Adult soft tissue sarcomas: Conventional therapies and molecularly targeted approaches

CANCER TREATMENT REVIEWS (2006) 32, 9–27

www.elsevierhealth.com/journals/ctrv

ANTI-TUMOUR TREATMENT

Adult soft tissue sarcomas: Conventional therapies and molecularly targeted approaches Simone Mocellin

a,c,

*, Carlo R. Rossi a, Alba Brandes b, Donato Nitti

a

a

Surgery Branch, Department of Oncological and Surgical Sciences, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy b Oncology Section, Department of Oncological and Surgical Sciences, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy c Istituto Oncologico Veneto - Istituto di Ricerca e Cura a Carattere Scientifico (IOV-IRCCS), via Gattamelata 64, 35128 Padova, Italy Received 12 July 2005; received in revised form 21 September 2005

KEYWORDS

Summary The therapeutic approach to soft tissue sarcomas (STS) has evolved over the past two decades based on the results from randomized controlled trials (RCT), which are guiding physicians in the treatment decision-making process. Despite significant improvements in the control of local disease, a significant number of patients ultimately die of recurrent/metastatic disease following radical surgery due to a lack of effective adjuvant treatments. In addition, the characteristic chemoresistance of STS has compromised the therapeutic value of conventional antineoplastic agents in cases of unresectable advanced/metastatic disease. Therefore, novel therapeutic strategies are urgently needed to improve the prognosis of patients with STS. Recent advances in STS biology are paving the way to the development of molecularly targeted therapeutic strategies, the efficacy of which relies not only on the knowledge of the molecular mechanisms underlying cancer development/progression but also on the personalization of the therapeutic regimen according to the molecular features of individual tumours. In this work, we review the state-of-the-art of conventional treatments for STS and summarize the most promising findings in the development of molecularly targeted therapeutic approaches. c 2005 Elsevier Ltd. All rights reserved.

Soft tissue sarcoma; Surgery; Chemotherapy; Radiotherapy; Molecular therapy; Targeted therapy; Gene therapy; Cancer vaccine



Introduction * Corresponding author. Tel.: +39 049 8211851; fax: +39 049 651891. E-mail address: [email protected] (S. Mocellin).



Soft tissue sarcomas (STS) are a heterogeneous group of rare mesenchymal tumours that account

0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.10.003

10 for roughly 1% of all adult malignancies.1 Currently, more than 50 histological types of STS have been identified, but the most common in adults are malignant fibrous histiocytoma (28%), leiomyosarcoma (12%), liposarcoma (15%), synovial sarcoma (10%), and malignant peripheral nerve sheath tumours (6%).2 Despite the variety of histological subtypes, STS present some common features. For instance, the clinical behaviour of most STS correlates with anatomic location, histological grade, and tumour size.3,4 Moreover, the prevalent metastatic pattern is hematogenous, with the lungs being the main target organ; by contrast lymphatic metastases are rare (<5%), except for few histological types (e.g., epithelioid sarcoma, synovial sarcoma, clear-cell sarcoma, angiosarcoma). However, the variability in patients’ clinical outcome underscores the heterogeneity of the biological aggressiveness of these tumours, the therapeutic management of which remains one of the most daunting tasks for oncologists. STS can occur anywhere in the body, but most originate in the extremities (60%), followed by the retroperitoneum (19%), abdominal/thoracic wall (15%), and head&neck (6%). As a corollary, radical resection can be functionally mutilating for patients and technically challenging for surgeons. Furthermore, most STS are characterized by relative resistance to chemotherapy, and the 5-year overall survival (OS) rate for STS of all stages is only 50–60%.5 Despite the improvements in the local control rate of limb STS treated with a multidisciplinary approach, a high frequency of recurrence/metastasis and poor OS remain significant problems, particularly in patients with highrisk STS (e.g., metastatic/recurrent disease, deep vs. superficial location, trunk/head&neck vs. extremity, tumour size >5 cm, intermediate-/ high- vs. low-grade).6 Nevertheless, recent advances in the biology of these tumours are paving the way to molecularly targeted therapeutic strategies that might change the natural history of STS.7,8 In this work, we reviewed the results of conventional treatments for STS and provide the reader with an overview on the most promising findings in the development of molecular therapeutic approaches to these tumours. To this aim, PubMed searches of the National Library of Medicine were performed with appropriate keywords, with the only restriction being English language. For ongoing clinical trials, the National Cancer Institute dedicated website (http://cancer.gov/clinicaltrials) was also searched.

S. Mocellin et al.

Standard treatments Extremity STS Surgery The surgical approach to STS has drastically changed over the last decades. In the 1970s, amputation was considered the standard treatment for limb STS and 50% of patients with extremity STS underwent amputation for local control of their tumours.9 However, large number of patients died of metastatic disease despite a local recurrence rate <15% after radical surgery. In 1982, a small randomized controlled trials (RCT) (n = 43) showed that limb-sparing surgery combined with radiotherapy could obtain a local recurrence rate of only 15%, with no difference in OS compared with amputation.10 In the 1980s, following the implementation of multimodality therapy (conservative surgery combined with radiotherapy or locoregional chemotherapy), wide peritumoural healthy tissue resections (compartmentectomy) compromising limb function were progressively abandoned, amputation rates dropped to less than 10%, and local recurrence rates remained low (5–15%).11 In the 1990s, improved selection of patients for adjuvant radiotherapy resulted from RCT, and technical advances in reconstructive surgery (e.g., pedicle or free tissue transfers, repair of bone defects with prostheses or autogenous bone grafts using micro-vascular techniques) allowed for the closure of large soft tissue defects,12 which contributed to minimize functional deficits in patients otherwise requiring amputation. The accumulated experience has allowed the definition of some practical guidelines. If applicable, the biopsy site/tract should be included en bloc with the resected specimen, as inadequate primary tumour resection can compromise the curative intent of surgery.13,14 STS are generally surrounded by a zone of compressed reactive tissue that forms a pseudocapsule, which may mistakenly be used by inexperienced surgeons to guide resection (enucleation). Microscopic extensions of tumour beyond the pseudocapsule (skip metastasis) must always be considered while planning surgery. Currently, wide local excision is the primary treatment strategy for extremity STS, with the goal to resect the tumour with a 1–2 cm margin of surrounding normal tissue. This strategy has been validated by long-term results.3,4 For instance, in a series of 77 patients treated with limb-sparing surgery without adjuvant treatments, the 10-year local recurrence rate was 7%, with a significant difference between patients who had a margin width greater or less than 1 cm (13% and 0%, respectively).15 These and other similar

Adult soft tissue sarcomas: Conventional therapies and molecularly targeted approaches findings indicate the importance of clinico-pathological (e.g., nomograms integrating standard prognostic factors) and molecular (e.g., detection of minimal residual disease by RT-PCR) criteria to select patients eligible for limb-sparing surgery without adjuvant treatment.16–21 Currently, patients who are candidates for this strategy are those with primary presentation and closest margin P1 cm, in whom local recurrence would not preclude subsequent limb salvage. When wide disease-free margins cannot be obtained owing to anatomic constraints, adjuvant radiotherapy is generally considered the standard approach for patients with primary tumours with no evidence of distant metastasis.4 After the NIH Consensus Conference in 1985, limb-sparing surgery for most patients with extremity STS was recommended.22 This is true also for most patients with STS of the hand and foot, which is a particularly challenging situation from the surgical viewpoint.23 As microscopically positive surgical margins imply an increased risk of local recurrence,24–27 amputation remains the only way to control local disease in the estimated 5–10% of patients whose tumour cannot be radically resected with a limb-sparing/function-preserving procedure at presentation, after neoadjuvant treatments, or following local recurrence.9,28 However, neither positive margins nor local recurrence appear to adversely affect OS.15,16,18,26,27,29 Thus, conservative surgery coupled with neoadjuvant/adjuvant treatments is generally recommended whenever achieving clear margins would require amputation or substantial functional compromise of an extremity.3 Radiotherapy The efficacy of radiotherapy in patients with STS amenable to conservative surgical resection is supported by two RCT30,31 and several single-institution studies.32–35 In the first RCT, 164 patients with completely resected extremity/trunk STS were either observed or underwent brachytherapy, a technique that consists of the direct application of radioactive seeds (iridium-192) into the tissue at risk of disease relapse (tumour bed) through catheters placed during surgery.30 Updated follow-up revealed that 10-year local disease-free survival (DFS) for the brachytherapy arm was 83% compared with 67% for patients treated with surgery alone (P = 0.39), with no difference in OS. However, patients with high-grade tumours had a 10-year local DFS of 90% with brachytherapy compared with 63% with surgery alone (P = 0.002). In the other RCT, 141 patients with limb STS were treated with limb-sparing surgery alone or combined with external-beam radiotherapy (EBRT); in addition, patients with high-grade tu-

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mours (n = 91) also received systemic chemotherapy.31 The 10-year local control rate for all patients receiving radiotherapy was 98% (highgrade 0%, low-grade 5%), compared with 70% (high-grade 22%, low-grade 36%) for those not receiving radiotherapy (P = 0.0001), without a significant impact on OS. The relatively low local recurrence rate even in patients receiving surgery alone – coupled with no local recurrences if margins were >1 cm – suggests that selected patients could safely be treated with surgery alone and avoid long-term morbidity from radiotherapy.36,37 Despite the consideration that radiotherapy is effective for local disease control purposes in high-grade tumours with surgical margin less than 1 cm, several aspects of its role in the management of limb STS remain debated. For instance, small tumours (<5 cm) are less frequently associated with local recurrence, indicating that radiotherapy may not be necessary in these patients.24,38 Accordingly, in some series adjuvant radiotherapy does not improve the 5-year local DFS or OS rates in this cohort of patients.39,40 However, other authors have drawn opposite conclusions.26 The optimal mode (external-beam/brachytherapy) and timing (preoperative/intraoperative/postoperative) of radiotherapy is also yet to be defined. Postoperative radiotherapy planning is based on tumour grade, status of surgical margins, and institutional preferences. The entire surgical scar and drain sites should be included in the field so that a near-full dose is given to the superficial skin. Proponents of preoperative radiotherapy claim some advantages to this approach.41,42 First, the better oxygenation of an undisturbed tumour bed might enhance the antitumour effect of radiation. Second, preoperative radiation fields may be smaller than those in postoperative radiation fields, and this may result in an improved functional outcome. Third, by shrinking the tumour, radiotherapy can facilitate surgical resection. The main limits of preoperative radiotherapy are the difficulty of pathologically assessing surgical margins in irradiated specimens and the increased rate of wound complications. In fact, in the only RCT so far performed,43 wound complications were more common with preoperative compared with postoperative radiotherapy (35% vs. 17%; P = 0.01), with the risk exclusively confined to lower extremity lesions. In the same trial, at 3.3 years median follow-up local control (93%) was identical, and progression-free survival was not significantly different in the two treatment arms. Limb function status was the same for both groups 12 months after surgery, but after 2 years, rates of fibrosis (56% vs. 28%; P = 0.003) and oedema (24% vs. 7%; P = 0.01) were higher in the

12 postoperative arm because of greater irradiation volumes and doses. Complementary systemic chemotherapy Adjuvant chemotherapy Several RCT have shown that adjuvant systemic chemotherapy does not improve either DFS or OS in patients with STS.44 The Sarcoma Meta-analysis Collaboration evaluated the effect of adjuvant chemotherapy on localized, resectable STS in 1568 patients from 14 trials of doxorubicin-based adjuvant chemotherapy.45 At 9.4 years median follow-up, the time to local and distant recurrence was significantly better in patients receiving doxorubicin-based chemotherapy than in the control group. However, the OS rate advantage in the treatment group was only 4%, which was not significant (P = 0.12). In a subset analysis, patients with extremity tumours (n = 886) showed a 7% benefit in survival (P = 0.029). In a subsequent RCT (n = 104),46 patients with resectable high-grade/large (>5 cm) or recurrent limb STS treated with an intensified anthracycline/ifosfamide combination showed a better DFS and OS rates as compared to controls, with the absolute benefit for OS being 13% and 19% at 2 and 4 years, respectively, although there was no difference in distant relapse rates at 4 years. These results have been criticized on the basis of a retrospective analysis made on a larger series of patients (n = 674) treated with pre- or postoperative chemotherapy: in fact, in this study the clinical benefits associated with doxorubicin-based chemotherapy in patients with high-risk (stage-III) extremity STS appear to vanish after 1-year follow-up.47 An ongoing RCT is testing the efficacy of radical surgery plus intensified adjuvant chemotherapy in a large cohort of patients (Table 1). Although the efficacy of this strategy is yet to be demonstrated, outside clinical trials an anthracycline/ifosfamide combination is often recommended to young patients with large/high-grade extremity STS.48 Neoadjuvant chemotherapy There are some theoretical advantages to neoadjuvant systemic treatment: (1) to increase the chances of limb salvage by shrinking tumour size; (2) to assess the tumour response in situ using radiological imaging and pathological evaluation after surgical resection; (3) to spare patients who do not respond to preoperative therapy the prolonged toxicities of an ineffective adjuvant treatment; conversely, patients who respond to preoperative chemotherapy can be selected for postoperative treatment as a chemotherapysensitive subset.

S. Mocellin et al. Importantly, no increase in the postoperative complication rate has been reported following neoadjuvant systemic chemotherapy.49 Nevertheless, there is scarce clinical evidence supporting the usefulness of such an approach.50–52 Although correlated with favourable clinical outcome, treatment-induced complete tumour necrosis occurs in only a minority of patients (69/496, 14%).53 Moreover, in another retrospective analysis assessing the impact of preoperative chemotherapy on the extent of the surgical procedure in 65 patients with stage-II/III limb/retroperitoneal STS, only eight patients (12%) showed a response sufficient for their operation to be reduced, while in another 6 cases (9%) the disease progressed enough to require an increase in the magnitude of their operation; furthermore, limb salvage could not be performed in any of the nine patients who were determined to require amputation before chemotherapy.54 Neoadjuvant concomitant radio-chemotherapy By exploiting the radiosensitizing effects of some chemotherapeutic drugs, neoadjuvant treatments that combine chemotherapy with concurrent external-beam radiotherapy may theoretically increase the limb-sparing rate and improve DFS.55 The initial approach consisted of intra-arterial doxorubicin and high-dose-per-fraction radiotherapy.56,57 Then, several groups tested other radio-chemotherapy approaches using systemic chemotherapy and alternative chemotherapeutic agents.58–60 Remarkably, when intra-arterial polychemotherapy was adopted, the favourable clinical outcome led investigators to question the need for combining radiotherapy.61 Overall, the small number of patients and the heterogeneity of series so far reported do not permit to compare (even historically) this strategy with others. High toxicity rates have been reported and most series include patients with STS at highrisk of recurrence, but not limb-threatening (unresectable) tumours. Nevertheless, the encouraging results in terms of tumour response (>50%) and local control (<15%) rates justifies continued investigation of preoperative chemoradiation regimens for localized STS. Isolated limb perfusion A locoregional approach proposed for the treatment of limb-threatening malignancies is represented by the hyperthermic isolated limb perfusion (HILP), a technically demanding surgical procedure that allows tumour drug concentrations to reach 20-fold higher than those achievable with systemic chemotherapy.62 This drug-delivery system also exploits the antitumour synergism be-

Adult soft tissue sarcomas: Conventional therapies and molecularly targeted approaches Table 1

Ongoing clinical trials of conventional and molecularly targeted treatments for soft tissue sarcomas (STS)

Study design Therapeutic regimen Phase III Phase III Randomized Phase III Phase III Phase III Phase III Phase III Phase II Phase II Phase II Phase II Phase II Phase II

Phase II

Phase II Phase II Phase II Phase I Phase I Phase I Phase I

13

2

Systemic chemotherapy: DXR (75 mg/m ) + IFO (5 g/m2) vs. observation Systemic chemotherapy (etoposide + IFO + DXR) ± regional hyperthermia Systemic chemotherapy: gemcitabine ± docetaxel Radiotherapy Systemic chemotherapy: vincristine + Dactinomycin + cyclophosphamide + DXR ± IFO Tyrosine-kinase inhibitor (imatinib); doserandomized study Tyrosine-kinase inhibitor (imatinib) vs. placebo Tyrosine-kinase inhibitor (SU011248) vs. placebo

Clinical setting

Study ID/Ref.

Adjuvant treatment for high-grade/recurrent STS Neoadjuvant treatment for high-risk/recurrent STS Advanced/metastatic STS Neoadjuvant treatment for retroperitoneal STS Advanced/metastatic STS

EORTC-62931 (accrual closed) EORTC-62961 Ref.123 ECOG-Z9031 EORTC-62012

Advanced/metastatic GIST

SWOG-S0033 (accrual closed) Adjuvant treatment for GIST NCT00041197 Advanced/metastatic GIST NCT00085618, resistant to imatinib NCT00094029 Isolated limb infusion with DLocally advanced extremity NCT00004250 actinomycin + melphalan STS mTOR inhibitor (AP23573, rapamycin analog) Advanced/metastatic STS NCT00093080 (no GIST) mTOR inhibitor (CCI-779, rapamycin analog) Advanced/metastatic STS NCT00087074 (including GIST) Tyrosine-kinase inhibitor (imatinib) Neoadjuvant/adjuvant NCT00028002 treatment for GIST Tyrosine-kinase inhibitor (imatinib) Advanced/metastatic EORTC-62027, dermatofibrosarcoma SWOG-S0345 Tyrosine-kinase inhibitor (erlotinib) Advanced/metastatic SWOG-S0330 malignant peripheral nerve sheath tumour Tyrosine-kinase inhibitor (gefitinib) Advanced/metastatic EORTC-62022 synovial sarcoma expressing HER1 Antiangiogenic therapy (bevacizumab, antibody HIV-positive/negative NCI-03-C-0110E to VEGF) Kaposi’s sarcoma Gene therapy (oblimersen, antisense Advanced/metastatic GIST NCT00091078 oligonucleotide targeting Bcl-2) resistant to imatinib MMP inhibitors (indinavir, saquinavir) Stage I–III HIV-negative NCT00003419 Kaposi’s sarcoma Cancer vaccine (TERT peptide + GM-CSF) STS (including GIST) and NCT00069940 brain tumours Cancer vaccine (NY-ESO1 peptides + GM-CSF) Stage II–IV STS expressing NCT00027911 NY-ESO1 Antiangiogenic therapy (sorafenib, protein kinase Advanced/metastatic solid NCI-05-C-0022 inhibitor) tumours Antiangiogenic therapy (VEGF decoy receptor) Advanced/metastatic solid NCT0004526 tumours

DXR: doxorubicin; GIST: gastrointestinal stromal tumours; IFO: ifosfamide; GM-CSF: granulocyte-macrophage colony stimulating factor; MMP: matrix metallo-proteinase; VEGF: vascular endothelium growth factor.

tween heat and some antineoplastic agents (e.g., melphalan, doxorubicin and tumour-necrosis-factor, TNF) and maximizes the likelihood of sterilizing microscopic skip metastases throughout the limb. Despite these premises, clinical results with both single chemotherapeutic agents (e.g., melphalan, doxorubicin) and polychemotherapy regimens did not meet the expectations in patients with STS.63 By contrast, when TNF (a cytokine with

antitumour and antiangiogenic properties)64 is added to the drug regimen, the complete and overall tumour response rates range from 10% to 90% and from 50% to 100%, respectively, and limb-sparing surgery is feasible in 70–100% of cases.65–69 At 2 years median follow-up, local DFS is 80–90%, with a secondary amputation being necessary in up to 5% of cases because of either HILP-related local toxicity or tumour recurrence. Although the

14 fear of TNF systemic toxicity has been tempered by the use of real-time monitoring of perfusate/ plasma drug leakage,70 severe locoregional toxicity occurs on average in 10% of patients. Despite the lack of RCT, TNF-based HILP is generally considered one of the most effective neoadjuvant treatments in terms of local disease control and limb-sparing rates in STS patients otherwise candidate for amputation.71 However, there is no evidence that HILP affects patients’ OS.

Retroperitoneal STS The prognosis of patients with retroperitoneal STS – which are mainly represented by liposarcomas and leiomyosarcomas – is worse than that of patients with extremity STS, with the 5-year OS rate being 40–50% and 60–70%, respectively.72–76 Large tumour size, high histological grade, unresectability, as well as positive resection margins are strongly associated with a worse prognosis. Surgery Unlike limb STS, about 75% of patients with retroperitoneal STS ultimately die of locally recurrent disease without distant metastasis, underscoring the importance of trying to achieve a complete resection at presentation.3 In all published series the best chance of cure is achieved in patients with margin-free tumour resection.77 In the largest single institution series (n = 500), median OS was 103 months in patients who underwent complete resection and only 18 months in those who underwent either incomplete resection or observation without resection.72 However, due to their large size (mean diameter 15–20 cm) and locally advanced presentation (infiltration of contiguous organs/structures occurs in 50–75% of cases),4 complete resection is feasible in only about a half of cases, and may require major surgical interventions including the en bloc resection of bowel segments, kidney, spleen, liver segments, pancreas, inferior vena cava and so forth. Adjuvant and neoadjuvant treatments Even with aggressive surgical management, local recurrence occurs in 50–60% of cases. In order to reduce the risk of disease relapse after surgery, several radiotherapy- and/or chemotherapy-based trials have been performed: unfortunately, there is no consensus regarding the benefit of these additional complementary treatments.77,78 As regards radiotherapy, available results suggesting clinical benefit are difficult to interpret

S. Mocellin et al. due to small patient numbers, non-randomized trial design, and use of different sequences (preoperative vs. postoperative) and concurrent treatments.35,41,78–80 Although reasonable doses of radiation can be delivered to the retroperitoneal space with acceptable toxicity and a delay in time to recurrence is likely to occur, the effect on OS is not evident. Doses must be restricted because of sensitive normal structures within the target volume, particularly small bowel. Large field sizes contribute to toxicity, generally favouring the use of preoperative radiotherapy that presents some theoretical advantages: (1) the gross tumour volume can be defined, allowing accurate treatment planning; (2) tumours can displace radiosensitive viscera outside the radiation field;80 and (3) lower radiation doses may be equally effective preoperatively due to better oxygenation of undisturbed tumour tissue. Based on these premises, a RCT of neoadjuvant radiotherapy is underway. Among the most recent developments of radiation-based treatments, intensity modulated radiotherapy (IMRT)–an advanced form of threedimensional conformal radiotherapy – holds promise.81 With IMRT, radiation beams are not only shaped at their perimeters but also have variable intensity across their profiles, which should greatly improve tumour targeting in a complex anatomical region such as the retroperitoneal space. As regards systemic chemotherapy, no available data support its routine use in the adjuvant setting for the treatment of retroperitoneal STS. As mentioned above, the largest meta-analysis on RCT of doxorubicin-based adjuvant systemic chemotherapy for adult STS (regardless of tumour site) showed no improvement in OS despite a longer disease-free time in the treatment arms.45 Other chemotherapeutic regimens/strategies have been the subject of non-randomized trials, including the combination of neoadjuvant chemotherapy with regional hyperthermia82 (currently under evaluation in a phase III study) or radiotherapy.55,79 Intraoperative treatments As compared to EBRT, intraoperative radiotherapy (IORT) allows for the administration of higher radiation doses, since sensitive organs can be shielded and the tumour bed can be selectively targeted by the radiation beam. The results from small phase I–II trials,60,83–86 although encouraging, are difficult to interpret, because of the combination with other therapeutic modalities (EBRT, systemic chemotherapy). In a small (n = 35) RCT (surgery/ IORT/EBRT vs. surgery/EBRT), the use of IORT was associated with a lower locoregional recurrence rate, but did not affect OS.87

Adult soft tissue sarcomas: Conventional therapies and molecularly targeted approaches Cytoreductive surgery combined with hyperthermic intraperitoneal intraoperative chemotherapy (HIIC) has already shown some interesting results for the control of peritoneal carcinomatosis.88,89 To assess the antitumour synergism of doxorubicin, cisplatin and heat for the treatment of intraabdominal sarcomatosis from retroperitoneal and visceral (mostly GIST) STS, phase I and II trials were conducted.90,91 Unfortunately, no improvement in local DFS or OS could be suggested in these historical control studies. Nevertheless, HIIC might be useful for the administration of more active regimens.92 For instance, following the satisfactory results obtained in patients with extremity STS, the addition of TNF to conventional HIIC regimens might represent an appealing way to treat locally advanced intra-abdominal STS.93 Photodynamic therapy (PDT) combines a photosensitizer (e.g., porphyrin derivatives retained in tumour tissues more than in normal tissues) with a laser light (in a wavelength range matching the photosensitizer’s absorption spectrum) to generate reactive oxygen species that ultimately kill tumour cells.94 Given the limited penetrance of the laser, this approach can be used only for tumours of the body surfaces (e.g., esophagus, bronchus, skin, peritoneum). The implementation of PDT for the treatment of intraperitoneal malignancies, including STS, is in its infancy,95–97 and further evaluation is warranted to judge its efficacy.

Local relapse and distant metastasis Surgery and complementary treatments Several reports suggest that the early recognition and treatment of local or distant disease recurrence can prolong survival.98–102 An isolated local recurrence should be treated aggressively with margin-negative resection. This frequently requires amputation in patients with extremity tumours, although acceptable rates of local control can be achieved in these patients with function-preserving resection combined with additional radiotherapy, with or without chemotherapy.28,103–105 The preferred treatment for locally recurrent retroperitoneal STS is also surgery, when complete resection is feasible. In the largest series thus far published, investigators were able to adequately resect recurrent tumours in 57% of the patients.72 However, adequate resection was possible in only 20% after the second recurrence and in 10% after the third one. Complete pulmonary resection can achieve longterm survival in 15–40% of patients with lung metastases who have fewer than four pulmonary

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nodules, long disease-free intervals, and no bronchial infiltration.101,102,106 Favourable prognostic factors are microscopically disease-free margins, young age (<40 years), and low histological grade. Unfortunately, most patients with recurrent/metastatic disease are not eligible for radical surgery or locoregional therapies and the only conventional therapeutic option for them is systemic chemotherapy: however, their prognosis is generally dismal (median OS: 10–12 months).107,108 Systemic chemotherapy Tumour response rates to chemotherapy in patients with stage-IV STS are generally disappointing.107,108 Doxorubicin and ifosfamide are the most active chemotherapeutic agents for metastatic adult STS with single-agent response rates of 16–36%.109 Combination regimens (usually containing anthracyclines) have response rates up to 35–60%, but have increased toxicity compared with single agents.4 In a large (n = 2185) retrospective analysis of patients with advanced/metastatic STS treated with anthracycline-containing regimens as first-line chemotherapy, OS time and tumour response rate were 51 weeks and 26%, respectively.110 At multivariate analysis, survival was favourably affected by low histological grade, long disease-free interval and young age, while tumour response was better in younger patients, high-grade tumours and liposarcoma. A recent meta-analysis of eight RCT (n = 2281) comparing doxorubicin-based combinations with doxorubicin as a single agent showed no differences in response rates (odds ratio, 0.79; P = 0.10) or survival (odds ratio, 0.84; P = 0.13).111 These trials generally involved insufficient numbers of patients to provide adequate power for testing responses to chemotherapy by histological subtype. Results from small series suggesting that synovial sarcoma may be particularly responsive to ifosfamide remain to be confirmed in larger studies.112,113 Non-controlled studies have suggested a direct proportionality between the dose of anthracyclines and ifosfamide and tumour response rates.114,115 However, the findings from two RCT oppose this hypothesis both in terms of tumour response and OS.116,117 Preliminary results of high-dose chemotherapy with autologous bone marrow/stem-cell support are controversial.118–121 Moreover, higher toxicity rates are reported and the results are often difficult to interpret due to the inclusion of pediatric patients.3 Favourable preliminary results obtained with novel drug/drug regimens (e.g., docetaxel alone or with gemcitabine, ifosfamide plus etoposide

16 and cisplatin, ecteinascidin)122–126 are under evaluation in ongoing RCT.

Molecularly targeted therapies Over the last two decades many insights regarding the molecular mechanisms underlying cancer development/progression have been confirmed in STS and a number of genetic (point mutations, deletions, amplifications) and chromosomal (translocations, aneuploidy) alterations specific to STS have been identified and linked to their pathogenesis.7,8,127 Overall, these molecular oncology findings are not only facilitating STS classification and prognosis prediction, but also fostering the development of molecularly targeted therapeutic strategies (Fig. 1). Gastrointestinal stromal tumours as a model Gastrointestinal STS account for 1–3% of all gastrointestinal cancers, up to 20% of small bowel malignancies and about 5% of all STS.5 As is true for non-gastrointestinal STS, high histological grade and large tumour size (>5 cm) adversely affect prognosis. Locoregional recurrence (peritoneal sarcomatosis) is the most common form of disease relapse, followed by liver metastasis. Both are associated with a dismal prognosis owing to the intrinsic aggressiveness of these tumours and the remarkable chemoresistance.128

S. Mocellin et al. On the basis of ultrastructural and immunohistological features, it is now accepted that most gastrointestinal tumours previously designated as STS (e.g., leiomyosarcomas) are GIST, which probably originate from the pacemaker cells of Cajal.129 To date, surgery is the primary treatment for GIST, as complete resection with negative margins, even in patients with locally advanced tumours, is associated with improved survival.130,131 The 5-year survival rate ranges from 20% to 44% for all patients with GIST and up to 75% for patients with early-stage tumours that have been completely excised. Recent insights into the pathogenesis of these tumours are giving new hope for improving their prognosis. GIST are characterized by the expression of c-Kit, a tyrosine-kinase receptor with cell growth regulatory functions that plays a key role in the pathogenesis of such tumours following the occurrence of activating mutations. The development of small-molecule inhibitors (e.g., tyrosinekinase inhibitor STI571, imatinib) initially tested in myeloid leukemia patients and then proven to mediate impressive tumour regressions in patients with GIST132 has rapidly become a paradigm of molecularly targeted anticancer therapy.133 A recent phase III RCT has demonstrated that patients with advanced GIST benefit significantly from imatinib treatment in terms of progression-free survival.134 Although many issues (e.g., acquired

Figure 1 Molecularly targeted therapeutic approaches to soft tissue sarcoma. TKR: tyrosine-kinase receptor; TNF: tumour necrosis factor; TNFR: TNF receptor; PDGF: platelet-derived growth factor; PDGFR: PDGF receptor; SCF: stem cell factor; EGF: epidermal growth factor; EGFR: EGF receptor; VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor; MMP: matrix metallo-proteinase; mTOR: mammalian target of rapamycin; PI3K: phosphatidylinositol3-kinase; MDR-1: multi-drug resistance protein-1; TERT: telomerase reverse transcriptase; TCR: T-cell receptor.

Adult soft tissue sarcomas: Conventional therapies and molecularly targeted approaches drug resistance, impact on OS, role in the adjuvant/neoadjuvant setting, long-term toxicity) are still being addressed (Table 1), imatinib represents the first active systemic therapy for unresectable locally advanced/metastatic GIST. Among non-gastrointestinal STS not expressing c-Kit, only dermatofibrosarcoma has been shown to be responsive to imatinib.135 The reason for this responsiveness hinges upon the fact that this lowgrade tumour is usually associated with the chromosomal translocation t(17:22), which ultimately results in the constitutive overexpression of platelet-derived growth factor (PDGF)-b. Accordingly, patients with advanced dermatofibrosarcoma may be successfully treated with imatinib, which specifically inhibits the tyrosine-kinase activity of cKit, ABL (myeloid leukemia) and PDGF-receptor. Interestingly, imatinib appears to exert a synergistic effect with standard chemotherapeutic drugs,136 and this might enhance the antitumour activity of their combination.137 On the other side, reports of acquired resistance to imatinib138 have fostered the development and clinical testing of alternative small-molecule inhibitors.139 Antiangiogenic therapy Angiogenesis has become an attractive target for cancer therapy with the potential to be effective for a variety of tumours.140 The use of antiangiogenic agents in the treatment of STS is even more attractive since some of these tumours arise from endothelial cells, and may induce both a direct antitumour effect and an antiangiogenic effect.141 However, the findings from the small series so far published are conflicting. For instance, the smallmolecule tyrosine-kinase inhibitor SU5416, a potent inhibitor of VEGF-receptors, has demonstrated some anti-sarcoma activity, particularly in patients with Kaposi’s sarcoma.142,143 These results have not been confirmed in a subsequent phase II trial.144 In a pilot study with a humanized monoclonal antibody blocking the angiogenesis-related integrinaVb3,145 there were no responses in 15 patients with leiomyosarcoma.146 Moreover, in a recent phase III RCT (highly-active antiretroviral therapy ± IM862) the effectiveness of IM862 (a synthetic dipeptide with antiangiogenic properties) for the treatment of HIV-positive Kaposi’s sarcoma has been refuted.147 A humanized anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve tumour response and survival rates in patients with metastatic colorectal cancer.148 STS can overexpress VEGF;149,150 noticeably, VEGF overexpression by Ewing’s sarcomas is linked to the activity of the EWS-ETS onco-

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protein, a product of the sarcoma-specific t(11;22) translocation.151 Therefore, STS might be effectively targeted by anti-VEGF therapy; this is being tested in an ongoing trial. Sorafenib is a potent inhibitor of protein-kinases involved in tumour angiogenesis (e.g., Raf-1, VEGFR, PDGFR, Flt-3, c-Kit) and possesses broadspectrum antitumour activity in cancer xenograft models, where analysis of microvessel density demonstrated significant inhibition of neovascularization.152 This novel drug is under clinical evaluation for the treatment of advanced solid tumours in combination with bevacizumab. Another way to block the VEGF-signaling pathway is to prevent VEGF from binding to its cell-surface receptors by administering soluble decoy-receptors. In animal models, this VEGF ‘‘trap’’ effectively suppresses tumour growth and vascularization in vivo.153 An ongoing phase I study is validating the feasibility of soluble decoy-receptor strategy in patients with lymphoma and advanced solid tumours. Overall, the role of these and other antiangiogenic agents as single anti-sarcoma agents remains to be demonstrated. Favourable preliminary results are prompting investigators to explore the potential of standard or metronomic chemotherapy combined with antiangiogenic agents.154–156 Matrix metalloproteinase inhibitors Matrix-metallo-proteinases (MMP) are a family of zinc-dependent enzymes that mediate degradation of extracellular matrix, a crucial step in tumour invasion and metastasis.157 Although MMP are absent or expressed at low levels in normal tissues, they are upregulated in many tumours, including STS.158–160 After showing promise in preclinical studies, numerous MMP-inhibitors (e.g., marimastat, prinomastat, metastat) are being evaluated for therapy in a variety of cancers.161 In preclinical sarcoma models these drugs have demonstrated antitumour activity in vivo.159,160, 162,163 To date, patients with STS have been enrolled only in small pilot trials.164–166 When administered orally to patients with AIDS-related Kaposis’s sarcoma, Col-3 (an oral chemically modified tetracycline derivative with potent inhibitory effects on MMP activity/production) was well tolerated and showed some antitumour activity.167 A reduced incidence and regression of Kaposi’s sarcoma and other tumours has been reported in AIDS patients treated with antiretroviral combination therapies containing HIV protease inhibitors (e.g., indinavir, saquinavir).147,168 Although these drugs were designed to selectively inhibit the HIV protease activity, they can also induce regression

18 of experimental sarcoma by inhibiting the activation of MMP-2, which ultimately blocks tumour angiogenesis/invasiveness.168 A phase II trial is assessing the effect of this novel class of MMPinhibitors on the progression of Kaposi’s sarcoma in HIV-negative individuals. Inhibitors of growth-factor signaling pathways One of the most active and promising areas of investigation in the field of molecular oncology is the development of drugs inhibiting the components of growth-factor signaling pathways,169 such as the ErbB receptor family, a group of tyrosinekinase receptors including ErbB1 (also known as epidermal growth-factor receptor [EGFR] or HER1), ErbB2 (HER2 or HER2/neu), ErbB3 (or HER3) and ErbB4 (or HER4). EGFR is overexpressed, dysregulated or mutated in many malignancies, including STS.170,171 Two main classes of EGFR inhibitors have been developed including monoclonal antibodies that target the extracellular domain of EGFR (e.g., cetuximab), and smallmolecule tyrosine-kinase inhibitors that target the receptor catalytic domain of EGFR (e.g., gefitinib, erlotinib). These drugs are in advanced phases of clinical experimentation for some epithelial cancers172 and are being tested in STS patients as well. As regards HER2/neu, a humanized recombinant IgG1j blocking antibody (trastuzumab) has been approved for the treatment of breast carcinoma and is in advanced phase of clinical evaluation for head&neck and lung carcinomas.169 The role of HER2/neu as a suitable therapeutic target for STS is debated, as variable results have been reported regarding its expression,173,174 prognostic value,175–177 and pathogenetic function.178,179 A convergence point of activation of several growth-factor receptors is downstream activation of the phosphatidylinositol-3-kinase (PI3K)-AKT/ PKB pathway, which can exert potent anti-apoptotic effects and thus favour tumour survival.180 Another consequence of activation of growthfactor-receptor signaling and/or activation of AKT is activation of the mammalian target of rapamycin (mTOR) pathway, which profoundly affects cell growth by regulating protein translation. mTOR is the target of rapamycin and its analogues, which are currently in clinical trials for the treatment of different cancer types, including STS.181 Gene therapy Although safety concerns have tempered the enthusiasm surrounding gene therapy,182 advances in gene-delivery (e.g., development of third-generation lenti-viral vectors, adenoviral vectors, and

S. Mocellin et al. encapsulated methods of delivering naked DNA183) and gene knock-down (e.g., RNA interference 184) technology are providing the hope for this approach. Results from preclinical sarcoma models are encouraging. For instance, tumour cell transfection with wild-type p53, which is lost in many cases of STS, causes tumour regression in 40% of treated mice185 and restores cancer sensitivity to doxorubicin by downregulating multidrug-resistance protein-1 (MDR1).186 Sarcoma regression has also been reported following both suicide-gene strategy (e.g., adenovirus-associated vector-2 encoding thymidine-kinase)187 and oligo-DNA antisense therapy targeting sarcoma cell survival-/proliferationrelated genes (e.g., insulin-like growth-factor-I receptor;88 Mcl-1, an anti-apoptotic Bcl-2 family member189). More recently, tumour regression has also been reported following RNA interferencemediated knock-down of oncogenes such as Met (a tumour growth/metastasis promoter)190 and survivin (an anti-apoptotic protein correlated with poor prognosis of STS patients).191,192 The tumour-selective delivery of systemic gene therapy remains one of the major limitations of this approach. Isolated limb perfusion, which can efficiently control the leakage from the perfusion circuit to the systemic circulation, has been proposed as a potential gene delivery system for limb STS.62 In animals, this strategy has been already validated for the treatment of STS.193,194 Among other strategies aimed at making highdose chemotherapy more tolerable,195 ‘‘reverse’’ gene therapy might be exploited for the transfer of MDR-1 gene to normal hematopoietic stem-cells and subsequent transplantation, which would reduce the hematotoxicity of antineoplastic drugs.187 Some initial attempts of gene therapy for patients with STS have been reported. In a phase I study the maximum tolerated dose of antisense oligo-DNA specific for type-I protein-kinase-A (a tumour-promoting factor) was determined.196 Using intratumoural injections of a plasmid encoding interleukin-2, other investigators observed tumour stabilization in 6/15 patients.197 Oncolytic adenoviruses lacking the E1B55K gene product for p53 degradation selectively replicate in and lyse p53-deficient tumour cells.198 In clinical trials, these genetically engineered viruses have been administered (together with chemotherapy) to patients with STS via intratumoural injections, and shown some significant antitumour activity.199,200 Some investigators have set-up a transgene encoding human TNF under control of a radiationinduced promoter.201 In a feasibility study, this transgene was coupled with radiotherapy for the treatment of patients with limb STS: of the 13

Adult soft tissue sarcomas: Conventional therapies and molecularly targeted approaches evaluable patients, eleven (85%) showed objective tumour responses (2 complete and 9 partial).202 Of the 11 patients who then underwent surgery, 10 (91%) showed a pathological complete/partial response. Only the conduct of prospective controlled trials will determine the relative contribution of gene therapy to this high tumour response rate. Cancer vaccines Active specific immunotherapy theoretically embodies the ideal tumour-killing system for three main reasons: (1) unlike chemotherapy, which follows a log-kill kinetics, the immune system can hunt-down the minimal residual disease on a single-cell basis; (2) the extreme selectivity of cytotoxic Tlymphocytes towards tumour cells guarantees minimal/absent toxicity; (3) once appropriately trained, the immune system can memorize the targeted tumour, thus, ensuring further protection against disease recurrence. Despite these premises and many successes in animal models, the results of such biotherapy in the clinical setting have not met the expectations owing to the difficulty of appropriately manipulating the highly complex immune network.203 The molecular identification of tumour-associated antigens (TAA) coupled with recent advances in tumour immunology have renewed the enthusiasm for the development of anticancer vaccination strategies.204,205 STS might represent an ideal target for active specific immunization.206,207 TAA commonly expressed by most solid tumours are weakly immunogenic due to their self origin: by contrast, highly immunogenic epitopes can be generated from fusion proteins resulting from STS-specific chromosomal translocations.208,209 These chimeric proteins are exquisitely tumour-specific and -unlike self antigens210 – their use for vaccination is not expected to cause any autoimmune toxicity. Finally, purification of the fusion gene product could be used for anti-sarcoma vaccination, like the use of idiotype protein for vaccination against B-cell lymphomas.211 Although STS express several known TAA212–214 and tumour regression can be observed in sarcoma animal models,215–217 active specific immunotherapy is in its infancy for the treatment of these tumours, only a handful of patients being so far enrolled.218–221 Pilot studies testing the immunogenicity STSspecific fusion site-deriving peptides have been successfully performed in pediatric and adult patients.222–224 Most TAA so far utilized in the clinical setting play a non-vital role in the metabolism of malignant cells (e.g., gp100, MAGE, CEA). Accordingly,

19

selection of tumour cells downregulating these TAA can be the only effect of anticancer vaccination. A new class of TAA is represented by antigens that are required by cancer cells to survive such as survivin and telomerase (a cell survival-related ribonucleoprotein), which have been already tested as TAA in preclinical and clinical models of anticancer vaccination.205 As regards STS, the EWS/ETS chimeric protein identified in most Ewing’s sarcomas promotes the overexpression of telomerase, thus, representing an ideal target for immunotherapy of this tumour.225 A phase I trial is testing the hypothesis that patients with STS can mount an effective immune response against a telomerase-derived peptide.

Conclusions The conduct of RCT over the past two decades has led to significant progress in the therapeutic management of patients with STS. Disease rarity and multidisciplinary treatment require subjects with suspected/known STS be referred to specialized centers where a dedicated team of pathologists, surgeons, oncologists and radiotherapists exists in order to provide patients with the best chance of cure.226 Despite some significant advances in terms of local disease control, further work is necessary to prove that systemic chemotherapy can improve the survival of patients clinically free of disease. Moreover, the characteristic chemoresistance of most STS has so far undermined the clinical utility of conventional antineoplastic agents in the setting of unresectable advanced/metastatic disease, and some investigators believe that current conventional therapy has reached the limits of efficacy.227 Therefore, novel therapeutic strategies are urgently needed to improve the prognosis of these patients. Thanks also to the implementation of novel high-throughput technologies (e.g., DNA-array and proteomics platforms),228,229 recent advances in the elucidation of STS biology are paving the way to the development of molecularly targeted therapeutic strategies. The dissection of the molecular mechanisms underlying cancer development/progression will not only facilitate the discovery of novel tumour ‘‘Achille’s heels’’ potentially targetable by novel cancer-selective drugs, but also allow for the personalization of the therapeutic regimen according to the molecular features of individual tumours. Current criteria for the formulation of a patient’s prognosis and prediction of treatment responsiveness rely upon traditional clinico-pathological factors (e.g., age,

20 performance status size, margin, grade, histological type),110,230,231 which are inadequate to accurately identify tumours with greater intrinsic aggressiveness/treatment resistance.4 The better understanding of the cascade of molecular events underlying STS metastasis/invasiveness and treatment sensitivity is providing investigators with pathogenesis-based information. This is essential both for the identification of patients requiring adjuvant therapy and the selection of the therapeutic approach most likely to be effective in each given patient.232–234 Only the implementation of such data in clinical protocols and the conduct of large trials with the novel tumour-selective drugs will allow investigators to test the enormous potential of the molecularly targeted treatment of STS.

Acknowledgements We thank the authors whose work was not cited due to lengthy considerations.

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