• soft tissue sarcoma;
  • angiogenesis;
  • vascular endothelial growth factor;
  • microvessel density;
  • bevacizumab


  1. Top of page
  2. Abstract
  3. Tumor Vascularity
  4. Vascular Endothelial Growth Factor
  5. Inhibitors of Angiogenesis

Soft tissue sarcomas (STSs) are a heterogeneous group of malignancies that includes >50 different subtypes, each with unique clinical and pathologic qualities. In general, there is a 50% cure rate, and most cures are achieved with complete surgical resection with or without radiation therapy. The results from chemotherapeutic agents for unresectable or metastatic disease have been disappointing with minimal long-term benefit. New targeted and novel agents are needed to improve response and survival. Tumor angiogenesis has been an intense focus in cancer therapy over the past decade. Several of numerous antiangiogenesis agents have been developed, and many already have been approved for the treatment of both solid and liquid tumors. Certain STSs are highly vascular tumors that often demonstrate angiogenesis markers. The objective of this review was to evaluate these angiogenesis markers in defining the role of angiogenesis in the treatment of patients with STS. In addition, the authors conducted an in-depth review of the results from using key antiangiogenesis agents in the treatment of STS. Cancer 2010. © 2010 American Cancer Society.

Soft tissue sarcomas (STSs) are tumors of mesenchymal origin with more than 50 different subtypes. These tumors are uncommon, and the mainstay of treatment is complete surgical resection, with or without radiation therapy, which results in a 50% cure rate. The outcome for patients with unresectable or metastatic disease, however, is unacceptably poor. Chemotherapeutic agents result in short-lived responses and generally do not improve survival. Novel and targeted agents are needed to improve the outcome of these patients.

It has been demonstrated that angiogenesis plays an important role in the growth and metastasis of several solid tumors. The response rates (RRs) to single-agent angiogenesis inhibitors generally are low; however, in combination with chemotherapy, these agents have produced improvements in overall survival in several solid tumors, including colon cancer and lung cancer.1, 2 Several of these agents have been approved for the treatment of cancer over the past decade. Angiogenesis markers can aid in defining the importance of angiogenesis in each tumor type, and several surrogate markers of angiogenesis have been evaluated extensively.3 In this report, we update implications of these markers for outcome and review current clinical trials with antiangiogenesis agents.

Tumor Vascularity

  1. Top of page
  2. Abstract
  3. Tumor Vascularity
  4. Vascular Endothelial Growth Factor
  5. Inhibitors of Angiogenesis

Microvessel density (MVD) is 1 of the first markers of angiogenesis that seem to correlate with outcome in some solid tumors. However, the value of MVD as a prognostic factor in STS is controversial. Comandone and colleagues correlated MVD and survival in 45 patients with extremity STS, mostly liposarcoma (LPS) and malignant fibrous histiocytoma (MFH).4 At a median follow-up of 23 months, patients who had low MVD had improved median disease-free survival (DFS) (24 months vs 15 months) and mean overall survival (OS) (62.7 months vs 36 months) compared with patients who had high MVD. In contrast, West et al observed no correlation between MVD and either the metastatic rate or OS in a study of 42 patients with extremity STS who had high-grade, deep, and large tumors (>5 cm).5 In their study, leiomyosarcoma (LMS) was the most common subtype, and it had a significantly high MVD. In addition, Saenz et al observed that MVD, as measured by factor VIII staining, did not correlate with outcome of a series of patients with high-grade extremity STS.6 Similar findings were reported by Yudoh et al in biopsies from 115 patients with STS.7 Those authors observed that MVD had no prognostic significance in these patients irrespective of subtype.

Vascular Endothelial Growth Factor

  1. Top of page
  2. Abstract
  3. Tumor Vascularity
  4. Vascular Endothelial Growth Factor
  5. Inhibitors of Angiogenesis

Another measure of angiogenesis is vascular endothelial growth factor A (VEGF) and the receptors (VEGF-R1, VEGF-R2, and VEGF-R3). VEGF isomer activates VEGF-R1 (Flt-1), which is a decoy receptor and is involved mostly in embryonic angiogenesis.8 In addition, VEGF activates VEGF-R2 (Flk-1/KDR), which is the most important receptor in tumor angiogenesis, promoting vascular proliferation, survival, and metastasis. VEGF-R3 (Flt-4) is involved mostly in lymphangiogenesis, promoting lymphatic vessel proliferation and lymph node metastasis.

The expression of tumor VEGF and high levels of serum VEGF have been correlated with outcome in many solid tumors, including STS. VEGF was overexpressed in 68 of 273 patients (25%) with STS in 1 study.9 Patients who had VEGF-positive STS had a shorter OS than patients who had VEGF-negative STS (31 month vs 45 months), although the difference did not reach statistical significance. However, in a subgroup analysis, patients with LMS who had VEGF-positive tumors (9 of 36 patients) had a much shorter OS (8 months vs 30 months; P < .01) than patients who had VEGF-negative tumors.

In another study, VEGF was correlated with tumor grade. Intermediate or high-grade tumors had a high rate of VEGF positivity (53 of 66 tumors; 84%) compared with 6 of 13 low-grade tumors (46%).10 VEGF expression was correlated with grade, but it was not correlated independently with OS. Iyoda and colleagues reported the correlation between VEGF overexpression and survival in 27 patients with STS of the thorax.11 In those patients, the tumors were located in the lung (n = 13), the chest wall (n = 9), or the mediastinum (n = 5). Most patients who had grade 3 tumors had strong overexpression of VEGF (83%) compared with patients who had grade 1 histologies (30%). Patients with absent or faint VEGF expression had a 5-year DFS rate of 83.3% compared with 13.2% for those with strong VEGF expression (P < .05). The results indicated that strong staining for VEGF was an independent prognostic factor for DFS in patients with STS of the thorax.

These contradictory results between studies may reflect the lack of consistency in grading VEGF between different pathologists. Measurements of serum VEGF levels may avoid these variations. Graeven and colleagues evaluated serum VEGF levels in 85 patients with STS before surgical resection.12 In addition, 33 patients had samples evaluated 3 weeks after surgery. High serum VEGF levels were correlated strongly with tumor grade and mass, with the highest levels observed in poorly differentiated tumors. It is noteworthy that serum VEGF levels did not change in the 33 patients who had samples drawn 3 weeks after surgery. The authors attributed this to wound healing and concluded that the levels should have been measured a few months after surgery.

Inhibitors of Angiogenesis

  1. Top of page
  2. Abstract
  3. Tumor Vascularity
  4. Vascular Endothelial Growth Factor
  5. Inhibitors of Angiogenesis

There are several ways to inhibit angiogenesis in STS, including blocking of VEGF, VEGF receptors, tyrosine kinase downstream signaling pathways, and endothelial inhibition. The treatment of STS with antiangiogenesis agents is relatively recent; thus, the results from most of the studies mentioned below have not been published but have been reported only at national meetings.

Antivascular endothelial growth factor antibodies

Bevacizumab (Bev) (Genentech, South San Francisco, Calif) is a humanized monoclonal anti-VEGF antibody. In theory, chemotherapy delivery to areas of high tumor vascularity could be compromised because of high interstitial pressure of deranged vessels. Antiangiogenesis agents could normalize the interstitial pressure by blocking the proliferation of tumor blood vessels. Although it has low activity as a single agent, when it was given with chemotherapy, Bev improved survival and/or RRs of patients with colon, nonsmall cell lung, and breast cancers in randomized studies.1, 2, 13 Currently, Bev is approved for these cancers in combination with chemotherapy.

Single-agent doxorubicin is currently the standard of care for the treatment of patients with STS and has produced RRs of 20% to 25%. Although combination therapies with other agents, mostly ifosfamide, increase RR, they have failed to demonstrate an improvement in OS. A phase 2 study of Bev combined with doxorubicin was conducted by D'Adamo et al14 In that study, 17 patients received doxorubicin 75 mg/m2 intravenous (iv) push and Bev 15 mg/kg iv every 3 weeks for up to 11 cycles (range, 1-11 cycles) followed by Bev maintenance. Dexrazoxane was administered after a total of 300 mg/m2 of doxorubicin. Eleven of those 17 patients had LMS mostly of uterine origin. The RR was 12% (2 partial responses [PRs]; 95% confidence interval, 1%-36%) with a median OS of 16 months. Six of 17 patients experienced cardiomyopathy, and it was unclear whether this was because of high doses of doxorubicin or because of the combination therapy. Cardiac toxicities have been reported for Bev/doxorubicin combinations. In a retrospective study, pegylated doxorubicin was administered with Bev to 20 patients with STS but resulted in an RR of only 15%.15 These disappointing results with RRs lower than those achieved with single-agent doxorubicin may be attributed to poor patient selection. Clearly, better therapeutic agents are needed to improve response and outcome in STS.

More recently, the combination of gemcitabine (G) and docetaxel (D) has become attractive in STS, because an RR of 53% was reported in uterine LMS, and the combination also demonstrated activity in other STS.16, 17 Bev has been combined with G and D in a phase 1/2 study in patients with previously untreated STS.18 G was administered at doses of 1000 mg/m2, 1250 mg/m2, or 1500 mg/m2 in escalating cohorts; D was administered at a dose of 50 mg/m2; and Bev was administered at a dose of 5 mg/kg. All drugs were given at 2-week intervals until patients experienced unacceptable toxicity or disease progression. Seven of 23 patients received this combination as neoadjuvant therapy before surgery. Patients were assessable if 2 full treatments were given, and the recommended dose was G 1500 mg/m2, D 50 mg/m2, and Bev 5 mg/kg every 2 weeks. The overall RR was 40% with 3 complete responses (2 angiosarcoma [AS] and 1 MFH) and 5 PRs (1 MFH, 2 LMS, 2 others). Grade 4 toxicities included pneumothorax and bowel perforation (4% each). There was no grade 3 or 4 hematologic toxicity; however, it is unclear whether granulocyte growth factors were given. A randomized study needs to be done to clearly define the additive effect of Bev. A selection of available trials with Bev in STS is summarized in Table 1.

Table 1. Selected Open Trials With Antiangiogenesis Agents in Soft Tissue Sarcoma
  1. NCT indicates National Clinical Trial; STS, soft tissue sarcoma.

Bevacizumab (NCT no.)
 Doxorubicin, ifosfamide, and bevacizumab in locally advanced or metastatic, intermediate or high-grade STS (00755261)
 Radiation and bevacizumab for primary STS or a localized recurrence (00356031)
 Bevacizumab in newly diagnosed or recurrent/refractory angiosarcoma (00288015)
Sunitinib (NCT no.)
 Recurrent or persistent leiomyosarcoma of the uterus (00378911)
 Recurrent or metastatic endometrial carcinosarcoma (00478426)
 Neoadjuvant sunitinib with radiation in locally advanced resectable STS (00753727)
Sorafenib (NCT no.)
 Sorafenib and dacarbazine in STS (00837148)
 Radiation therapy, sorafenib, and surgery in STS (00805727)
 Sorafenib in treating patients with Kaposi sarcoma (00304122)
 Sorafenib, epirubicin, ifosfamide, and radiation therapy followed by surgery in treating patients with high-risk, stage II or III STS  (00822848)
 Sorafenib, pemetrexed, and cisplatin in treating patients with advanced solid tumors, including STS (00703638)
Dasatinib (NCT no.)
 Trial of dasatinib in advanced sarcomas (00464620)
 Dasatinib, ifosphamide, carboplatin, and etoposide in treating young patients with metastatic or recurrent malignant solid tumors  (00788125)
 Dasatinib and bevacizumab in treating patients with solid tumors, including sarcoma, that are metastatic or unresectable (00792545)
Pazopanib (NCT no.)
 A randomized, double-blind, phase 3 trial of pazopanib in patients with STS whose disease has progressed during or after previous  therapy (00538239)
 Treating patients with metastatic STS that has recurred or has not responded to treatment (00753688)
Thalidomide (NCT no.)
 Etoposide, cyclophosphamide, thalidomide, celecoxib, and fenofibrate in treating young patients with recurrent or progressive cancer,  including sarcoma (00357500)
Paclitaxel (NCT no.)
 Paclitaxel in treating patients with locally advanced or metastatic angiosarcoma or lymphangiosarcoma (00217607)
 Paclitaxel, carboplatin, and BSI-201 in the treatment of advanced, persistent, or recurrent uterine cancer or carcinosarcoma (00588744)
 Carboplatin, paclitaxel, and pegfilgrastim in treating patients with stage III or IV carcinosarcoma (00352300)

Small-molecule vascular endothelial growth factor receptor tyrosine kinase inhibitors

Sunitinib (Sutent; Pfizer Inc., New York, NY) is a multitargeted tyrosine kinase inhibitor (TKI). It binds to the adenosine-triphosphate domain of kit and platelet-derived growth factor receptor (PDGFR). It also blocks Flt-3, neurotrophic factor receptor, and colony-stimulating factor-1. In addition, it has antiangiogenesis activity by blocking VEGF-R1, VEGF-R2, and VEGF-R3. This property is not shared by imatinib. The RR to sunitinib has been evaluated in 36 patients with nongastroinstestinal stromal tumor (non-GIST) STS (12 LMS, 12 LPS, 11 MFH, 1 fibrosarcoma).19 The drug was well tolerated, although 1 patient developed congestive heart failure, and 1 patient developed pulmonary emboli. There was 1 PR, and 29 of 36 patients had stable disease (SD) for at least 12 weeks. In another phase 2 study, patients were grouped based on their histology with (Group 1) or without (Group 2) a known prior response to TKI.20 Eleven of 20 patients in the first group had SD, including 5 patients with LMS and 1 patient with AS, 3 of which were sustained at the Week 16 follow-up. There was 1 PR in the second group that was sustained at Week 32. SD was observed in 6 of 19 patients, and 4 of those patients remained stable at Week 16. There are multiple phase 2 studies ongoing with sunitinib in STS (Table 1).

Sorafenib (Nexavar: Onyx, Emeryville, Calif and Bayer, Leverkusen, Germany) is also a multitargeted TKI. It specifically inhibits Raf, PDGFR, VEGF-R2, VEGF-R3, and c-kit. An attractive mechanism of action of sorafenib is simultaneous targeting of the Raf/Mek/Erk pathways. Two phase 2 studies have been reported with single-agent sorafenib in STS. In the first study, patients who had different subtypes were entered in 6 groups, each with a separate Simon 2-stage design, depending on response.21 Patients received sorafenib at 400 mg orally twice a day. Two of 37 patients (6%) with LMS had a PR with a median time to progression of 5.2 months. Five of 37 patients (14%) with AS had a response (4 PRs, 1 complete response) with a median time to progression of 5.5 months. Although 78 of 122 patients (64%) needed a dose reduction, the steady-state pharmacokinetics were similar between full dosed and dose-reduced patients. Two fatalities were reported because of hemorrhage and intestinal perforation. Grade 3 or 4 hypertension and cardiomyopathy also were observed.

In an intergroup study (Southwest Oncology Group study 0505), 37 patients received sorafenib; and, although there were no confirmed responses, 7 of 9 patients with vascular tumors had SD with a median progression-free survival (PFS) of 4.7 months and median OS of 13.5 months.22 The most common adverse events were fatigue, diarrhea, and hand-foot syndrome. Currently, there are multiple trials ongoing with sorafenib in combination with chemotherapy and/or radiation in STS (Table 1).

Dasatinib (Sprycel; Bristol-Myers Squibb, New York, NY) is another multiple TKI with unique qualities. Dasatinib inhibits PDGFR, epidermal growth factor receptor, VEGF-R2, and cellular focal adhesion kinase. The Src family results in over activity of hypoxia-inducible factor 1 (HIF-1), which subsequently increases VEGF expression through tumor hypoxia.23, 24 It has been demonstrated that dasatinib inhibits Src in 12 human sarcoma cell lines and subsequently inhibits cell migration and invasion.25 A cooperative group study is ongoing in the Sarcoma Alliance of Research through Collaboration to evaluate the efficacy and toxicity of dasatinib in STS and osteosarcoma. Combination studies also are under way (Table 1).

Pazopanib (GlaxoSmithKline, Philadelphia, Pa) is a new multi-TKI that blocks VEGF-R1, VEGF-R2, VEGF-R3, PDGFR, and c-kit. This drug has demonstrated activity in other solid tumors. A phase 2 study was reported in intermediate or high-grade, metastatic or advanced STS.26 The primary endpoint was PFS at 12 weeks. The drug was given orally at 800 mg daily to 4 groups of patients with STS stratified by histology. At 12 weeks, 27 of 80 patients were progression free. Clinical benefit was observed in patients with LMS, in patients with synovial sarcoma, and in the miscellaneous group, but not in patients with LPS. A randomized study with pazopanib versus placebo is ongoing in STS because of the encouraging phase 2 results (Table 1).


Thalidomide is an oral agent that changes the microenvironment of the tumor through cytokines. Thalidomide also improves the oxygenation of the tumor vascular bed during the first few days and sensitizes the tumor to radiation therapy.27 In addition, it inhibits VEGF and basic fibroblast growth factor, leading to inhibition of angiogenesis. In 1 clinical trial, 29 patients with refractory uterine LMS received thalidomide, and 24% experienced stabilization of disease.28 The median PFS of 1.9 months was disappointing, and the median OS was 8.3 months. It is worth noting that the most common grade 3 adverse events were neurologic toxicity and dyspnea. Thalidomide in combination with temozolomide has been evaluated in a phase 2 study in patients with unresectable or metastatic LMS.29 Temozolomide was given at a dose of 150 mg/m2 daily for 7 days followed by 1 week off and thalidomide at 200 mg daily. The RR was 10%, and 24% of patients achieved SD. Thalidomide had to be dose reduced or discontinued in many patients because of toxicity. The role of thalidomide in patients with STS is unclear. A phase 2 combination therapy study is ongoing (Table 1).


Paclitaxel is a taxane that inhibits microtubular assembly. This drug has antiangiogenesis effects by inhibiting endothelial motility and proliferation as well as invasiveness.30 The drug also lowers the interstitial pressure and induces endothelial apoptosis.31 In general, paclitaxel has not been effective in STS with the exception of AS. A prospective study of paclitaxel in AS (the ANGIOTAX study) was reported for patients with unresectable AS.32 Paclitaxel was administered over 60 minutes at a dose of 80 mg/m2 on Days 1, 8, and 15 every 28 days. The primary endpoint was the nonprogression rate after 2 cycles. Thirty patients with AS were treated, including 10 patients who had AS of the breast. Ten patients had radiotherapy-induced AS, including 9 patients who had a history of breast adenocarcinoma. The nonprogression rate at 2 months was 74%, and 5 of 27 evaluable patients had a PR (18%). It is noteworthy that 3 patients were able to undergo complete resection of their residual tumor, and 2 of 3 patients currently are alive with no evidence of disease. Combination studies with other chemotherapeutic agents are ongoing (Table 1). This is a great example of selecting a drug that is suitable for a specific sarcoma subtype.

Mammalian target of rapamycin inhibitors

The mammalian target of rapamycin (mTOR) controls the production of HIF-a and HIF-b (hypoxia inducible factor), which, as transcription factors, mediate the expression of several angiogenic genes. These genes produce VEGF and angiopoietin-2, which, in turn, form new blood vessels and new vessel extensions or sprouting.33 In addition, mTOR plays a role in cell proliferation, motility, metabolism, adhesion, and survival.33-35

There are several mTOR inhibitors in clinical trial for sarcomas, notably, ridaforolimus (deforlimus; AP23573), everolimus (RAD 001), and temsirolimus (CCI-779). Oral ridaforolimus (AP23573; Ariad Pharmaceuticals, Cambridge, Mass) has been evaluated in a phase 1 study that included 85 patients with recurrent or refractory sarcoma.36 A clinical benefit response (SD or better) was reported in 23 of 85 patients (27%). The dose-limiting toxicity was aphthous, ulcer-like mouth sores, but it was well tolerated otherwise. A large, prospective phase 2 trial of AP23573 in STS revealed a clinical benefit rate of 29% (n = 212).37 The authors of that study suggested that patients who achieve a clinical benefit have an improved OS. In contrast, a phase 2 trial of CCI-779 in STS failed to demonstrate meaningful efficacy in 41 patients with advanced STS.38

To establish the role of these agents in STS, a phase 3 trial with AP23573 has been initiated in patients with metastatic soft tissue or bone sarcomas. The SUCCEED (Sarcoma Multicenter Clinical Evaluation of the Efficacy of Ridaforolimus) trial is a randomized, double-blind, placebo-controlled study evaluating the PFS and OS in patients who have achieved a good response after chemotherapy.


  1. Top of page
  2. Abstract
  3. Tumor Vascularity
  4. Vascular Endothelial Growth Factor
  5. Inhibitors of Angiogenesis

This is the era for angiogenesis inhibitors in cancer therapy. The importance of these agents in STS treatment has been highlighted in this article. Most antiangiogenesis agents do not have single-agent activity according to standard Response Evaluation Criteria in Solid Tumors (RECIST).39 These tumor measurements are 1-dimensional, and the tumor activity measured by positron emission tomography scanning is not taken into account with RECIST. However, the Choi criteria measure tumor density as well as size to assess response and currently is the accepted method of response assessment in patients with GIST.40 The Choi criteria are more sensitive than RECIST and are correlated significantly with the time to progression and disease-specific survival.41 It is possible that the response to antiangiogenesis agents should be measured according to Choi criteria, because some patients benefit clinically but have no response according to RECIST. Sarcoma researchers should attempt to standardize the assessment of these agents not only in terms of criteria for response but also in terms of what constitutes a meaningful response.

Antiangiogenesis agents should be combined with other novel or chemotherapeutic agents to improve response. Antiangiogenesis agents can stabilize the interstitial pressure of the tumor vasculature and allow better chemotherapy delivery to the tumor bed. Ultimately, randomized studies are needed to demonstrate the benefit of angiogenesis inhibitors combined with chemotherapy. However, STSs are uncommon cancers, and large studies are difficult to complete. Therefore, it may be impossible to demonstrate the kinds of small and meaningful benefits that have been produced in lung or colon cancer studies.

It is premature to speculate which inhibitors appear most promising. One major impediment is the large number of STS histologic subtypes, each with different tumor characteristics and clinical behaviors. Not all subtypes would be expected to respond to an antiangiogenesis approach, and different types may respond to different inhibitors. Targeted agents must be identified individually for specific subtypes to maximize results. Trials should focus on sarcoma subtypes with a likely possibility to respond to angiogenesis inhibitors. MVD or VEGF may prove to be prognostic factors in certain STS types, such as LMS, and efforts should be made to investigate this further. However, it has not yet been determined whether MVD or VEGF will predict response to these antiangiogenesis agents. This has not been the case in other malignancies.

Angiogenesis inhibitors provide a new and exciting therapeutic option for patients with STS. The angiogenesis pathway in STS needs to be explored further to identify the most effective agent for specific STS subtypes.


  1. Top of page
  2. Abstract
  3. Tumor Vascularity
  4. Vascular Endothelial Growth Factor
  5. Inhibitors of Angiogenesis
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