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Angiosarcoma: State of the art and perspectives
Critical Reviews in Oncology/Hematology 80 (2011) 257–263
Angiosarcoma: State of the art and perspectives Nicolas Penel a,b,c,∗ , Sandrine Marréaud a,b , Yves-Marie Robin c , Peter Hohenberger a,b b
a EORTC Headquarters, Belgium EORTC Soft Tissue and Bone Sarcoma Group, Belgium c Centre Oscar Lambret, France
Accepted 8 October 2010
Contents 1.
2. 3.
4. 5.
6. 7.
Introduction and epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Constitutional risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Exogenous risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Primary breast AS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. AS of scalp and face . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Stewart-Treves syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. AS in irradiated fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment and prognostic factors of localized as . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of metastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Doxorubicin-based regimen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Taxane-based regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Molecular targeted therapy area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract We propose a literature review of available data on angiosarcoma (AS). AS account for 1% of adult soft tissue sarcoma. Two risk factors are well-establish chronic lymhoedema, previous radiotherapy. Clinical presentations of AS are heterogeneous. Large resection followed, if possible, by adjuvant radiotherapy is the cornerstone of curative intent treatment of localized forms. There are no convincing data supporting the administration of adjuvant chemotherapy. For metastatic or locally advanced AS, doxorubicin and weekly paclitaxel seem to provide the longer progression-free survival. Three phase II or parts of phase II trials have been published in the last 2 years, investigating weekly paclitaxel, sorafenib and imatinib, demonstrating that clinical trials are feasible for such rare diseases. Biological evidences for the key role of angiogentic factors have been accumulated during the last years and support the further investigation of anti-angiogenetic agents alone and almost combination with chemotherapy in such disease. © 2010 Elsevier Ireland Ltd. All rights reserved. Keywords: Angiosarcoma; Weekly paclitaxel; Prognostic factors; Angiogenesis
∗
Corresponding author at: Centre Oscar Lambret, 3, rue F Combemale, 59020 Lille, France. Tel.: +33 3 20 29 59 20; fax: +33 3 20 29 59 63. E-mail addresses: [email protected], [email protected] (N. Penel).
1040-8428/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2010.10.007
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1. Introduction and epidemiology Angiosarcomas (AS) account about 2–3% of adult soft tissue sarcomas [1–3]. Despite their rarity AS display remarkable clinical heterogeneity in term of presentation and behavior. These tumors can occur in any location of the body (two-thirds are cutaneous – mainly in head and neck area – one-fourth arise in soft tissue) [4–5]. The dedicated literature is spare, but some recent results of three phase II trials modify our knowledge of this rare disease. Data for this review were identified by searches of MEDLINE, Current contents, PubMed, and references from relevant articles using the search terms “angiosarcomas” and “human”. Only papers published in English between 1966 and 2010 were included. 1.1. Constitutional risk factors In about 3% of all cases, AS occur in the context of genetic predisposing syndrome, such as bilateral retinoblastoma, Recklinghausen neurofibromatosis, Ollier’s disease, Maffuci’s disease, and Xeroderma pigmentosus [3,4,6]. Compared to other histological subtypes of soft tissue sarcoma, none of these syndromes is specifically associated with AS. 1.2. Exogenous risk factors About a third of liver AS seems caused by some environmental carcinogenic: exposure to thorium dioxide (thorotrast used in the past for cerebral arteriography), occupational exposure to arsenical insecticide or to polyvinyl chloride (PVC, synthetic rubber industry). Many case-control studies have well established the relationship between occupational exposure to PVC and liver AS [7,8]. The carcinogenesis of PCV chronic exposure had been formally established in rat model [9]. The polymorphism of some xenobiotic metabolism enzymes could predispose to the occurrence of liver AS in workers exposed to PVC [8]. Chronic lymphedema, whatever its cause and radiotherapy are two classical risk factors for skin and soft tissue AS. The classical form is the Stewart-Treves syndrome that terms AS developed of lymphedema following breast cancer treatment [10–12]. This syndrome remains very rare. AS developed in irradiated field occur within the 8 years following the radiotherapy and are particularly frequent after treatment of breast cancer and lymphoma. The relative risk for AS occurrence is about six after radiotherapy [13]. AS in irradiated fields represent about 3–10% of all AS [3–5].
2. Histology and biology The histopathological features of AS can be quite diverse, ranging from well differentiated to poorly differentiated
tumors [6,14,15]. The FNCLCC 3-scale grade is suitable for AS [2,5]. In the Fayette series, the 5-year overall survival rates are, respectively, 72%, 45% and 23% for grade 1, grade 2 and grade 3 AS (p = 0.03) [5]. Low-grade AS represent about 25% of all AS. They are characterized by vasoformative pattern of growth and well-developed vascular channels. Differential diagnosis between post-radiotherapy vascular benign lesions and low-grade AS remains challenging [16,17]. High-grade AS and intermediate AS represent about 75% of all cases. Mitosis and necrosis are frequent. High-grade AS are generally densely cellular malignancies with only focal vascular channel formation. The cancer cells range from spindled to epithelioid. The prognostic value of “epithelioid form” is debated. In these cases, the diagnosis can be confirmed by imunohistochemistry. AS are usually positive for factor VIII-related antigen, CD34 and CD31 [6,14,15]. In opposite to Kaposi sarcoma, AS are negative for Human Herpes Virus 8 immunostaining [17]. By convention, “Lymphangiosarcoma” terms AS arising in the setting of chronic lymphoedema (Stewart-Treves syndrome). Analysis of AS Karyotypes do not reveal specific cytogenetic marker, such specific translocation. The genetic alterations are nonspecific, complex and unbalanced. Elevated expressions of both MDM2 and p53 are seen in about 14/19 AS [18]. Ras mutations are frequent in liver AS associated to thorotrast or chloride vinyl exposure [19]. Manner et al. had found that MYC amplification is seen in 55% (18/33) lymphoedema-associated or radio-induced AS and is absent in de novo AS (0/28) [20].
3. Clinical presentation 3.1. Overview Clinical presentations are multiple due to the ubiquitous character of AS. The median age is about 52–62 in largest series [5,6,21,22]. Excluding breast and skin and scalp AS, the sex ratio is 1 [5,6,21,22]. The three most frequent primary sites are face and scalp, extremities soft tissue and breast [5,6,21,22]. The primary lesion is multifocal in about 10–15% [22]. Lymph node involvement is present at the initial diagnosis in about 10–15% of soft tissue AS, in about 5% of scalp AS and rarely in primary breast AS [22–25]. About 15% of patients present metastatic disease at the time of diagnosis [4,5,26]. The 5-year overall survival of non-metastatic AS is about 31–43% in recent large series [4,5,22,27]. Nevertheless, the survival depends on the primary site (see below), the 10-year overall survival is about 28% for extremities soft tissue AS, 21% for scalp AS and about 0% for other primaries [22]. After local treatment, most of recurrences (75%) occur within the 24 months [22]. Four particular forms of AS are more precisely depicted below.
N. Penel et al. / Critical Reviews in Oncology/Hematology 80 (2011) 257–263
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Table 1 Localized angiosarcomas: prognostic factors identified by univariate analysis in largest retrospective series. Ref
Tumors
n
5 4 22 14 27 15 30 26 6
All All All All Skin Skin Scalp Breast Soft tissue
161 125 67 55 47 44 29 55 80
Size
Grade
Margins
Depth
Yes
Yes
Yes
Yes
Yes Yes Yes Yes Yes Yes Yes
Yes Yes *
Yes Yes Yes *
Other (1) (2) (3) (4) (5) (6) (7) (8) (9)
(1) Presence of metastasis, performance status, necrosis. (2) Visceral primary. (3) Head and neck location, other location than extremities. (4) Age superior to 50, mitotic count. (5) Presence of metastasis, mitotic count, tumor recurrence. (6) Absence of inflammation. (7) Multifocality, age over 70. (8) Age over 50, tumor recurrence. (9) Mitotic count, age over 67, retroperitoneal primary.
3.2. Primary breast AS
3.5. AS in irradiated fields
AS represent less than 1 out of 2000 primary breast cancers [28,29]. Primary breast AS occurs exclusively in women aged between 30 and 50. The best chance of survivals is offered to the patients underwent mastectomy. After mastectomy, the margins are clear in the vast majority of cases [5,26]. Axillary lymph node dissection is not a routine procedure because node involvement is quite rare in such particular form of AS [26]. The 5-year overall survival is about 50–60% [5,26].
This form represents about 15% of all AS. The three most frequent histological types of sarcoma developed in irradiated fields are: osteosarcoma (30%), undifferentiated spindle cells sarcoma (15%) and AS (15%). The most frequent cases occur in chest walls, about 8 years after the treatment of breast cancer or lymphoma [4,26]. In the Vorburger and the Fury series, the prognosis of primary breast AS and the chest wall AS arising in irradiated fields are quite similar [4,26]. Large curative intent surgery is the sole validated treatment for this form of AS.
3.3. AS of scalp and face This is the most common form of AS (one-third of all cases [Abraham]). The median age is 70–75 years [15,22,27,30,31]. There is a male predominance for this particular AS form [15,22,27,30,31]. The typical lesions are usually bruised-like macules, multifocal, deeply infiltrative and occasionally ulcerated or with intermittent bleeding. The propensity of scalp AS to exhibit a diffuse pattern of clinically undetectable spread makes resection difficult and extensive. Moreover, at diagnosis the cervical lymph nodes are not rare (5% in the Mark series). Despite curative intent surgery, clears margins could be obtained in only 20–30% of cases [27,30]. Regarding that margin status is the key prognostic factor [30], this could explain the high rate of local relapse or persistent disease (about 75%) [15,30]. The 5-year overall survival is less than 30% [5,22,30]. 3.4. Stewart-Treves syndrome About 90% of AS associated with chronic lymphedema occur following mastectomy for breast cancers [10,11]. This is an exceptional complication of breast cancer treatment (about 8 cases out of 410,000 breast cancers treated [32]). In these cases, the median interval is about 10 years (4–27). The prognosis of this form is particularly poor, less than 10% of patients survived 5 years or longer. In two large series, the long-term survivors have usually been treated by radical surgery, either disarticulation or amputation [10,11].
4. Treatment and prognostic factors of localized as Angiosarcomas ideally require medical attention from a knowledgeable multidisciplinary medical team [33]. The cornerstone of the treatment is a large en-bloc resection [5,14,15,21,27,30]. Surgical procedures obviously differ according to primary locations. In the cases of liver AS, resection is possible in few cases whereas liver transplantation is contraindicated. Clear margins could be relatively easily obtained after mastectomy for primary breast AS and large resection of soft tissue AS (about 85% [21]). Conversely, clear margins are rarely obtained for scalp AS despite large resection with reconstruction by loco regional flap (about 20% [22,30]). Regarding the high incidence of lymph node involvement at early stage (5–13%), the node surgery is debatable [24,25]. Similarly than to other soft tissue sarcomas, postoperative radiotherapy is recommended in most cases of AS. For example, the median overall survival is about 36 months after adjuvant therapy compared to 9 months without adjuvant radiotherapy (p = 0.033) in the Pawlik series [30]. In the Mark series, the 5-year overall survival is about 45% with adjuvant radiotherapy and about 20% without this treatment (p = 0.03). It is noteworthy that some radiation oncologists are reluctant to irradiate AS arising in irradiated fields treated by large surgery. There is no consistent data supporting adjuvant chemotherapy for this tumor, despite the fact
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Table 2 Metastatic angiosarcomas: results of the three phase II clinical trials. Ref
Treatment
n
Pts
47 43 48
Sorafenib 800 mg/d Weekly paclitaxel Imatinib 600 mg/d
40 30 16
Chemo-naive and pre-treated Chemo-naive and pre-treated Chemo-naive and pre-treated
PFR @ 3 months 64% 75% 20%
PFR @ 6 months
RR
mPFS
mOS
31% 24% –
13% 19% 12.5%
3.8 4.0 2.7
14.9 8.0 –
PFR: progression-free rate, RR: best response rate, mPFS: median progression free survival (in months), mOS: median overalll survival (in months).
that up to 50% of AS will develop distant metastasis [4–6,14,15,21,22,26,27,30]. The limited number of cases, the retrospective nature of the studies, the heterogeneity of study populations render very challenging the analysis of prognostic factors across the different published series. The most important prognostic factors seem to be the tumor size (with a threshold set at 5 cm in most cases) [6,15,22,26,30], the grade [5,6,22,26,27] and the margin status [5,6,27] (Table 1). Numerous other prognostic factors have been cited: mitotic count [6,22,27], older age [6,22,30], and some particular primary location such retroperitoneal AS [6] or head and neck location [22].
5. Treatment of metastatic disease The most common metastatic site is the lung; nevertheless, any metastatic site is possible [4,5,21]. Pneumothorax is a classical presenting form feature of metastatic scalp AS [22,30]. The median overall survival is about 8–12 months at this stage [5,21]. Until 2008, the literature data consist in numerous case reports. Many case-reports suggest the efficacy of numerous chemotherapy agents (such as liposomal doxorubicin, vinorelbine, and metronomic trosfosfamide) or molecular targeted agents (such as thalidomide, sunitinib, and bevacizumab) [34–38], etc.
5.2. Taxane-based regimens Fata et al. [39] had first reported that 8/9 patients suffering from scalp angiosarcoma achieved a partial response with paclitaxel (175 mg/m2 /3 weeks). The median progressionfree survival was 5 months. Schlemmer et al [40] had reported the EORTC experience with paclitaxel in patients with metastatic angiosarcoma. Different schedules had been used (3 weeks and weekly regimens). The overall response rate was 20/32 with 1 complete response. The median progression-free survival was 7.6 months. The response rate was 6/8 in patients with scalp and skin angiosarcomas compared to 14/24 cases in patients with other primary locations [40]. Numerous case-reports suggest the potential interest of taxanes for the treatment of metastatic or advanced AS, arising in scalp [41] or breast [42]. This had been confirmed by a phase II trial assessing the efficacy of the weekly paclitaxel regimen (80 mg/m3 d1, d8, d15, 21-day cycle) [43]. The response rate is about 20%; but the non-progression rate is about 75% at 3 months and 24% at 6 months. The efficacy is quite similar in chemotherapy-naïve patients and pretreated patients. Three patients with aggressive and locally advanced disease received this regimen provide tumor growing stop in the three cases, allowing a large en bloc resection. In two cases, there is no viable residual cell and in third case, the remaining tumor displays less than 5% of identifiable residual cells (Table 2). This is a specific characteristic of AS since taxanes are clearly ineffective for other histological subtypes of soft tissue sarcoma [44–46].
5.1. Doxorubicin-based regimen Large clinical trials investigating doxorubicin-based regimens in patients with advanced or metastatic soft tissue sarcoma did not usually individualize the outcome of patients with AS. Moreover, there is no large retrospective series reporting the efficacy of doxorubicin-based regimen. Many reports suggest a high rate of objective response with doxorubicin-based regimen but these responses seem to be transient [5,6]. For example, Fury et al. report that the median progression-free survival is 3.7 months with doxorubicin alone (12 patients) and 5.4 months with doxorubicin plus ifofamide combination (7 patients) [5]. Fayette et al. report that doxorubicin or ifosfamide-based regimens provide objective response in 7 out of 17 evaluable patients (26%) [6]. By analogy with other histological subtypes of soft tissue sarcoma, doxorubicin-regimen remains the recommended first-line regimen.
5.3. Molecular targeted therapy area Two recent phase II trials are available (Table 2). Maki et al. had evaluated the efficacy of sorafenib (800 mg/d) in this disease. The response rate is about 13%; the non-progression rate is about 65% at 3 months and 31% at 6 months [47]. The toxicity seems to be less manageable than previously reported with other tumors such as liver or kidney cancers. A dose reduction is necessary in about 60% of patients [47]. Chugh et al. report the efficacy of imatinib (600 mg/d) in patients with advanced or metastatic AS. The response rate is about 12% and the non-progression rate is only 20% at 3 months [48]. Regarding these data, weekly paclitaxel and sorafenib needs further evaluations. Moreover, the publication of these three trials clearly demonstrates that conduct clinical trial in such rare disease is feasible with rapid accrual (about 2 years in the three studies).
N. Penel et al. / Critical Reviews in Oncology/Hematology 80 (2011) 257–263 Table 3 Major remaining questions. Prognostic factors of localized AS Incidence of lymph node involvement at early stage and role of node surgery Efficacy of doxorubicin-based regimens Efficacy of anti-angionetic agents (alone or in combination with chemotherapy) Role of MDR phenotype and beta-tubulin isotypes in paclitaxel resistance Role of pro-angiogenetic growth factor profiles in resistance to kinase inhibitors (sorafenib, imatinib, etc.)
Another ongoing trial investigates the activity of bevacizumab alone (15 mg/kg/3 weeks) in patients advanced angiosarcoma or epithelioid hemangiopericytoma [49]. Some preliminary data have been presented (ASCO Annual meeting in 2009). Twenty-six patients are assessable for response, with 3 partial responses (3–16 cycles) and 13 stable disease (3–22 cycles). But, we do not know the rate of response and non-progression in the subpopulation of patients with angiosarcoma.
6. Perspectives Two points warrant further exploration to better target the AS treatment: mechanisms of drug resistance in AS and/or the role of angiogenetic agents (Table 3). The best understood mechanisms of resistance to paclitaxel in vitro are MDR phenotypes [50] and modification of beta-tubulin isotypes. Moreover MDR phenotypes display cross-resistance to doxorubicin and paclitaxel, two major drugs of the AS treatment. To our knowledge there is no published data exploring the expression of, for instance, Class-III tubulin in AS. Dumontet et al. had demonstrated using an in vitro model that betatubulin isotypes are implied in the sarcoma cell line resistance to paclitaxel [51]. Houghton et al. had shown that vincristine-resistant rhabdomyosarcoma display altered beta-tubulins [52]. The most important recent findings highlight the crucial role of pro-angiogenic growth factors and their receptors in AS [53–62]. in vitro studies have demonstrated that the mRNA and proteins of the following growth factors and receptors are over expressed in AS cellular lines: VEGFA , VEGFC , VEGF-R1 , VEGF-R3 , VPF, FLT-A, KDR (FLK-1), ETS-1 [53–62]. Several couples of V-EGF/V-EGF Receptors seem to be involved at early stage of AS development [55]. Itakura et al. had shown that V-EGF A is overexpressed in 32 out of 34 human AS, VEGFC in 4 out 34 cases, VEGF-R1 in 22 out of 34 cases and V-EGF-R3 in 27 out of 34 cases [57]. Out of these numerous pro-angiogentic factors, vascular permeability factor (VPF) could be of major importance. VPF is a potent inducer of microvascular hyperpermeability, as well as a selective endothelial cell mitogen. VPF interacts with cells by the way of two high affinity receptor tyrosine kinases: flt1 and kdr, both are selectively
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expressed by vascular endothelium. Strong expression of kdr had been reported in two cases of scalp AS [53,62]. Recently Antonescu et al. had shown a strong KDR protein expression in primary breast AS and AS arising in irradiated chest wall [61]. Moreover, 10% of AS display mutations of kdr. Furthermore, in vitro studies have demonstrated that mutated KDR are sensitive to kinase inhibitors [61]. An increasing in the activating phosphorylation of transduction cascade proteins (MAP Kinases) depending of raf have been established in AS. This could be another explanation of sorafenib efficacy in such disease [58]. Lahat et al. have found an overexpression of V-EGF Receptors and the intracellular second messengers (p-AKT, p-4EBP1 and eIF4E) in a series of 68 human AS [63]. These data support further study of the AKT/mTOR pathway inhibitor alone or in combination in the treatment of AS [63]. As previously mentioned some objective responses have been seen with anti-angiogentic agents (see Table 2), and many preclinical data suggest the high frequency of activating mutation of VEGF-R [61], the over-expression of VEGF and then the activation of second messengers [63]. The inhibition of this constitutively activated axis, for example by tyrosine kinase inhibitor or by bevacizumab could play a role in the treatment of AS.
7. Conclusion AS is a rare and heterogeneous sarcoma. The overall prognosis is poor; in a series of 182 non-metastatic soft tissue sarcoma, Singer et al. had described that the histological diagnosis of AS carried with a 13-fold risk of death [64]. Large en bloc surgery following by radiotherapy could be recommended for localized disease. Weekly paclitaxel and sorafenib needs further evaluations. Today, two points needs further studies: (i) analysis of prognostic factors of localized disease in large multicenter database allowing reliable statistical analysis and (ii) estimate the efficacy of doxorubicinbased regimen in large retrospective database and prospective clinical trial. There is a body of evidence to explore the efficacy of anti-angiogentic agents (alone or almost in combination with chemotherapy) in such disease (Table 3).
Reviewer Antoine Italiano, M.D. Ph.D., Institut Bergonié, Department of Medical Oncology, 229 cours de l’Argonne, F-33000 Bordeaux, France.
References [1] Torosian MH, Friedrich C, Godblod J, Hadju SI, Brennan M. Soft-tissue sarcoma: initial characteristics and prognostic factors in patients with or without metastatic disease. Sem Surg Oncol 1988;4:13–9.
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Biography Nicolas Penel, M.D. (1999), Ph.D. (2007), is medical oncologist at Oscar Lambret Cancer Center, Lille, France and currently post-doctoral fellow at the EORTC Headquarter. His main clinical expertise field is the treatment of adult soft tissue sarcoma and rare cancers (uveal or mucosal melanoma, chordoma, cancer of unknown primary). His main research field is the methodology of exploratory clinical trials (phases 0, 1 and 2). He is member of ASCO, AACR, French Sarcoma Group, EORTC Soft Tissue and Bone Sarcoma Group and the European New Drug Development Network. Since 1999, he is author or coauthor of more than 100 indexed medical publications. He is study coordinator of 7 clinical trials. The present review had been written during his fellowship at EORTC Headquarters.
Angiosarcoma: State of the art and perspectives Nicolas Penel a,b,c,∗ , Sandrine Marréaud a,b , Yves-Marie Robin c , Peter Hohenberger a,b b
a EORTC Headquarters, Belgium EORTC Soft Tissue and Bone Sarcoma Group, Belgium c Centre Oscar Lambret, France
Accepted 8 October 2010
Contents 1.
2. 3.
4. 5.
6. 7.
Introduction and epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Constitutional risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Exogenous risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Histology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Primary breast AS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. AS of scalp and face . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Stewart-Treves syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. AS in irradiated fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment and prognostic factors of localized as . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of metastatic disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Doxorubicin-based regimen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Taxane-based regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Molecular targeted therapy area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
258 258 258 258 258 258 259 259 259 259 259 260 260 260 260 261 261 261 261 263
Abstract We propose a literature review of available data on angiosarcoma (AS). AS account for 1% of adult soft tissue sarcoma. Two risk factors are well-establish chronic lymhoedema, previous radiotherapy. Clinical presentations of AS are heterogeneous. Large resection followed, if possible, by adjuvant radiotherapy is the cornerstone of curative intent treatment of localized forms. There are no convincing data supporting the administration of adjuvant chemotherapy. For metastatic or locally advanced AS, doxorubicin and weekly paclitaxel seem to provide the longer progression-free survival. Three phase II or parts of phase II trials have been published in the last 2 years, investigating weekly paclitaxel, sorafenib and imatinib, demonstrating that clinical trials are feasible for such rare diseases. Biological evidences for the key role of angiogentic factors have been accumulated during the last years and support the further investigation of anti-angiogenetic agents alone and almost combination with chemotherapy in such disease. © 2010 Elsevier Ireland Ltd. All rights reserved. Keywords: Angiosarcoma; Weekly paclitaxel; Prognostic factors; Angiogenesis
∗
Corresponding author at: Centre Oscar Lambret, 3, rue F Combemale, 59020 Lille, France. Tel.: +33 3 20 29 59 20; fax: +33 3 20 29 59 63. E-mail addresses: [email protected], [email protected] (N. Penel).
1040-8428/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2010.10.007
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1. Introduction and epidemiology Angiosarcomas (AS) account about 2–3% of adult soft tissue sarcomas [1–3]. Despite their rarity AS display remarkable clinical heterogeneity in term of presentation and behavior. These tumors can occur in any location of the body (two-thirds are cutaneous – mainly in head and neck area – one-fourth arise in soft tissue) [4–5]. The dedicated literature is spare, but some recent results of three phase II trials modify our knowledge of this rare disease. Data for this review were identified by searches of MEDLINE, Current contents, PubMed, and references from relevant articles using the search terms “angiosarcomas” and “human”. Only papers published in English between 1966 and 2010 were included. 1.1. Constitutional risk factors In about 3% of all cases, AS occur in the context of genetic predisposing syndrome, such as bilateral retinoblastoma, Recklinghausen neurofibromatosis, Ollier’s disease, Maffuci’s disease, and Xeroderma pigmentosus [3,4,6]. Compared to other histological subtypes of soft tissue sarcoma, none of these syndromes is specifically associated with AS. 1.2. Exogenous risk factors About a third of liver AS seems caused by some environmental carcinogenic: exposure to thorium dioxide (thorotrast used in the past for cerebral arteriography), occupational exposure to arsenical insecticide or to polyvinyl chloride (PVC, synthetic rubber industry). Many case-control studies have well established the relationship between occupational exposure to PVC and liver AS [7,8]. The carcinogenesis of PCV chronic exposure had been formally established in rat model [9]. The polymorphism of some xenobiotic metabolism enzymes could predispose to the occurrence of liver AS in workers exposed to PVC [8]. Chronic lymphedema, whatever its cause and radiotherapy are two classical risk factors for skin and soft tissue AS. The classical form is the Stewart-Treves syndrome that terms AS developed of lymphedema following breast cancer treatment [10–12]. This syndrome remains very rare. AS developed in irradiated field occur within the 8 years following the radiotherapy and are particularly frequent after treatment of breast cancer and lymphoma. The relative risk for AS occurrence is about six after radiotherapy [13]. AS in irradiated fields represent about 3–10% of all AS [3–5].
2. Histology and biology The histopathological features of AS can be quite diverse, ranging from well differentiated to poorly differentiated
tumors [6,14,15]. The FNCLCC 3-scale grade is suitable for AS [2,5]. In the Fayette series, the 5-year overall survival rates are, respectively, 72%, 45% and 23% for grade 1, grade 2 and grade 3 AS (p = 0.03) [5]. Low-grade AS represent about 25% of all AS. They are characterized by vasoformative pattern of growth and well-developed vascular channels. Differential diagnosis between post-radiotherapy vascular benign lesions and low-grade AS remains challenging [16,17]. High-grade AS and intermediate AS represent about 75% of all cases. Mitosis and necrosis are frequent. High-grade AS are generally densely cellular malignancies with only focal vascular channel formation. The cancer cells range from spindled to epithelioid. The prognostic value of “epithelioid form” is debated. In these cases, the diagnosis can be confirmed by imunohistochemistry. AS are usually positive for factor VIII-related antigen, CD34 and CD31 [6,14,15]. In opposite to Kaposi sarcoma, AS are negative for Human Herpes Virus 8 immunostaining [17]. By convention, “Lymphangiosarcoma” terms AS arising in the setting of chronic lymphoedema (Stewart-Treves syndrome). Analysis of AS Karyotypes do not reveal specific cytogenetic marker, such specific translocation. The genetic alterations are nonspecific, complex and unbalanced. Elevated expressions of both MDM2 and p53 are seen in about 14/19 AS [18]. Ras mutations are frequent in liver AS associated to thorotrast or chloride vinyl exposure [19]. Manner et al. had found that MYC amplification is seen in 55% (18/33) lymphoedema-associated or radio-induced AS and is absent in de novo AS (0/28) [20].
3. Clinical presentation 3.1. Overview Clinical presentations are multiple due to the ubiquitous character of AS. The median age is about 52–62 in largest series [5,6,21,22]. Excluding breast and skin and scalp AS, the sex ratio is 1 [5,6,21,22]. The three most frequent primary sites are face and scalp, extremities soft tissue and breast [5,6,21,22]. The primary lesion is multifocal in about 10–15% [22]. Lymph node involvement is present at the initial diagnosis in about 10–15% of soft tissue AS, in about 5% of scalp AS and rarely in primary breast AS [22–25]. About 15% of patients present metastatic disease at the time of diagnosis [4,5,26]. The 5-year overall survival of non-metastatic AS is about 31–43% in recent large series [4,5,22,27]. Nevertheless, the survival depends on the primary site (see below), the 10-year overall survival is about 28% for extremities soft tissue AS, 21% for scalp AS and about 0% for other primaries [22]. After local treatment, most of recurrences (75%) occur within the 24 months [22]. Four particular forms of AS are more precisely depicted below.
N. Penel et al. / Critical Reviews in Oncology/Hematology 80 (2011) 257–263
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Table 1 Localized angiosarcomas: prognostic factors identified by univariate analysis in largest retrospective series. Ref
Tumors
n
5 4 22 14 27 15 30 26 6
All All All All Skin Skin Scalp Breast Soft tissue
161 125 67 55 47 44 29 55 80
Size
Grade
Margins
Depth
Yes
Yes
Yes
Yes
Yes Yes Yes Yes Yes Yes Yes
Yes Yes *
Yes Yes Yes *
Other (1) (2) (3) (4) (5) (6) (7) (8) (9)
(1) Presence of metastasis, performance status, necrosis. (2) Visceral primary. (3) Head and neck location, other location than extremities. (4) Age superior to 50, mitotic count. (5) Presence of metastasis, mitotic count, tumor recurrence. (6) Absence of inflammation. (7) Multifocality, age over 70. (8) Age over 50, tumor recurrence. (9) Mitotic count, age over 67, retroperitoneal primary.
3.2. Primary breast AS
3.5. AS in irradiated fields
AS represent less than 1 out of 2000 primary breast cancers [28,29]. Primary breast AS occurs exclusively in women aged between 30 and 50. The best chance of survivals is offered to the patients underwent mastectomy. After mastectomy, the margins are clear in the vast majority of cases [5,26]. Axillary lymph node dissection is not a routine procedure because node involvement is quite rare in such particular form of AS [26]. The 5-year overall survival is about 50–60% [5,26].
This form represents about 15% of all AS. The three most frequent histological types of sarcoma developed in irradiated fields are: osteosarcoma (30%), undifferentiated spindle cells sarcoma (15%) and AS (15%). The most frequent cases occur in chest walls, about 8 years after the treatment of breast cancer or lymphoma [4,26]. In the Vorburger and the Fury series, the prognosis of primary breast AS and the chest wall AS arising in irradiated fields are quite similar [4,26]. Large curative intent surgery is the sole validated treatment for this form of AS.
3.3. AS of scalp and face This is the most common form of AS (one-third of all cases [Abraham]). The median age is 70–75 years [15,22,27,30,31]. There is a male predominance for this particular AS form [15,22,27,30,31]. The typical lesions are usually bruised-like macules, multifocal, deeply infiltrative and occasionally ulcerated or with intermittent bleeding. The propensity of scalp AS to exhibit a diffuse pattern of clinically undetectable spread makes resection difficult and extensive. Moreover, at diagnosis the cervical lymph nodes are not rare (5% in the Mark series). Despite curative intent surgery, clears margins could be obtained in only 20–30% of cases [27,30]. Regarding that margin status is the key prognostic factor [30], this could explain the high rate of local relapse or persistent disease (about 75%) [15,30]. The 5-year overall survival is less than 30% [5,22,30]. 3.4. Stewart-Treves syndrome About 90% of AS associated with chronic lymphedema occur following mastectomy for breast cancers [10,11]. This is an exceptional complication of breast cancer treatment (about 8 cases out of 410,000 breast cancers treated [32]). In these cases, the median interval is about 10 years (4–27). The prognosis of this form is particularly poor, less than 10% of patients survived 5 years or longer. In two large series, the long-term survivors have usually been treated by radical surgery, either disarticulation or amputation [10,11].
4. Treatment and prognostic factors of localized as Angiosarcomas ideally require medical attention from a knowledgeable multidisciplinary medical team [33]. The cornerstone of the treatment is a large en-bloc resection [5,14,15,21,27,30]. Surgical procedures obviously differ according to primary locations. In the cases of liver AS, resection is possible in few cases whereas liver transplantation is contraindicated. Clear margins could be relatively easily obtained after mastectomy for primary breast AS and large resection of soft tissue AS (about 85% [21]). Conversely, clear margins are rarely obtained for scalp AS despite large resection with reconstruction by loco regional flap (about 20% [22,30]). Regarding the high incidence of lymph node involvement at early stage (5–13%), the node surgery is debatable [24,25]. Similarly than to other soft tissue sarcomas, postoperative radiotherapy is recommended in most cases of AS. For example, the median overall survival is about 36 months after adjuvant therapy compared to 9 months without adjuvant radiotherapy (p = 0.033) in the Pawlik series [30]. In the Mark series, the 5-year overall survival is about 45% with adjuvant radiotherapy and about 20% without this treatment (p = 0.03). It is noteworthy that some radiation oncologists are reluctant to irradiate AS arising in irradiated fields treated by large surgery. There is no consistent data supporting adjuvant chemotherapy for this tumor, despite the fact
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Table 2 Metastatic angiosarcomas: results of the three phase II clinical trials. Ref
Treatment
n
Pts
47 43 48
Sorafenib 800 mg/d Weekly paclitaxel Imatinib 600 mg/d
40 30 16
Chemo-naive and pre-treated Chemo-naive and pre-treated Chemo-naive and pre-treated
PFR @ 3 months 64% 75% 20%
PFR @ 6 months
RR
mPFS
mOS
31% 24% –
13% 19% 12.5%
3.8 4.0 2.7
14.9 8.0 –
PFR: progression-free rate, RR: best response rate, mPFS: median progression free survival (in months), mOS: median overalll survival (in months).
that up to 50% of AS will develop distant metastasis [4–6,14,15,21,22,26,27,30]. The limited number of cases, the retrospective nature of the studies, the heterogeneity of study populations render very challenging the analysis of prognostic factors across the different published series. The most important prognostic factors seem to be the tumor size (with a threshold set at 5 cm in most cases) [6,15,22,26,30], the grade [5,6,22,26,27] and the margin status [5,6,27] (Table 1). Numerous other prognostic factors have been cited: mitotic count [6,22,27], older age [6,22,30], and some particular primary location such retroperitoneal AS [6] or head and neck location [22].
5. Treatment of metastatic disease The most common metastatic site is the lung; nevertheless, any metastatic site is possible [4,5,21]. Pneumothorax is a classical presenting form feature of metastatic scalp AS [22,30]. The median overall survival is about 8–12 months at this stage [5,21]. Until 2008, the literature data consist in numerous case reports. Many case-reports suggest the efficacy of numerous chemotherapy agents (such as liposomal doxorubicin, vinorelbine, and metronomic trosfosfamide) or molecular targeted agents (such as thalidomide, sunitinib, and bevacizumab) [34–38], etc.
5.2. Taxane-based regimens Fata et al. [39] had first reported that 8/9 patients suffering from scalp angiosarcoma achieved a partial response with paclitaxel (175 mg/m2 /3 weeks). The median progressionfree survival was 5 months. Schlemmer et al [40] had reported the EORTC experience with paclitaxel in patients with metastatic angiosarcoma. Different schedules had been used (3 weeks and weekly regimens). The overall response rate was 20/32 with 1 complete response. The median progression-free survival was 7.6 months. The response rate was 6/8 in patients with scalp and skin angiosarcomas compared to 14/24 cases in patients with other primary locations [40]. Numerous case-reports suggest the potential interest of taxanes for the treatment of metastatic or advanced AS, arising in scalp [41] or breast [42]. This had been confirmed by a phase II trial assessing the efficacy of the weekly paclitaxel regimen (80 mg/m3 d1, d8, d15, 21-day cycle) [43]. The response rate is about 20%; but the non-progression rate is about 75% at 3 months and 24% at 6 months. The efficacy is quite similar in chemotherapy-naïve patients and pretreated patients. Three patients with aggressive and locally advanced disease received this regimen provide tumor growing stop in the three cases, allowing a large en bloc resection. In two cases, there is no viable residual cell and in third case, the remaining tumor displays less than 5% of identifiable residual cells (Table 2). This is a specific characteristic of AS since taxanes are clearly ineffective for other histological subtypes of soft tissue sarcoma [44–46].
5.1. Doxorubicin-based regimen Large clinical trials investigating doxorubicin-based regimens in patients with advanced or metastatic soft tissue sarcoma did not usually individualize the outcome of patients with AS. Moreover, there is no large retrospective series reporting the efficacy of doxorubicin-based regimen. Many reports suggest a high rate of objective response with doxorubicin-based regimen but these responses seem to be transient [5,6]. For example, Fury et al. report that the median progression-free survival is 3.7 months with doxorubicin alone (12 patients) and 5.4 months with doxorubicin plus ifofamide combination (7 patients) [5]. Fayette et al. report that doxorubicin or ifosfamide-based regimens provide objective response in 7 out of 17 evaluable patients (26%) [6]. By analogy with other histological subtypes of soft tissue sarcoma, doxorubicin-regimen remains the recommended first-line regimen.
5.3. Molecular targeted therapy area Two recent phase II trials are available (Table 2). Maki et al. had evaluated the efficacy of sorafenib (800 mg/d) in this disease. The response rate is about 13%; the non-progression rate is about 65% at 3 months and 31% at 6 months [47]. The toxicity seems to be less manageable than previously reported with other tumors such as liver or kidney cancers. A dose reduction is necessary in about 60% of patients [47]. Chugh et al. report the efficacy of imatinib (600 mg/d) in patients with advanced or metastatic AS. The response rate is about 12% and the non-progression rate is only 20% at 3 months [48]. Regarding these data, weekly paclitaxel and sorafenib needs further evaluations. Moreover, the publication of these three trials clearly demonstrates that conduct clinical trial in such rare disease is feasible with rapid accrual (about 2 years in the three studies).
N. Penel et al. / Critical Reviews in Oncology/Hematology 80 (2011) 257–263 Table 3 Major remaining questions. Prognostic factors of localized AS Incidence of lymph node involvement at early stage and role of node surgery Efficacy of doxorubicin-based regimens Efficacy of anti-angionetic agents (alone or in combination with chemotherapy) Role of MDR phenotype and beta-tubulin isotypes in paclitaxel resistance Role of pro-angiogenetic growth factor profiles in resistance to kinase inhibitors (sorafenib, imatinib, etc.)
Another ongoing trial investigates the activity of bevacizumab alone (15 mg/kg/3 weeks) in patients advanced angiosarcoma or epithelioid hemangiopericytoma [49]. Some preliminary data have been presented (ASCO Annual meeting in 2009). Twenty-six patients are assessable for response, with 3 partial responses (3–16 cycles) and 13 stable disease (3–22 cycles). But, we do not know the rate of response and non-progression in the subpopulation of patients with angiosarcoma.
6. Perspectives Two points warrant further exploration to better target the AS treatment: mechanisms of drug resistance in AS and/or the role of angiogenetic agents (Table 3). The best understood mechanisms of resistance to paclitaxel in vitro are MDR phenotypes [50] and modification of beta-tubulin isotypes. Moreover MDR phenotypes display cross-resistance to doxorubicin and paclitaxel, two major drugs of the AS treatment. To our knowledge there is no published data exploring the expression of, for instance, Class-III tubulin in AS. Dumontet et al. had demonstrated using an in vitro model that betatubulin isotypes are implied in the sarcoma cell line resistance to paclitaxel [51]. Houghton et al. had shown that vincristine-resistant rhabdomyosarcoma display altered beta-tubulins [52]. The most important recent findings highlight the crucial role of pro-angiogenic growth factors and their receptors in AS [53–62]. in vitro studies have demonstrated that the mRNA and proteins of the following growth factors and receptors are over expressed in AS cellular lines: VEGFA , VEGFC , VEGF-R1 , VEGF-R3 , VPF, FLT-A, KDR (FLK-1), ETS-1 [53–62]. Several couples of V-EGF/V-EGF Receptors seem to be involved at early stage of AS development [55]. Itakura et al. had shown that V-EGF A is overexpressed in 32 out of 34 human AS, VEGFC in 4 out 34 cases, VEGF-R1 in 22 out of 34 cases and V-EGF-R3 in 27 out of 34 cases [57]. Out of these numerous pro-angiogentic factors, vascular permeability factor (VPF) could be of major importance. VPF is a potent inducer of microvascular hyperpermeability, as well as a selective endothelial cell mitogen. VPF interacts with cells by the way of two high affinity receptor tyrosine kinases: flt1 and kdr, both are selectively
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expressed by vascular endothelium. Strong expression of kdr had been reported in two cases of scalp AS [53,62]. Recently Antonescu et al. had shown a strong KDR protein expression in primary breast AS and AS arising in irradiated chest wall [61]. Moreover, 10% of AS display mutations of kdr. Furthermore, in vitro studies have demonstrated that mutated KDR are sensitive to kinase inhibitors [61]. An increasing in the activating phosphorylation of transduction cascade proteins (MAP Kinases) depending of raf have been established in AS. This could be another explanation of sorafenib efficacy in such disease [58]. Lahat et al. have found an overexpression of V-EGF Receptors and the intracellular second messengers (p-AKT, p-4EBP1 and eIF4E) in a series of 68 human AS [63]. These data support further study of the AKT/mTOR pathway inhibitor alone or in combination in the treatment of AS [63]. As previously mentioned some objective responses have been seen with anti-angiogentic agents (see Table 2), and many preclinical data suggest the high frequency of activating mutation of VEGF-R [61], the over-expression of VEGF and then the activation of second messengers [63]. The inhibition of this constitutively activated axis, for example by tyrosine kinase inhibitor or by bevacizumab could play a role in the treatment of AS.
7. Conclusion AS is a rare and heterogeneous sarcoma. The overall prognosis is poor; in a series of 182 non-metastatic soft tissue sarcoma, Singer et al. had described that the histological diagnosis of AS carried with a 13-fold risk of death [64]. Large en bloc surgery following by radiotherapy could be recommended for localized disease. Weekly paclitaxel and sorafenib needs further evaluations. Today, two points needs further studies: (i) analysis of prognostic factors of localized disease in large multicenter database allowing reliable statistical analysis and (ii) estimate the efficacy of doxorubicinbased regimen in large retrospective database and prospective clinical trial. There is a body of evidence to explore the efficacy of anti-angiogentic agents (alone or almost in combination with chemotherapy) in such disease (Table 3).
Reviewer Antoine Italiano, M.D. Ph.D., Institut Bergonié, Department of Medical Oncology, 229 cours de l’Argonne, F-33000 Bordeaux, France.
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Biography Nicolas Penel, M.D. (1999), Ph.D. (2007), is medical oncologist at Oscar Lambret Cancer Center, Lille, France and currently post-doctoral fellow at the EORTC Headquarter. His main clinical expertise field is the treatment of adult soft tissue sarcoma and rare cancers (uveal or mucosal melanoma, chordoma, cancer of unknown primary). His main research field is the methodology of exploratory clinical trials (phases 0, 1 and 2). He is member of ASCO, AACR, French Sarcoma Group, EORTC Soft Tissue and Bone Sarcoma Group and the European New Drug Development Network. Since 1999, he is author or coauthor of more than 100 indexed medical publications. He is study coordinator of 7 clinical trials. The present review had been written during his fellowship at EORTC Headquarters.