXO-based or DOXO+IFO, various regimens Significant difference (p<0.0001) RR 0.88 (0.80-0.97)
NA, Not available; DOXO, doxorubicin; IFO, ifosfamide; DFS, disease-free survival; OS, overall survival; HR, hazard ratio; OR, odds ratio.
option. Surgical treatment or ablation or RT of extra- pulmunary metastases without chemotherapy is considered in only a small number of patients with palliative intent (39).
Radiotherapy
Adjuvant radiotherapy. Radiotherapy is administered after surgery with the rationale to sterilize microscopic tumor localizations, thus permitting more conservative surgery, especially if the tumor is adjacent to vital structures. Post- operative RT is indicated for the majority of patients with high-grade tumors and for selected patients with large or marginally excised low-grade tumors. In detail, RT is recommended in patients with intermediate or high grade tumor, >5 cm of diameter or <5 cm if deep to overlying fascia (category 1). RT may be indicated in low grade, deep and large-size STS and/or in absence of adequate margins, after multi-sciplinary discussion (category 2B) (1-5, 40-42).
The radiation dose is 60-66 Gy with fractions of 1.8-2 Gy (42-45). Intraoperative radiation and brachitherapy may be options in selected cases (1-5, 42). In case of local recurrence, every attempt should be made to regain local control by further surgery and RT (1-5, 42, 44).
Neoadjuvant radiotherapy. Pre-operative RT seems to be associated with increased post-operative complications but with less late toxicity compared to adjuvant RT (1-5, 44, 45).
A dose of 50 Gy in 1.8-2 Gy fractions should be given, followed by surgery approximately 6 week after RT. If tumour margins are positive, further RT at a dose of 10-16 Gy may be administered. It is not used routinely but only in selected cases, for instance when the tumor is of borderline operability or for certain radiosensitive histological subtypes such as myxoid liposarcoma (category 2B) (1-5, 44-47).
Chemotherapy
Adjuvant chemotherapy. Early post-operative chemotherapy might improve the progression free- and, possibly, overall survival. Controversial results have so far been obtained from clinical studies due to the rarity of the disease and the heterogeneity of tumor site, grade and histology (1-5).
At the beginning of 1970s, doxorubicin was identified as the first cytotoxic agent active in sarcomas. The National Cancer Institute (NCI) performed the first randomized trial of adjuvant doxorubicin, cyclophosphamide and methotrexate in high- grade sarcomas (48). The patients who received chemotherapy reported a lower rate of relapse and cancer-related death. In the following years, some other trials were conducted, but the accrual was always too low and final data were not significant. Three meta-analyses of published data were conducted in the early 1990s (49). They all show that adjuvant chemotherapy may prolong PFS and OS. In 1997, the Sarcoma Meta-Analysis
Rastrelli et al: Soft Tissue Sarcoma: Diagnosis, Treatment, Follow-up (Review)
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l.
Collaboration (SMAC) analyzed published and unpublished data on adjuvant therapy (50). The individual data of 1,568 patients were pooled from 14 clinical trials comparing chemotherapy with doxorubicin versus observation after the resection of a localized sarcoma. At a median follow-up time of 9.4 years, adjuvant chemotherapy resulted in a significant risk reduction of local and distant relapse. Subgroup analyses on extremity-located sarcomas revealed a significant impact on survival with an absolute gain of 7% at ten years (50). The heterogeneity of the trials, some of which also included low- grade or small sarcomas, the non-standardized dose of doxorubicin, the absence of ifosfamide in the treatment plan and the inconsistent use of RT determinated some criticisms on the findings of this meta-analysis.
Furthermore, a small trial (59 patients) of adjuvant doxorubicin, ifosfamide and dacarbazine was conducted by the Austrian Cooperative Soft Tissue Study Group (51). With a follow-up of 41 months, the PFS rate appeared better among the patients treated with chemotherapy, but after 97 months no other differences were detectable (52).
Another randomized trial of adjuvant epirubicine with or without ifosfamide was conducted in 88 patients with high-
risk sarcomas (53). The study closed early due to a slow rate of accrual and it remained underpowered. However, after a median follow-up of eight years, the DFS and OS rates were significantly better for patients receiving chemotherapy.
The Italian Sarcoma Group conducted one of the largest positive adjuvant trials, published in 2001 (54). One hundred and four patients with high-grade sarcomas of the extremities or girdles were enrolled after radical resection and radiation therapy. Patients were randomized into chemotherapy (epirubicine and ifosfamide) or observation. A positive trend in distant relapse-free survival was found after two years, and after four years the superiority of the chemotherapy arm in OS was demonstrated. Unfortunately, after a median follow-up of 90 months, the difference in OS was no longer statistically significant (55).
Recently, the results of the EORTC 62931 adjuvant chemotherapy trial was reported (56). The trial enrolled 351 patients with resected non-metastatic sarcoma who received five cycles of doxorubicin and ifosfamide or observation. This trial, the largest adjuvant study ever undertaken, failed to demonstrate any advantage from adjuvant chemotherapy.
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Author N Regimen Results
Santoro [66] 663 Doxorubicin vs. CYVADIC vs. doxorubicin + ifosfamide DFS: 46 vs. 48 vs. 44 weeks OS: 52 vs. 51 vs. 55 weeks
Edmonson [67] 279 Doxorubicin vs. doxorubicin, ifosfamide vs. ORR: 20% vs. 34% vs. 32% (p=0.03) Mitomycin, doxorubicin, cisplatin No differences in survival
Chang [68] 17 Doxorubicin vs. doxorubicin+streptozotocin Duration of response and OS for both groups were similar
Antman [69] 340 Doxorubicin and dacarbazin±ifosfamide ORR: 17% vs.…
Soft tissue sarcomas (STS) are a rare and heterogeneous group of tumors, ubiquitous in their site of origin. A multi- disciplinary approach (involving pathologists, radiologists, surgeons, radiation therapists, medical oncologists) is necessary in all cases. Over the past years, many advances have been made in the diagnosis and treatment of these malignancies (1- 5). In UK, clinical management guidelines have been developed under the auspices of The British Sarcoma Group (BSG) and the National Institute for Health and Care Excellence (NICE) has drawn up the “Improving Outcomes Guidance for people with sarcoma (IOG)” (3, 4). In USA, The National Comprhensive Cancer Network (NCCN) has recently published the soft tissue sarcoma guidelines (1). In Europe, the European Society of Medical Oncology (ESMO) and, in Italy, the Italian Society of Medical Oncology (AIOM) have just revised their guidelines (2, 5). According to the NCCN’s Categories of Evidence and Consensus for STS, reported in Table I, all recommendations are category 2A unless otherwise specified in the text (1).
Moreover, this review is based on the BSG, NCCS and ESMO guidelines together with the National Institute for Health (NIH) and Clinical Excellence Improving Guidance for people with sarcoma (NICE-IOG) and all the most recent scientific literature related to STS is based on searches conducted in: Medline, CANCERNET PDQ, Cochrane Library Database of Systematic Reviews.
Epidemiology
STS are tumors of mesenchymal cell origin, arising from muscles, tendons, synovial membranes, fat and connective tissues. More than 50 different histological subtypes of sarcomas exist with a prevalence of fuso-cellular forms in adult age (1-5).
Adult STS are rare (1% of all adult neoplasms) with an estimated incidence averaging 3-5/100,000/year in Europe,
5251
Correspondence to: Saveria Tropea, Melanoma and Sarcoma Unit, Veneto Institute of Oncology IOV-IRCCS Padova, Italy. Tel/Fax: +39 498212137 and +39 498218349, e-mail: [email protected]
Key Words: Soft tissue sarcomas, surgery, radiotherapy, chemotherapy, limb perfusion, follow-up, metastatic disease, review.
ANTICANCER RESEARCH 34: 5251-5262 (2014)
Review
Soft Tissue Limb and Trunk Sarcomas: Diagnosis, Treatment and Follow-up
MARCO RASTRELLI1, SAVERIA TROPEA1, UMBERTO BASSO2, ANNA ROMA2, MARCO MARUZZO2 and CARLO RICCARDO ROSSI1
1Melanoma and Sarcoma Unit, Veneto Institute of Oncology IOV-IRCCS Padova, Padova, Italy; 2Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS Padova, Padova, Italy
0250-7005/2014 $2.00+.40
and 8,700 new cases/year are estimated in the USA. The incidence rate of STS changes in relation to age with a first peak in paediatric age, followed by a plateau from the age of 20 until 60 years, after which it reaches its highest peak. Approximately, half of all STS patients with intermediate- or high-grade tumors develop metastatic disease, which requires systemic treatment with a 5-year overall survival (OS) of not more than 55% (1-5).
Aetiology
The vast majority of STS are not associated with an identifiable aetiology. Many risk factors are known, such as exposure to ionizing radiation or chemical agents (e.g. pesticides) but it is difficult to demonstrate a clear causal relationship (1-5).
Moreover, recent studies have demonstrated genetic associations with STS, such as the 10% lifetime risk of malignant peripheral nerve sheath tumor (MPNST) in individuals with familial neurofibromatosis by mutation in the NF1 gene or an increased risk of sarcomas in families with polyposis and Li-Fraumeni syndrome (related to mutation in the p-53 tumor suppressor gene) or a genetic alteration of regulatory gene RB-1 (familial Retinoblastoma) (6-9).
Clinical Presentation
STS may involve any anatomical area; 60% of cases develop in the limbs, 10% in the trunk and 15% in the retroperitoneum. These tumors generally occur as considerable size solid masses and they may cause pain, soreness or other dysfunctions only when they increase in size, pressing against nearby nerves and muscles (1-5).
Any soft tissue lump should be considered malignant, until proven otherwise, and patients should be referred to a diagnostic centre if their lump shows any of the following clinical features: -increasing in size (the best indicator); -size >5 cm; -deep to deep fascia; -painful. The risk of malignancy is greater when more of these clinical features are present (1-5).
Investigation
Imaging. The preferred and elective method of investigation in patients with STS is contrast-enhanced magnetic resonance imaging (MRI), but also computed tomography (CT) or ultrasound (US) with the use of contrast agents may be appropriate imaging modalities (1-5, 10-13). MRI defines as malignant a mass with an inhomogeneous signal intensity in T2-weighted images (10, 14-16). US shows sarcoma as a large
inhomogeneous and hypoechoic mass, hypervascularised, encapsulated or with a pseudocapsule (12, 13). CT has a more specific role in calcified lesions to exclude a myositis ossificans and in patients in whom MRI cannot be performed (10-12).
After histological diagnosis of STS, it is necessary to proceed with additional exams.
Patients with STS should be staged with high resolution chest CT to identify possible lung metastases and, depending on histological type and grade, a CT abdomen-pelvis, as well as an US of regional lymph nodes may also be indicated. Positron emission tomography- CT (PET- CT) may be useful to clarify eventual doubts (17).
Biopsy. The standard approach to diagnosis of a suspicious mass consists of multiple core needle biopsies (FNAB), preferably US guided and using >14-16 G needles (1-5).
An incisional biopsy may be useful if FNAB results inadequate or if abundant material is necessary to make a histological diagnosis. Excisional biopsy may be performed for <5 cm superficial lesion, but it is not recommended. The biopsy should be planned in such a way that the biopsy pathway and the scar can be removed by definitive surgery to reduce the risk of seeding (18).
Fine needle aspiration cytology (FNAC) is not recommended as a primary diagnostic modality, but it may be useful in confirming disease recurrence or metastases.
Histology. Histological diagnosis should be performed according to the World Health Organization (WHO) classification (1-5).
Malignancy grade should be provided in all cases. In Europe, the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is generally used. It distinguishes three malignancy grades based on differentiation, necrosis and mitotic rate (Table II) (19-20).
Because of tumor heterogeneity, an FNAB may not provide accurate information about grade. In addition, certain translocation-driven sarcomas have a relatively uniform cellular morphology and can be misleadingly scored as intermediate- rather than high-grade. Some sarcomas are not considered gradable (as alveolar soft tissue sarcoma, epithelioid sarcoma, clear cell sarcoma), while for other istotypes, grading has no prognostic value (as malignant tumor of the peripheral nerve sheath) (20-21). For cases characterized by a chromosomal translocation or for doubtful diagnoses or when the clinical pathological presentation is unusual, pathological diagnosis should be complemented with molecular pathology (fluorescent in situ hybridisation -FISH- or reverse transcription polymerase chain reaction -RT-PCR-) (19-21).
A pathological expert second opinion is strongly recommended in all cases when the original diagnosis is made outside a reference centre.
ANTICANCER RESEARCH 34: 5251-5262 (2014)
5252
According to the recommendations for STS reporting of the Royal College of Pathologists, the pathology report should include an appropriate description of tumor margins, tumour size, tumour depth and grade.
Four categories of margins have been described histologically: - Intralesional (margins run through tumor and therefore tumour remains); - Marginal (margins run through pseudocapsule and the local recurrence rate is high because of tumour satellites); - Wide surgery; - Radical (the tumor, including affected compartments, is removed and a minimal risk of local recurrence is present) (21-23).
Pathologists, in collaboration with surgeons, should make the pathological assessment of margins.
If preoperative treatment was carried out, the pathology report should include histological assessment. However, the percentage of residual vital cells has no specific prognostic significance (21-22).
The collection of tumour samples and frozen tissue is recommended both for future research and because new molecular pathology assessment could be performed at a later stage. Informed consent for tumor banking should be obtained from the patient to enable later analyses and research.
Staging
The most widely-accepted STS staging classification is the American Joint Committee on Cancer (AJCC)/International Union against Cancer (UICC) stage classification system (Table III) (1-5, 24-25).
Management
Standard treatment. Conservative surgery combined with post-operative RT is the standard treatment of STS and it permits a high local control rate, avoiding possible functional and aesthetic damage. RT is not given in case of low-grade tumors that have been completely resected or in patients with high-grade, superficial tumors < 5cm resected with wide margins (Table IV) (1-5, 26-28).
Surgery
Surgical treatment for localized disease. Surgery must be performed by a surgeon specifically trained in sarcoma treatment. Resecability evaluation should be determined by a multidisciplinary group that includes the surgeon.
The primary aim of surgery is to obtain the complete excision of the tumor with a margin of normal tissue (R0). If a wide excision with negative margins is not possible without the sacrifice of critical anatomical structures (e.g. major nerves, blood vessels), it may be acceptable to leave planned microscopic-positive margins. This possibility
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should balance the risk of recurrence with morbidity of more radical surgery and it should be discussed with the patient (1-5, 26-28).
For patients who have undergone surgery and have unplanned positive margins (R1), re-operation should be carried-out if negative margins can be achieved without major morbidity. In case of macroscopic residual disease (R2), re-excision is mandatory if adequate margins can be obtained (1-5, 22, 26-28).
Patients with tumors that, due to their size and position, are considered borderline-resectable should be evaluated for neoadjuvant therapy with RT or CT depending on histology of the tumor and performance status of the patients (1-5, 26-8).
The surgical techniques are: - Wide local excision consists in the excision of the tumor associated with a portion of healthy contiguous muscle tissue with a thickness of at least 1 cm and fascial or adventitial tissue macroscopically unscathed. It must include all possible contaminated areas by previous surgical treatment (e.g. scars, drain holes). It is useful to check tumor margins with biopsy and to delimit the area of excision with metal clips to facilitate post-operative RT. If locoregional lymph nodes are metastatic, a lymph node dissection should be performed. Wide local excision is sufficient for small superficial sarcomas. Radical excision (compartimentectomy) involves the whole anatomic compartment (muscle, fascia, nerves and blood vessels) and is considered an appropriate treatment for high grade intracompartimental tumors instead of wide excision associated with RT. Local recurrences occur in 15% of patients. Amputation is rarely indicated after the advent of neoadjuvant treatment (hyperthermic isolated limb perfusion -HILP- or chemo-RT) but in cases of pathological fractures, tumor multifocality, recurring disease after multimodal treatment or when the limb residual functional may be insufficient, amputation may be the best surgical treatment to obtain local control and a chance for cure. The level of amputation is placed proximally to the articulation close to the tumor (1-5, 26-30).
Isolated limb perfusion. Hyperthermic isolated limb perfusion (HILP) can be performed as an alternative to amputation. HILP employs local anticancer drugs (melphalan and tumor necrosis factor-alpha (TNF-α) at 38/41C, for 60 min, administered to the affected limb, using arterial and venous cannulation and a tourniquet at the limb to prevent systemic leakage (1-5, 30-34).
When followed by local tumor excision, it permits an overall limb sparing rate of 70% and in 30% of cases a complete tumour necrosis is documented. HILP may also be considered for palliation (31-34).
Surgical treatment for advanced disease. In patients with metastatic disease, CT combined with or without RT is the most indicated treatment (category 2B). Also, surgical resection may be acceptable, taking into account patient’s symptoms (e.g. pain or fungation), co-morbidity and the morbidity after surgery, and after discussion with the patient (1-5, 30).
The decision regarding metastasectomy should be based on the disease-free period after primary surgery, total number of metastases and their respectability, tumor growth and evolution (1-5, 30).
Thus, metacronous (disease-free interval ≥ 1 year) resectable lung metastases, in the absence of extrapulmunary disease (confirmed by abdominal CT scan, bone scan or PET-CT) should be resected as standard treatment. Chemotherapy may be optionally administered after surgery, but no evidence suggests that this combined approach improves outcome; rather it is often given before surgical treatment in order to assess tumor response (1-5, 35-38).
On the other hand, in case of resectable synchronous metastases without extra-pulmunary disease, chemotherapy usually represents the first-line treatment and surgery of residual disease may be an option, especially when the tumor responds to systemic treatment (1-5). Only highly selected cases of extrapulmunary metastases are treated with chemotherapy and after multi-disciplinary evaluation; surgery of remaining metastases may be considered an
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Table II. Adjuvant chemotherapy compared to observation: meta-analyses.
Author Number of trials Chemotherapy regimen DFS (95% CI) OS (95% CI) analyzed
Tierney [101] 15 DOXO-based, various regimens NA OR 0.59 (0.45-0.78) SMAC [98] 14 DOXO-based, various regimens HR 0.75 (0.64-0.87) HR 0.91 (0.78-1.07) Pervaiz [102] 18 DOXO-based or DOXO+IFO, various regimens OR 0.67 (0.56-0.82) HR 0.77 (0.64-0.93) O’Connor [103] 18 DOXO-based or DOXO+IFO, various regimens OR 0.71 (0.54-0.85) OR 0.79 (0.58-0.85) Afonso [104] 18 DOXO-based or DOXO+IFO, various regimens Significant difference (p<0.0001) RR 0.88 (0.80-0.97)
NA, Not available; DOXO, doxorubicin; IFO, ifosfamide; DFS, disease-free survival; OS, overall survival; HR, hazard ratio; OR, odds ratio.
option. Surgical treatment or ablation or RT of extra- pulmunary metastases without chemotherapy is considered in only a small number of patients with palliative intent (39).
Radiotherapy
Adjuvant radiotherapy. Radiotherapy is administered after surgery with the rationale to sterilize microscopic tumor localizations, thus permitting more conservative surgery, especially if the tumor is adjacent to vital structures. Post- operative RT is indicated for the majority of patients with high-grade tumors and for selected patients with large or marginally excised low-grade tumors. In detail, RT is recommended in patients with intermediate or high grade tumor, >5 cm of diameter or <5 cm if deep to overlying fascia (category 1). RT may be indicated in low grade, deep and large-size STS and/or in absence of adequate margins, after multi-sciplinary discussion (category 2B) (1-5, 40-42).
The radiation dose is 60-66 Gy with fractions of 1.8-2 Gy (42-45). Intraoperative radiation and brachitherapy may be options in selected cases (1-5, 42). In case of local recurrence, every attempt should be made to regain local control by further surgery and RT (1-5, 42, 44).
Neoadjuvant radiotherapy. Pre-operative RT seems to be associated with increased post-operative complications but with less late toxicity compared to adjuvant RT (1-5, 44, 45).
A dose of 50 Gy in 1.8-2 Gy fractions should be given, followed by surgery approximately 6 week after RT. If tumour margins are positive, further RT at a dose of 10-16 Gy may be administered. It is not used routinely but only in selected cases, for instance when the tumor is of borderline operability or for certain radiosensitive histological subtypes such as myxoid liposarcoma (category 2B) (1-5, 44-47).
Chemotherapy
Adjuvant chemotherapy. Early post-operative chemotherapy might improve the progression free- and, possibly, overall survival. Controversial results have so far been obtained from clinical studies due to the rarity of the disease and the heterogeneity of tumor site, grade and histology (1-5).
At the beginning of 1970s, doxorubicin was identified as the first cytotoxic agent active in sarcomas. The National Cancer Institute (NCI) performed the first randomized trial of adjuvant doxorubicin, cyclophosphamide and methotrexate in high- grade sarcomas (48). The patients who received chemotherapy reported a lower rate of relapse and cancer-related death. In the following years, some other trials were conducted, but the accrual was always too low and final data were not significant. Three meta-analyses of published data were conducted in the early 1990s (49). They all show that adjuvant chemotherapy may prolong PFS and OS. In 1997, the Sarcoma Meta-Analysis
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Collaboration (SMAC) analyzed published and unpublished data on adjuvant therapy (50). The individual data of 1,568 patients were pooled from 14 clinical trials comparing chemotherapy with doxorubicin versus observation after the resection of a localized sarcoma. At a median follow-up time of 9.4 years, adjuvant chemotherapy resulted in a significant risk reduction of local and distant relapse. Subgroup analyses on extremity-located sarcomas revealed a significant impact on survival with an absolute gain of 7% at ten years (50). The heterogeneity of the trials, some of which also included low- grade or small sarcomas, the non-standardized dose of doxorubicin, the absence of ifosfamide in the treatment plan and the inconsistent use of RT determinated some criticisms on the findings of this meta-analysis.
Furthermore, a small trial (59 patients) of adjuvant doxorubicin, ifosfamide and dacarbazine was conducted by the Austrian Cooperative Soft Tissue Study Group (51). With a follow-up of 41 months, the PFS rate appeared better among the patients treated with chemotherapy, but after 97 months no other differences were detectable (52).
Another randomized trial of adjuvant epirubicine with or without ifosfamide was conducted in 88 patients with high-
risk sarcomas (53). The study closed early due to a slow rate of accrual and it remained underpowered. However, after a median follow-up of eight years, the DFS and OS rates were significantly better for patients receiving chemotherapy.
The Italian Sarcoma Group conducted one of the largest positive adjuvant trials, published in 2001 (54). One hundred and four patients with high-grade sarcomas of the extremities or girdles were enrolled after radical resection and radiation therapy. Patients were randomized into chemotherapy (epirubicine and ifosfamide) or observation. A positive trend in distant relapse-free survival was found after two years, and after four years the superiority of the chemotherapy arm in OS was demonstrated. Unfortunately, after a median follow-up of 90 months, the difference in OS was no longer statistically significant (55).
Recently, the results of the EORTC 62931 adjuvant chemotherapy trial was reported (56). The trial enrolled 351 patients with resected non-metastatic sarcoma who received five cycles of doxorubicin and ifosfamide or observation. This trial, the largest adjuvant study ever undertaken, failed to demonstrate any advantage from adjuvant chemotherapy.
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Author N Regimen Results
Santoro [66] 663 Doxorubicin vs. CYVADIC vs. doxorubicin + ifosfamide DFS: 46 vs. 48 vs. 44 weeks OS: 52 vs. 51 vs. 55 weeks
Edmonson [67] 279 Doxorubicin vs. doxorubicin, ifosfamide vs. ORR: 20% vs. 34% vs. 32% (p=0.03) Mitomycin, doxorubicin, cisplatin No differences in survival
Chang [68] 17 Doxorubicin vs. doxorubicin+streptozotocin Duration of response and OS for both groups were similar
Antman [69] 340 Doxorubicin and dacarbazin±ifosfamide ORR: 17% vs.…
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