Soft Tissue Limb and Trunk Sarcomas: Diagnosis, Treatment and

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; Oncology 1, Veneto Institute of Oncology IOV-IRCCS Padova, Padova, Italy

2Medical

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; -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

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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, 18-80 yrs Grade 3 Grade 3, size > 5 cm, 18-65 yrs Grade 3 Grade 2 or 3, or= 8 cm or grade II/III size >or= 8 cm or grade II/III Grade III-IV

5-year OS

option. Surgical treatment or ablation or RT of extrapulmunary metastases without chemotherapy is considered in only a small number of patients with palliative intent (39).

NS, 65% vs. 64% 87% vs. 58% (p=0.0003) 7yrs=79% vs. 45% (p=0.003) NS, 68% vs. 71%

Rastrelli et al: Soft Tissue Sarcoma: Diagnosis, Treatment, Follow-up (Review)

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ANTICANCER RESEARCH 34: 5251-5262 (2014) Table IV. Clinical trials on advanced/metastatic chemotherapy. Author

N

Regimen

Results

Santoro [66]

663

Doxorubicin vs. CYVADIC vs. doxorubicin + ifosfamide

Edmonson [67]

279 17

Doxorubicin vs. doxorubicin, ifosfamide vs. Mitomycin, doxorubicin, cisplatin Doxorubicin vs. doxorubicin+streptozotocin

Antman [69]

340

Doxorubicin and dacarbazin±ifosfamide

Nielsen [71] Patel [74] Verma [73]

124 37 --

Judson [106]

455

High-dose ifosfamide High-dose ifosfamide Meta-analysis of chemo-regimen with or without ifosfamide Doxorubicin vs. doxorubicin + ifosfamide

Le Cesne [75]

104

Trabectedin

Demetri [77]

270

Trabectedin 24 h vs. trabectedin 3 h

Hensley [77]

34

Gemcitabine and docetaxel in leiomyosarcoma

44 369

Dacarbazin Pazopanib vs. placebo

DFS: 46 vs. 48 vs. 44 weeks OS: 52 vs. 51 vs. 55 weeks ORR: 20% vs. 34% vs. 32% (p=0.03) No differences in survival Duration of response and OS for both groups were similar ORR: 17% vs. 32% (p=0.002) TTP: 4 vs. 6 months (p=0.02) OS: 12 vs. 13 months (not significant) TTP 15 weeks, PR 16% ORR 19% Ifosfamide improves ORR (RR 1.52, p=0.009) No OS difference (RR 0.98, p=0.76) PFS 4.6 vs. 7.4 months (p=0.003) OS 12.8 vs. 14.3 months (not significant) ORR 14% vs. 26% (p5 cm tumor, chemosensistive histology), informing the patients on the possible risks and benefits of treatment. Patients with R1 resection could benefit from post-operative chemotherapy but they should be re-operated whenever possible, since chemotherapy should not be viewed as a substitute for inadequate surgery (category 2B) (60).

Neoadjuvant chemotherapy. Neoadjuvant chemotherapy is the administration of cytotoxic drugs before surgery in order to reduce the tumor size facilitating its removal and to kill microscopic metastatic disease. In sarcomas, the concept of neoadjuvant therapy is to date highly controversial. Several phase II trials have demonstrated that preoperative chemotherapy achieves a higher response rate even if benefits in terms of PFS or OS have not been shown (1-5, 61). A phase II clinical trial was performed by the EORTC Soft Tissue and Bone Sarcoma Group: (62) patients with high-risk sarcoma underwent three cycles of preoperative chemotherapy before surgery. With a median follow-up time of seven years the DFS and OS were not improved from preoperative chemotherapy. Since the accrual was very slow it was not possible to extend the trial to the subsequent phase III. DeLaney designed a study of neoadjuvant chemotherapy interdigitated with RT in high grade sarcomas (63). The patients received mesna, adriamycin, ifosfamide and dacarbazine (MAID) concurrent with RT. This aggressive chemo-radiotherapy provided high rates of disease control: DFS, metastases-free survival and OS at 5 years were significantly improved in the MAID group. Recently, a ten year follow-up update of the MAID trial demonstrated that DFS and OS still remained appreciably high compared to control arm (64). The Italian and Spanish Sarcoma Group evaluated three versus five cycles of chemotherapy in localized high-risk sarcomas of the extremities and trunk wall in adults in a phase III trial (65). At 5 years, no significant differences in OS probability were observed. The conclusion was that adjuvant chemotherapy may be omitted after three preoperative cycles. German investigators performed a phase II non-randomized trial to evaluate the efficacy of neoadjuvant and adjuvant chemoradiation therapy in high risk sarcoma. At 2 years, OS and DFS rates were 83% and 63%, respectively. Following this trial, the Italian and Spanish Sarcoma Group have launched a new neoadjuvant chemotherapy trial with an innovative proof of concept design to evaluate histotypetailored chemotherapy (EUDRA-CT 2010-023484-17). In summary, the indications for neoadjuvant chemotherapy remain controversial: localized high risk soft tissue sarcoma with size greater than 5 cm and chemosensitive subtypes could be considered an indication for preoperative chemotherapy (category 2B). Chemotherapy in advanced disease. Approximately 50% of patients develop distant metastases with a median survival of 12 months from the diagnosis of metastases. Generally, a metastatic tumor cannot benefit from surgery or radiation therapy because of the extension of the disease and the impossibility to achieve radical treatment on the metastatic sites (1-5). Adults with a metastatic soft tissue sarcoma have a median overall survival of 12 months and are generally treated

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ANTICANCER RESEARCH 34: 5251-5262 (2014) in the same way, regardless of the biological differences between the different histological subtypes. The first conventional approach is a chemotherapy based on anthracycline. Doxorubicin is the first-line standard therapy, either as monochemotherapy or in association with ifosfamide. Doxorubicin has a clear antitumour activity in soft tissue sarcomas, inducing a response rate of 16-27% and with a median survival up to 12 months (66-69). In a recent review, the authors underlined that doxorubicin monotherapy at an appropriate dose is the regimen which achieved the best results in terms of overall survival (70). In the following years, several phase II and III trials were conducted to evaluate the efficacy and tolerability of doxorubicin in association with other drugs. Among these, ifosfamide demonstrated an antitumour activity in advanced sarcomas. A multicentre phase II study conducted by the EORTC demonstrated that the drug produced outcomes not inferior to those achieved by doxorubicin (71, 72). Thus, ifosfamide has been used as single-agent in chemotherapeutic treatments. Aside from this application, ifosfamide is frequently part of a combination regimen, mostly with doxorubicin, although the superiority of the combination versus single-agent use has not been clearly addressed; a clear benefit on OS has not been demonstrated, but it is reasonable to expect a higher response rate. Thus the association of ifosfamide may be the treatment-of-choice for patients with a good performance status (73). High-dose ifosfamide could be a therapeutic option for patients previously treated with standard dose, after failure of first line therapy (71, 74). Some other agents have been explored over the last few years and the only true new drug for advanced STS to be approved is trabectedin, a marine alkaloid initially isolated from an invertebrate sea squirt, Ecteinascidin turbinate. One hundred and four patients, from all over Europe, were enrolled in a phase II trial to evaluate the activity and safety of trabectedin (75). The median OS for the patients was 9.2 months, unusually long in heavily pretreated patients, and the 6-month PFS was comparable to others reported from different second line agents for sarcomas. A further phase II trial demonstrated the efficacy and activity of trabectedin in pretreated sarcomas, especially leiomyosarcoma and liposarcomas, and, based on these data, trabectedin has been approved worldwide with notable exceptions being the United States and Australia (76). Gemcitabine-plus-docetaxeal is another combination regimen that was found to be active in advanced disease, despite the general lack of activity of docetaxel in sarcomas. In a phase II trial, 34 patients with leiomyosarcoma were treated with gemcitabine and docetaxel reporting a response in 50% of doxorubicin pretreated patients (77). Some other retrospective data have been reported, confirming the activity of this combination and a phase III trial comparing gemcitabine-plus-docetaxel versus doxorubicin in first-line is ongoing in the United Kingdom (78).

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First reported as an active agent in 1970s, dacarbazine is currently used as second line therapy in advanced sarcomas after failure of anthracycline and/or ifosfamide. A phase II trial demonstrated its anti-tumoral activity and it is to date a valuable choice to be considered (79). More recently in 2013, pazopanib has been approved after a randomized, double blinded, placebo-controlled phase III trial: (80) Three hundred and sixty-nine patients with metastatic unresectable pretreated sarcoma were randomly assigned to pazopanib or placebo revealing a 4.6-month benefit in PFS. Little evidence of activity of other drugs in specific histological subtypes has been reported, but most of them are based on retrospective series or phase II trials, and randomized validating trials are either lacking or ongoing: paclitaxel in angiosarcoma (81), sunitinib in alveolar soft part sarcoma and clear cell sarcoma (82), sunitinib or temozolomide and bevacizumab in solitary fibrous tumor (83), mTOR inhibitors in PEComa (84).

Prognosis and Follow-up Prognosis can be estimated on the basis of tumor grade, depth, size, diagnosis and age of patient. Local recurrence is related to grade, margins of excision and use of RT. Generally, most relapses arise in the first five years following diagnosis; low grade tumors may recur late. Relapses most often occur to the lungs. Early detection of local or metastatic recurrence to the lungs may have prognostic implications, considering that lung metastases are asymptomatic at an early stage when they are operable (1-5, 85). There is no absolute agreement on the optimal routine follow-up policy. Following most STS guidelines, it is recommended that: - Patients with intermediate or high grade STS are followed-up every 3-4 months for the first 2-3 years, then twice a year for up to 5 years and annually thereafter. Patients with low-grade sarcomas should be followed-up every 4-6 months for 3-5 years, then annually. Standard follow up practice consists of: - clinical history and investigation of any symptoms of the patient; - use of US or MRI to detect local relapse (86); - routine chest X-ray, with consequent CT, to detect pulmonary metastases (87); In certain cases, this followup can be adapted to the individual risk of the patients, performing chest-abdomen CT or other investigations on the basis of clinical suspicion.

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Received June 19, 2014 Revised July 25, 2014 Accepted July 28, 2014