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Sarcomas |
aErasmus University Medical Center, Rotterdam, The Netherlands; bRadboud University Nijmegen Medical Center, Nijmegen, The Netherlands; cCentre Léon Bérard, Lyon, France
Key Words. Soft tissue sarcoma • Angiogenesis • Vascular endothelial growth factor (VEGF)
Correspondence: Stefan Sleijfer, M.D., Ph.D., Department of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands. Telephone: 31-10-7041733; Fax: 31-10-7041003; e-mail: s.sleijfer{at}erasmusmc.nl
Received August 22, 2008; accepted for publication October 1, 2008; first published online in THE ONCOLOGIST Express on November 5, 2008.
Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: Jean-Yves Blay, GlaxoSmithKline; Honoraria: None; Research funding/contracted research: Stefan Sleijfer, noncommercial interest; Ownership interest: None; Expert testimony: None; Other: None.
The authors disclose that the article discusses unlabeled, investigational, or alternative use(s) of: pazopanib (GlaxoSmithKline), antiangiogenic; sorafenib (Bayer), antiangiogenic; sunitinib (Pfizer), antiangiogenic.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.
This article is available for continuing medical education credit at CME.TheOncologist.com
Learning Objectives
After completing this course, the reader should be able to:
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ABSTRACT |
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INTRODUCTION |
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Like all human tumor types, angiogenesis is an absolute prerequisite for the growth and dissemination of non-GIST STSs. Angiogenesis is a complex process, regulated by numerous pro- and antiangiogenic factors. Of all the proangiogenic factors, such as platelet-derived growth factor (PDGF), transforming growth factor, tumor necrosis factor, and interleukin-8, in particular, vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been elucidated as key players. Following successes with drugs interfering in the VEGF–VEGFR pathway in other tumor types, such as renal cell cancer, colorectal cancer, and breast cancer, trials exploring these drugs have been initiated in non-GIST STS as well, and recently the first preliminary results were presented.
This review addresses the currently known role of angiogenesis in non-GIST STS and focuses on the studies with angiogenesis inhibitors performed so far.
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ANGIOGENIC PARAMETERS IN NON-GIST STS |
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In two studies using immunohistochemistry, there was an association between VEGF expression and histological tumor grade, but no association with disease-free or overall survival in patients with localized STS [5, 6]. In another study, enzyme-linked immunosorbent assay was used to assess VEGF expression, which enables a more quantitative determination. VEGF expression above the median level was an independent poor prognostic factor for metastasis-free and overall survival times in patients with localized disease [7]. High VEGF levels in STS patients have been found not only in tumor tissue, but also in the blood. In several studies, STS patients appeared to have elevated VEGF blood levels, compared with healthy controls [8–12]. Similar to the tissue levels, blood VEGF levels were related to histological grade [8, 10], and in several studies, though not in all, to a worse outcome as well in patients with localized disease [9, 10]. Not surprisingly, given the heterogeneity of non-GIST STSs, VEGF expression has been suggested to differ considerably among the diverse entities. The strongest VEGF expression was seen in tumors with epithelioid features, such as epithelioid sarcomas and alveolar soft part sarcomas, the latter being characterized by marked vascularity [13]. High VEGF expression levels have also been described in patients with malignant fibrous histiocytoma, dermatofibrosarcoma protuberans, and leiomyosarcoma [14]. In contrast to VEGF, data on VEGFR expression are rather scarce. In angiosarcomas, 65% had expression of VEGFR-2, and low expression was a poor prognostic factor for overall survival [15].
In addition to the VEGF–VEGFR pathway, several other factors involved in angiogenesis have been examined in STSs, though not so extensively. Using gene-expression profiling by microarray analysis, a variety of angiogenic genes were found to be upregulated in STS tumor tissue compared with normal tissue. These include the PDGF receptor (PDGFR), MMP-2, and Notch-1 and Notch-4 [12]. Several of these factors have been found to impact the outcome of non-GIST STS patients. For example, elevated expression of PDGF-B in tumors was associated with increased cell growth and histological grade [16]. Furthermore, levels of circulating basic fibroblast growth factor (bFGF) and angiopoietin-2 were higher in advanced STS patients than in healthy controls [8, 9, 11, 12]. In general, there was a relationship between these levels and grade [8], but an association with outcome was not consistently seen in all studies [11]. Also with respect to these angiogenic factors, there are differences among the diverse subtypes. The highest bFGF levels have been reported in fibrosarcoma and leiomyosarcoma patients [12]. Furthermore, alveolar soft part sarcoma, a highly vascular tumor, has a specific profile of upregulated angiogenic genes, probably induced by the specific fusion protein (ASPSCR1–TFE3) that is pathognomonic for this entity [17].
Factors involved in extracellular matrix breakdown, which is also essential for angiogenesis, are also related to outcome in STS patients. Patients with increased tumor tissue levels of MMP-2, MMP-9, and urokinase plasminogen activator had a worse outcome than patients with lower levels [18, 19]. In localized STS, high expression of CD100, a glycoprotein with a wide array of physiological functions, including promoting angiogenesis, was an independent prognostic factor for short disease-free survival and overall survival durations [20].
Collectively, many studies point to an important role for angiogenic factors in many STS entities (Table 2). In particular, for VEGF the data are accumulating, but for proangiogenic factors other than VEGF the evidence is less robust. Different assays, studies including small numbers of patients, and, above all, heterogeneity of the assessed tumor types are likely to account for this.
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MECHANISMS DRIVING VEGF–VEGFR ACTIVATION IN NON-GIST STS |
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Another mechanism that may induce increased expression of VEGF is through hypoxia-inducible factor (HIF)-1
. HIF-1 is a transcription factor that can be activated by numerous mechanisms including hypoxia, disrupted function of the Von Hippel-Lindau protein, mutation in the p53 gene, and increased activation of the phosphatidylinositol 3' kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) pathway, the latter being involved in the signal transduction of many growth-stimulating factors. After activation, HIF-1 binds to the hypoxia response element present in the promoter region of several genes, including VEGF. In a study in patients with localized STSs, increased expression of HIF-1 was found in >70% of cases. In addition, high or moderate HIF-1 expression was independently associated with a poor overall survival. Unfortunately, the relatively low number of cases studied did not allow comparison among the different tumor entities [22]. HIF-1 expression was found diffusely throughout the tumors sections, rendering it unlikely that tumor hypoxia would be the only driving force for HIF-1 expression in STS [22]. In that case, HIF-1 expression would be expected to mainly occur in hypoxic areas of the tumors. Therefore, other mechanisms, such as activation of the PI3K–Akt–mTOR pathway, are more likely to account for the increased HIF-1 expression. The finding that mTOR inhibition yields interesting antitumor activity in a phase II study [23] highly suggests that this pathway can indeed be activated in STS.
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VEGF-INDUCED RESISTANCE AGAINST CHEMOTHERAPY |
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In preclinical models from other tumor types, several mechanisms have been revealed by which increased VEGF–VEGFR activity yields chemoresistance. VEGF has been described to increase Bcl-2 levels, a well-known antiapoptotic factor [25]. Furthermore, activation of VEGFR yields resistance against several cytotoxic agents through induction of survivin, another antiapoptotic factor [26].
Another VEGF-driven mechanism that may partially account for lower sensitivity to systemic agents is through an effect on the interstitial fluid pressure. As a result of the fragile tumor vasculature that is more permeable than normal vasculature, almost all solid tumors are characterized by greater fluid pressure of the tumor interstitium than of adjacent tissues. This higher interstitial fluid pressure hinders the uptake of drugs from the peripheral circulation into tumors and consequently may contribute to resistance [27]. Inhibition of VEGFR has been shown to decrease the interstitial fluid pressure of tumors, thereby facilitating drug uptake [27]. Also, inhibition of PDGFR, for example, by imatinib, results in a reduced interstitial tumor pressure [27].
So, several mechanisms may underlie the generally worse outcome of patients with tumors with high VEGF expression (Table 3), but it is unlikely that the whole spectrum of mechanisms has been elucidated yet.
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ANGIOGENESIS INHIBITORS IN NON-GIST STS |
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The understanding of the involvement of the VEGF–VEGFR pathway in non-GIST STS, together with the antitumor activity of compounds targeting this pathway in other tumor types, prompted the exploration of these drugs in the clinic. Roughly, there are two drug classes by which the VEGF–VEGFR pathway can be inhibited: monoclonal antibodies and tyrosine kinase inhibitors (TKIs). So far, the most widely explored monoclonal antibody targeting the VEGF–VEGFR pathway in oncology is bevacizumab, an antibody directed toward VEGF. However, studies with bevacizumab as a single agent, or with other monoclonal antibodies against VEGF or VEGFR, are not available in STSs.
With respect to TKIs, three drugs have been assessed for their effects against non-GIST STSs. Sorafenib is a TKI that targets the tyrosine kinase activity of several factors, including PDGFR and VEGFR-1, VEGFR-2, and VEGFR-3. In a relatively small study [31], published only in abstract form so far, sorafenib was assessed at a dose of 400 mg twice daily. Response rate was the primary endpoint, and three different STS tumor entities were examined: STSs of vascular origin (angiosarcomas and solitary fibrous tumors), leiomyosarcomas, and liposarcomas. In the 37 patients evaluable for response, only two responses were encountered: one in the nine patients with vascular STS tumors and one in the 19 accrued patients with leiomyosarcomas. The median progression-free survival times were 4.7, 1.7, and 1.8 months for patients with vascular sarcomas, liposarcomas, and leiomyosarcomas, respectively [31].
In a larger study of sorafenib, also available only in abstract form, 147 patients who had received one or fewer lines of prior treatment were entered [32]. Sorafenib was administered at 400 mg twice daily and six different strata were assessed: leiomyosarcomas, malignant fibrous histiocytomas, malignant peripheral nerve-sheath tumors, vascular sarcomas, synovial sarcomas, and a group with all remaining eligible STS tumor types. Again, response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST) was the primary endpoint, and a Simon two-stage design was applied for each stratum separately. Of the 37 angiosarcoma patients, five experienced a response. In the leiomyosarcoma cohort, two of the 37 patients had a response, while in the other strata no responses according to the RECIST were seen. The median times to progression for the leiomyosarcoma, angiosarcoma, and other strata were 5.2, 5.5, and 2.8 months, respectively [32]. Toxicities with sorafenib were similar to those encountered in other tumor types [33, 34].
The outcomes of both these two studies look disappointing at first glance. However, the response rate served as the primary endpoint in both studies. It is increasingly being recognized that the antitumor activity of VEGFR TKIs is not adequately reflected in objective responses, but is better described in terms of progression-free survival. In advanced GIST patients who failed imatinib, sunitinib as a second-line therapy produced a response rate of only 7%, but induced a fourfold longer progression-free survival time than with placebo [35]. Likewise, sorafenib in patients with advanced renal cell carcinoma yielded a 10% response rate while the progression-free survival time was double what was seen with placebo [33]. Furthermore, sorafenib induced a 2% response rate in patients with advanced hepatocellular carcinoma but produced a longer median time to radiological progression and overall survival, by 2.7 and 2.8 months, respectively, compared with placebo [34]. As a result, many consider the progression-free rate (PFR) at a certain time point a more relevant endpoint when screening the antitumor activity of compounds targeting angiogenesis. Based on a large dataset from the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG), Van Glabbeke et al. [36] provided, for that purpose, PFRs at 3 and 6 months associated with active and inactive therapies for second-line treatment in advanced STS patients. According to this analysis, agents that induce a 3-month PFR >40% warrant further investigation. As in both studies on sorafenib, >50% of the angiosarcoma patients were progression free at 3 months, which applies also to leiomyosarcoma patients in one study [31, 32]; sorafenib seems to exhibit interesting antitumor activity in some STS entities. Data on overall survival are awaited with interest.
Sunitinib is another TKI that inhibits the signal transduction of several factors including c-Kit, VEGFR, and PDGFR. Sunitinib was studied in two different phase II studies, both available only in abstract form. In a study on patients with advanced disease who received up to three different lines of prior chemotherapeutic regimens, continuous sunitinib at a daily dose of 37.5 mg resulted in one partial response in a patient with a desmoplastic small round-cell tumor, and seven of 39 patients remained progression free at 16 weeks [37]. Another study explored sunitinib at 50 mg daily from day 1 to 28 every 6 weeks in four different cohorts: liposarcomas, malignant fibrous histiocytomas, fibrosarcomas, and leiomyosarcomas. All patients received a maximum of three prior lines of therapy. In one patient, a partial response was seen and 29 of the 36 patients were progression free at 3 months after the initiation of sunitinib [38], meeting the criteria for an active drug according to the definitions based on the EORTC-STBSG analysis [36].
Another TKI that has been explored in STS is pazopanib. Pazopanib targets many factors, including VEGFR-1, VEGFR-2, and VEGFR-3, PDGFR- and PDGFR-β, and c-Kit, at concentrations that can be achieved in humans. In a study of the EORTC-STBSG, daily pazopanib at 800 mg was assessed in advanced STS patients who were ineligible for chemotherapy or had previously received no more than two cytotoxic agents for advanced disease [39]. Patients had documented progression according to the RECIST before accrual in this study. For reasons mentioned above, the primary endpoint was the 3-month PFR. Four different strata were studied: leiomyosarcomas, liposarcomas, synovial sarcomas, and a group comprising all other STS types that were allowed. A Simon two-stage design was applied for each stratum. In total, 142 patients were accrued. In line with what would be expected from a VEGFR TKI, pazopanib was well tolerated, with fatigue, hypertension, and diarrhea as the most frequent side effects. Other relevant toxicities included mild myelosuppression, liver toxicity, vomiting, and hypopigmentation. Grade 3 or 4 toxicities were rare. After the first stage, the liposarcoma stratum was closed because of lack of activity. In contrast, after complete accrual, the 3-month PFR in the cohorts of leiomyosarcomas, synovial sarcomas, and the other STS types met the predefined 3-month PFR for warranting further exploration [39].
Recently, mTOR inhibitors have also been assessed in STS [23]. However, because it is uncertain whether or not these agents exert their antitumor effects through inhibiting angiogenesis, these agents are not discussed in this review.
All together, VEGFR TKIs such as pazopanib, sunitinib, and sorafenib induce interesting antitumor activity in some STS tumor types. Of course, the true value of these drugs can be established only in randomized studies. For pazopanib, a worldwide placebo-controlled randomized phase III study in non-GIST STSs other than liposarcomas will start accrual shortly.
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COMBINATIONS |
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In a single-arm phase II study, bevacizumab was combined with doxorubicin in 17 patients with metastatic STS [40]. Despite the use of dexrazoxane for cumulative doxorubicin doses >300 mg/m2, greater than expected cardiotoxicity was seen. Of the 17 patients, six experienced a grade >2 decline in ejection fraction. With respect to antitumor activity, only two of the 17 patients achieved a response, the primary endpoint. However, as mentioned above, the response rate may not be the most suitable parameter to assess antitumor activity of regimens containing VEGF-targeting agents. The finding that 11 patients had stable disease for >12 weeks, while, additionally, in some of these patients clear cystic alterations in tumor lesions occurred, suggests that this combination has antitumor activity [40]. Of note, the lack of a randomized study design renders it very difficult to draw firm conclusions on the precise antitumor activity of this drug combination. Furthermore, given the heterogeneity among the different histological tumor types in terms of chemosensitivity, inclusion of particular STS entities can greatly influence the outcomes. In this study, 65% of the patients had a leiomyosarcoma, a rather chemoresistant subtype, but this tumor type constitutes approximately 25% of all STSs.
Nevertheless, despite the unacceptably high incidence of cardiotoxicity from the combination of bevacizumab and doxorubicin seen in this study [40], combinations of compounds targeting the VEGF–VEGFR pathway with conventional cytotoxic drugs seem worthwhile to explore in STS. Data on combined approaches with other angiogenesis inhibitors and conventional agents in STS have not been reported yet. Instead of doxorubicin, ifosfamide may be an attractive combination treatment partner to explore in STS given its lack of cardiotoxicity [3].
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CONCLUSIONS |
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VEGF expression, both in tumor tissue and in the blood, has been shown to be associated with tumor grade and, though not consistently, also with outcome in localized disease. The reasons why VEGF expression is adversely related to outcome in STS are not exactly known. Several mechanisms are probably involved, including a higher potency of these tumors to metastasize and resistance to chemotherapy.
Currently, there are preliminary findings strongly suggesting that VEGFR TKIs such as sorafenib and pazopanib exhibit antitumor activity in STS. Again, sensitivity seems to differ among the STS entities. Based on the outcome of a phase II study [39], a global placebo-controlled phase III study with pazopanib will be initiated by the end of 2008 in STS entities, with the exception of liposarcomas. In addition to establishing the true value of VEGFR TKIs in STS, there is a great need to identify prognostic and predictive factors for outcome using such agents. Besides histopathological entities, factors potentially worthwhile exploring include gene-expression profiling of tumor tissue, expression of components of the VEGF–VEGFR pathway, such as VEGF and VEGFR themselves, and also HIF1, and determination of circulating angiogenic factors. Recently, polymorphisms in the VEGF gene with functional activity were found to be associated with survival in early-stage non-small cell lung cancer [41]. It is tempting to see whether or not the same holds for STS and whether such polymorphisms affect the outcome using VEGF-targeting drugs.
In addition to agents impacting the VEGF–VEGFR pathway, novel agents targeting other components involved in angiogenesis are being developed. These include inhibitors of PDGFR, bFGF, MMPs, integrins, and many others. Given the assumed role of some of these targets, these drugs look worthwhile to explore in non-GIST STS.
Not only as single agents, but also combined with other agents, compounds targeting the VEGF–VEGFR system deserve further study. The first study of such a combination consisting of bevacizumab and doxorubicin was characterized by a higher incidence of cardiomyopathy [40]. By using ifosfamide, which is considered a reasonable alternative to doxorubicin, in such a combination, the problem of cardiotoxicity may be circumvented.
Furthermore, monitoring of the antitumor activity of angiogenesis inhibitors, especially when given as a single agent, should be carefully considered because the common and widely applied RECIST and World Health Organization response criteria are likely to underreport the efficacy of these novel agents.
Angiogenesis inhibition has proven to be a valuable approach to treat numerous tumor types and it is likely that its use can be expanded to particular STS entities as well. Their true value, however, can be established only in appropriately designed and conducted trials. Given the rarity of STS in general and the specific subtypes in particular, this will be a major task, which can be accomplished only through the increasingly ongoing international collaboration.
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AUTHOR CONTRIBUTIONS |
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Financial support: Stefan Sleijfer; Winette T.A. van der Graaf; Jean-Yves Blay
Administrative support: Stefan Sleijfer; Winette T.A. van der Graaf; Jean- Yves Blay
Provision of study materials: Stefan Sleijfer; Winette T.A. van der Graaf; Jean-Yves Blay
Collection/assembly of data: Stefan Sleijfer; Winette T.A. van der Graaf; Jean-Yves Blay
Data analysis: Stefan Sleijfer; Winette T.A. van der Graaf; Jean-Yves Blay
Manuscript writing: Stefan Sleijfer; Winette T.A. van der Graaf; Jean-Yves Blay
Final approval of manuscript: Stefan Sleijfer; Winette T.A. van der Graaf; Jean-Yves Blay
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REFERENCES |
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as a biomarker of outcome in soft-tissue sarcomas. Virchows Arch 2006;449:673–681.[Medline]
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