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Originally published as JCO Early Release 10.1200/JCO.2008.17.3146 on September 22 2008 © 2008 American Society of Clinical Oncology. Phase II Trial of Weekly Paclitaxel for Unresectable Angiosarcoma: The ANGIOTAX Study
From the Département de Cancérologie Générale, Unité de Biostatistiques, and Département d’Imagerie Médicale, Centre Oscar Lambret; Equipe d’Accueil 2694, Santé Publique, Epidémiologie et modélisation des maladies chroniques, Université Lille II, Lille; Département d’Oncologie Médicale, Institut Bergonié, Bordeaux; Département d’Oncologie Médicale, Centre Jean Perrin, Clermont-Ferrand; Département d’Oncologie Médicale, Centre Val d’Aurelle, Montpellier; Département d’Oncologie Médicale, and Unité L’Institut National de la Santé et de la Recherche Médicale 590, Centre Léon Bérard; Service d’Oncologie Médicale, Hôpital Edouard Herriot, Lyon; Département d’Oncologie Médicale, Institut Curie; Bureau des Etudes Cliniques et Thérapeutiques, Fédération Nationale des Centres de Lutte Contre le Cancer, Paris; Département d’Oncologie Médicale, Centre Eugène Marquis, Rennes; Département d’Oncologie Médicale, Centre Georges-François Leclerc, Dijon; Département d’Oncologie Médicale, Centre Antoine Lacassagne, Nice; Département d’Oncologie Médicale, Institut Claudius Regaud, Toulouse; Département d’Oncologie Médicale, Centre René Gauducheau, Nantes; and the Département d’Oncologie Médicale, Centre René Huguenin, Saint-Cloud, France Corresponding author: Nicolas Penel, MD, Département de Cancérologie Générale, Centre Oscar Lambret, 3 rue Frédéric Combemale, 59020, Lille, France; e-mail: n-penel{at}o-lambret.fr
Purpose The objective of this phase II trial was to assess the efficacy and toxicity of weekly paclitaxel for patients with metastatic or unresectable angiosarcoma. Patients and Methods Thirty patients were entered onto the study from April 2005 through October 2006. Paclitaxel was administered intravenously as a 60-minute infusion at a dose of 80 mg/m2 on days 1, 8, and 15 of a 4-week cycle. The primary end point was the nonprogression rate after two cycles. Results The progression-free survival rates after 2 and 4 months were 74% and 45%, respectively. With a median follow-up of 8 months, the median time to progression was 4 months and the median overall survival was 8 months. The progression-free survival rate was similar in patients pretreated with chemotherapy and in chemotherapy-naïve patients (77% v 71%). Three patients with locally advanced breast angiosarcoma presented partial response, which enabled a secondary curative-intent surgery with complete histologic response in two cases. One toxic death occurred as a result of a thrombocytopenia episode. Six patients presented with grade 3 toxicities and one patient presented with a grade 4 toxicity. Anemia and fatigue were the most frequently reported toxicities. Conclusion Weekly paclitaxel at the dose schedule used in the current study was well tolerated and demonstrated clinical benefit.
Angiosarcomas represent a rare type of visceral and soft tissue sarcoma, accounting for less than 2% of all visceral and soft tissue sarcomas.1,2 Various clinical forms have been described include primary angiosarcoma of the scalp,3 angiosarcoma associated with lymphedema,4,5 primary breast angiosarcoma,6,7 angiosarcoma arising in irradiated areas,6-8 and vinyl chloride–induced liver angiosarcomas.9 These clinical presentations share an aggressive behavior, leading to a short median survival (15 to 30 months) with a less than 12% survival rate at 5 years.1,6-9 Recently, a retrospective study has suggested the efficacy of paclitaxel in the treatment of primary angiosarcoma of the scalp,3 with an objective response reported in eight of nine patients and a median progression-free survival of 5 months. This objective response rate seemed to be superior to the results previously obtained with doxorubicin-based chemotherapy.3 Moreover, weekly paclitaxel demonstrated significant activity on Kaposi's sarcoma, another vascular-derived tumor.10,11 The mode of action of paclitaxel involves the stabilization of microtubules through the inhibition of the depolymerization process.12,13 This inhibition of depolymerization is observed during the metaphase/anaphase transition of mitosis.12 Paclitaxel exhibits a wide spectrum of antitumoral activity, including breast cancers (even those refractory to anthracyclines), lung cancers, squamous cell carcinomas of the upper respiratory/digestive tracts, stem cell tumors, lymphomas, and Kaposi's tumors.13-20 Weekly administration of paclitaxel induces a clear increase in dose-intensity, without significant enhancement of toxicity, for fragile or heavily pretreated patients with ovarian,16,17 lung,18,20 or gastric cancers.19 Therefore, we conducted a multicenter phase II trial to assess the efficacy and toxicity of the weekly paclitaxel regimen in patients with metastatic or unresectable angiosarcomas.
Study Population and Eligibility Criteria The patients considered for this study were required to be 18 years of age and older. All had histologically proven metastatic or advanced angiosarcomas, reviewed within the pathology committee of the French Sarcoma Group, and were not amenable to radiotherapy or curative-intent surgery. Angiosarcomas not amenable to curative-intent surgery after multidisciplinary decision making were considered to be locally advanced and unresectable and could be included in the present trial. Any prior systemic therapy for angiosarcoma was allowed. Measurable or assessable disease with computed tomography scan or magnetic resonance imaging was required as per Response Evaluation Criteria in Solid Tumors (RECIST).21 Additional inclusion criteria were as follows: WHO performance status  2 and weight loss of less than 20% of body weight before illness, adequate contraception during treatment, adequate hematologic function (granulocytes > 1,500/µL and platelet count > 100,000/µL), adequate liver function (total bilirubin < 3x the upper limit of normal, ALT and AST < 2.5 x the upper limit of normal), adequate renal function (calculated creatinine clearance > 60 mL/min), normal cardiac function (left ventricular ejection fraction  50%). Regarding angiosarcomas arising in irradiated fields, inclusion is allowed when there is any clinical argument suggesting a possible evolution of the prior cancer treated by radiotherapy. All patients signed an informed consent form approved by the ethics review committee of Lille University (date of approval by Lille Comité Consultatif de Protection des Personnes se Prêtant à la Recherche Biomédicale (CCPPRB): December 20, 2004). Exclusion criteria included the following: pregnant or breast-feeding women, patients already treated with more than two lines of chemotherapy, Kaposi's sarcoma or positive HIV serology, hepatic failure, known allergy to paclitaxel or cremophor, or a severe underlying comorbid disease that could alter compliance.
Study Design
Study End Points and Data Analysis During the study, patients underwent clinical, hematologic, and biologic evaluations at days 1, 8, and 15 of each cycle. Disease was assessed by comparing unidimensional tumor measurements (computed tomography scan or magnetic resonance imaging) on pre- and peritreatment imaging studies after two, four, and six cycles and every 3 months thereafter. We assessed the response according to RECIST.21 An independent third-party radiologist panel reviewed selected imaging studies to verify all imaging performed during the treatment period with the trial drug to ensure consistent, unbiased application of RECIST.
The number of patients was initially calculated using a Minimax two-stage design (P0 = 10%, P1 = 30%, The Kaplan-Meier method was used to calculate the time to progression and survivals.23 Objective response was assessed among the assessable population (n = 27); overall survival and progression-free survival were both defined from the start of treatment to the date of death or to the date of the last follow-up for overall survival, and to the date of disease progression or death, or censored at the last follow-up for progression-free survival. Both were assessed among the intent-to-treat population (n = 30).
Ethical Considerations
Patient Characteristics From April 2005 to October 2006, 30 patients (19 women and 11 men) were enrolled onto the study in 12 centers. All were eligible. Pretreatment characteristics of the 30 patients are summarized in Table 1. The median age of the study population was 67 years (range, 23 to 85 years), and the median performance status was 1. Distant metastases were observed in 22 cases (74%). Eight nonmetastatic cases were considered as locally advanced and unresectable after multidisciplinary decision making. The median time between the diagnosis of angiosarcoma and the inclusion in this trial was 3.8 months. Fédération Nationale des Centres de Lutte Contre le Cancer grading was available in 28 patients; 13 (43%) of 30 tumors were grade 3 tumors, whereas 10 tumors (33%) were grade 2 and five tumors (17%) were grade 1. Primary tumors sites were visceral in eight patients (three in liver, two in kidney, one in small bowel, one in bone, and one in penis) and from soft tissue, skin, or scalp in 22 patients. In 10 patients (33%), tumors arose from breast (skin in nine patients and mammary gland in one patient). Ten tumors arose in irradiated fields: in breast skin or in the chest wall after treatment of previous breast adenocarcinoma in nine patients and in subclavicular and axillary areas after treatment of previous head and neck squamous cell carcinoma in one patient. Eleven patients (36%) had received previous first-line anthracycline-based chemotherapy. Two patients had previously received second-line systemic chemotherapy before inclusion.
Safety and Toxicity A total of 102 cycles of chemotherapy were administered. The median number of cycles was three (range, one to six cycles); 26 patients received at least two cycles. Dose reduction and treatment delays were necessary for three and five patients, respectively. Excluding four patients who did not receive at least two cycles, the mean dose-intensity was 53.4 mg/m2/wk (standard deviation = 5.9). The relative dose-intensity was 89%. Table 2 lists the maximum toxicity observed per patient. Severe toxicity was observed in two patients within the first two cycles (two cases of febrile neutropenia, with CNS toxicity in the older patients). There was one toxic death owing to thrombocytopenia in a context of general condition deterioration.
Efficacy The response rates after two, four, and six cycles are summarized in Table 3. The nonprogression rate after two cycles was 74% (95% CI, 57% to 90%). With a median follow-up of 8 months, the median time to progression was 4 months (Fig 1). The median overall survival was 8 months. The overall survival rates at 6, 12, and 18 months are, respectively, 56%, 38%, and 21% (Fig 1).
Five patients (18.5%) of 27 assessable patients had a partial response after two cycles, three of those patients with locally advanced angiosarcomas of breast skin were considered amenable to curative-intent surgery. These three patients were considered by a multidisciplinary committee as having disease that was not amenable to curative-intent surgery before paclitaxel treatment because the lesions were multifocal, locally extensive, and rapidly growing. Two of these patients had a complete histologic response (Table 4). The third patient presented a clinical partial response but had persistent disease at histologic analysis. The nonprogression rates after two cycles (10 of 13 v 10 of 14) and the median overall survival (P = .37 with log-rank test) were similar in patients pretreated with chemotherapy and in chemotherapy-naïve patients.
We report herein the first prospective multicentric phase II clinical trial for metastatic or locally advanced angiosarcoma. This study establishes the efficacy of weekly paclitaxel as a treatment for metastatic or locally advanced angiosarcoma. After independent radiologic review, the nonprogression rate was 74% at 2 months (95% CI, 57% to 90%) and 42% at 4 months (95% CI, 21% to 64%). Five patients had an objective response and three patients with locally advanced disease presented objective response and therefore were amenable to curative-intent surgery, with two complete histologic responses and long disease-free survival (17 and 19 months). Toxicity was manageable and expected (Table 2). The median time to progression was 4 months, and overall survival was 7.6 months. These results were observed in an unfavorable population with poor prognosis factors:5-8 eight patients had primary tumors arising from viscera, 10 patients had primary tumors arising from irradiated fields, 11 patients had previously received anthracycline-based chemotherapy, and the median age was 67 years. The schedule proposed in this study was evaluated in other indications, with similar adverse effect profile.17-20 Weekly administration may enable the improvement of the therapeutic index and reduce toxicities in fragile or heavily pretreated patients. Some previous retrospective studies suggested the efficacy of paclitaxel in patients with angiosarcomas, especially face and scalp angiosarcomas.3,24-26 Fata et al3 reported eight objective responses in nine scalp angiosarcomas treated with paclitaxel 170 mg/m2. Skubitz et al24 reported five objective responses in eight patients treated with different paclitaxel schedules. Other antiangiogenic treatments such as thalidomide27 and metronomic chemotherapy28 have also induced objective responses in advanced angiosarcomas. This scientific literature data and the present findings support the activity of antiangiogenic therapies in a subset of different clinical forms of angiosarcomas. This study has some limitations. Given the lack of previously published clinical trials on angiosarcomas, it was conducted as a one-step phase II study including 30 patients. Angiosarcomas are heterogeneous by nature, and the efficacy of this regimen could be variable in the different types of angiosarcomas (eg, visceral angiosarcomas v others; breast angiosarcoma v other visceral angiosarcomas, de novo breast angiosarcomas v radiation-induced angiosarcomas); unfortunately, subgroup analysis is not feasible with this small sample size. Nevertheless, the survival of patients with grade 3 tumors (Fig 2A; P = .58) and radiation-induced angiosarcomas (Fig 2B; P = .11) was similar to that of other angiosarcomas. Moreover, because of the heterogeneous nature of angiosarcomas, especially regarding anatomic locations of primaries, the definition adopted in this study for locally advanced could be debated in different research groups. We had considered as locally advanced the cases that were deemed to be not amenable to curative-intent surgery after multidisciplinary decision making. By default, we could not provide more precise surgical or anatomic definition because of the different possible primary sites. The concept of nonresectability in sarcoma is complex and may vary with the expertise of the centers. However, we chose this definition to be pragmatic, based on the center's decision, as in routine practice.
The mode of action of weekly paclitaxel in patients with unresectable angiosarcomas remains unclear. Paclitaxel is not considered an active agent in other types of sarcomas. However, this drug is also effective in patients with Kaposi's sarcoma, another vascular-derived tumor.10,11 In vitro, microtubule-targeted drugs such as paclitaxel exhibit potent antiangiogenic activity at a low-dose concentration.12,29,30 Pasquier et al29 characterized two distinct effects of paclitaxel on human endothelial cells: cytostatic effects at low concentrations and cytotoxic at high concentrations. The cystostaxic effect of paclitaxel is associated with increases in the mitochondrial membrane potential, p53 expression, and modification of the Bax/Bcl-2 ratio,29 whereas the cytotoxic effect involves an inhibition of endothelial cell proliferation without apoptosis induction and without any structural modification of the microtubule network.29 Angiosarcoma thus represents a valid model to investigate angiogenesis inhibitors. Doxorubicin-based chemotherapy remains the treatment of choice in metastatic soft tissue sarcomas.31-34 Nevertheless, it is becoming increasingly clear that histologic subtypes differ in their susceptibility to chemotherapy and that treatment strategy should therefore be tailored according to histologic subtypes.31,33 For example, aggressive fibromatoses are particularly sensitive to imatinib mesylate,35,36 myxoid liposarcomas to ecteinascidin,37 synovial sarcoma to ifosfamide,38 leiomyosarcomas to gemcitabine combined with docetaxel,39 rhabdomyosarcomas to cyclophosphamide and vinorelbine,40 and so on. In three previous phase II trials, paclitaxel seemed to be totally ineffective in patients with metastatic sarcoma when they are considered as a homogeneous group.25,41,42 Now, phase II trials not taking into account the heterogeneity of sarcomas may yield to inappropriate conclusions if, for example, a rare sensitive subtype is minimally presented in a phase II trial.34 Stratified phase II studies of histologic subtypes or of the expression of biologic targets are now needed to show the potential activity of one drug for one histologic subtype.31,33 In conclusion, weekly paclitaxel seems to be an effective and well-tolerated treatment for patients with unresectable angiosarcoma and constitutes a good comparator for further clinical trials.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Binh Nguyen Bui, Novartis (C), PharmaMar (C) Stock Ownership: None Honoraria: None Research Funding: Isabelle Ray-Coquard, Merck Sereno; Jean-Yves Blay, Novartis, Pfizer Expert Testimony: None Other Remuneration: None
Conception and design: Nicolas Penel, Charles Fournier, Marta Jimenez, Jean-Yves Blay Financial support: Marta Jimenez Administrative support: Marta Jimenez Provision of study materials or patients: Nicolas Penel, Binh Nguyen Bui, Jacques-Olivier Bay, Isabelle Ray-Coquard, Sophie Piperno-Neumann, Pierre Kerbrat, Nicolas Isambert, Frédéric Peyrade, Emmanuelle Bompas, Etienne G.C. Brain, Jean-Yves Blay Collection and assembly of data: Charles Fournier, Marta Jimenez Data analysis and interpretation: Nicolas Penel, Charles Fournier, Sophie Taieb, Jean-Yves Blay Manuscript writing: Nicolas Penel, Charles Fournier, Marta Jimenez, Jean-Yves Blay Final approval of manuscript: Nicolas Penel, Binh Nguyen Bui, Jacques-Olivier Bay, Didier Cupissol, Isabelle Ray-Coquard, Sophie Piperno-Neumann, Pierre Kerbrat, Sophie Taieb, Marta Jimenez, Nicolas Isambert, Frédéric Peyrade, Christine Chevreau, Emmanuelle Bompas, Etienne G.C. Brain, Jean-Yves Blay
The following centers participated in this study: Centre Oscar Lambret, Lille (five patients); Institut Bergonié, Bordeaux (five patients); Centre Jean Perrin, Clermont-Ferrand (four patients); Centre Val d’Aurelle, Montpellier (four patients); Centre Léon Bérard, Lyon (three patients); Institut Curie, Paris (two patients); Centre Eugène Marquis, Rennes (two patients); Centre Antoine Lacassagne, Nice (one patient); Institut Claudius Regaud, Toulouse (one patient); Centre René Huguenin, Saint-Cloud (one patient); Centre Georges-François Leclerc, Dijon (one patient); and Centre René Gauducheau, Nantes, France (one patient).
We thank the Fédération Nationale des Centres de Lutte Contre le Cancer (Céline Mahier-Aït Oukhatar, Patricia Nezan, Carole Delavault, and Jean Genève). We also thank the independent data monitoring committee members (Martine Van Glabbeke, Axel Le Cesne, and Laurent Mignot) and Jean-Pierre Meurant and Elodie Desrennes for data management.
published online ahead of print at www.jco.org on September 22, 2008. Supported by La Ligue National Contre le Cancer, Mayne Pharma France, and Chugai Pharma France. Presented in oral format at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-4, 2007, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= 5%, 1-β = 80%). Planned accrual was 25 assessable patients. The second stage was allowed if at least one response of 15 patients was observed in the first stage. At the end of the second stage, the treatment will be considered effective if at least six responses are observed.
