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Background: Desmoid tumours/aggressive fibromatosis (DT/AF) are infrequent soft-tissue neoplasms. They usually behave as indolent diseases. However, they may grow locally infiltrating or compressing adjacent structures. The role of local treatment is limited and only a few drugs have shown activity. Cases presentation: We report the outcome of two patients affected by progressive DT/AF treated with the angiogenesis inhibitor pazopanib in two different institutions. Both patients achieved dramatic improvement in their symptoms and radiological signs of response. The clinical benefit lasted for more than 1 year and it is still ongoing. Conclusions: Pazopanib is an active treatment in DT/AF. It is the first time this has been reported. Keywords: Aggressive fibromatosis, Desmoid tumour, Imatinib, Pazopanib, PDGFR, Pegylated doxorubicin, Sorafenib, VEGFR Background systemic treatment should be considered. A widely ac- Desmoid tumours/aggressive fibromatosis (DT/AF) are cepted strategy in first-line setting is hormone treat- rare soft-tissue neoplasms that usually arise from the ment, based on the relatively frequent overexpression of abdomen although extremities are also a common site oestrogen receptors, used in combination with nonste- of presentation [1,2]. They may be associated with genetic roidal anti-inflammatory drugs (NSAIDs) [7,8]. If this conditions such as Gardner’s syndrome . Patients’ treatment proves ineffective, cytotoxic chemotherapy is survival is usually good as DT/AF lack the capacity to a valid alternative. Pegylated liposomal doxorubicin has metastasize although anatomical disease site is important. shown signs of activity although it is not without toxicity Interestingly, the treatment paradigm has changed in the . Several targeted agents have been recently assessed last decade. Aggressive upfront approaches are now under with promising results. The, tyrosine-kinase inhibitor debate since nearly 50% of patients have relatively indolent imatinib has been proven to have activity in phase II disease . Thus, surveillance at initial presentation is studies [10,11]. Also, recent encouraging data with the the current standard of care in most centres. However, antiangiogenic drug sorafenib have been published it may become a symptomatic disease as it can grow where the rate of clinical benefit was very high (70%). In locally infiltrating or compressing adjacent structures . addition, partial response (PR) and stable disease (SD) Surgery is one treatment choice when technically feas- rates were 25% and 70% respectively. Furthermore, 92% ible however rates of recurrence and post-treatment mor- of patients showed features of increased tumour fibrosis bidity are high . Radiotherapy is also an option but and loss of cellularity as demonstrated by an early change there are real concerns surrounding late effects including in MRI T2 signal . These data support further development of second malignancies which is important investigation into the role of antiangiogenic agents in to consider given the young age of most patients. When DT/AF. local treatment with curative intent is not achievable, Pazopanib is one of the latest antiangiogenic drugs de- veloped. It has recently been approved by the U.S. Food * Correspondence: firstname.lastname@example.org and Drug Administration (FDA) and by the European The Royal Marsden Hospital, Sarcoma Unit, Fulham Road, SW3 6JJ London, Medicines Agency (EMA) for the treatment of advanced UK renal cancer and soft-tissue sarcomas (STS). We present Full list of author information is available at the end of the article © 2013 Martin-Liberal et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Martin-Liberal et al. Clinical Sarcoma Research 2013, 3:13 Page 2 of 5 http://www.clinicalsarcomaresearch.com/content/3/1/13 here the first report of clinical activity of pazopanib in DT/AF. These encouraging results might be the initial a step in the development of a new effective therapy this challenging disease. Cases presentation This is the report of the clinical outcome of two patients affected by unresectable DT/AF treated with pazopanib in two different UK institutions: The Royal Marsden Hospital, London and Belfast City Hospital, Belfast. Data were retrospectively collected and imaging was reviewed by a Sarcoma Unit radiologist from The Royal Marsden Hospital. Patient 1 Patient 1 is a female who presented at the age of 42 years with a painful mass in the right axilla. A biopsy showed features consistent with DT/AF. The patient did not have personal or family history of Gardner’s syndrome or colonic polyps. Surgical resection was performed in two occasions but residual disease remained. As the pain in the axilla increased, treatment with tamoxifen 40 mg once daily (od) was initiated one year after the second surgery. However, there was an increase in the size of the mass and worsening of symptoms in the form of restricted movement and neuropathic pain, so pegylated liposomal doxorubicin was advised. Unfortunately, chemotherapy had to be stopped after one cycle due to an allergic Figure 1 Axial T2 weighted MRI images of the thorax at reaction. Subsequent treatment with methotrexate and baseline (a) and following 10 months of pazopanib (b). A large vinblastine was given. Symptoms were stabilized although plaque of fibromatosis encases the lateral right hemithorax the patient experienced disabling toxicities such as severe extending into the axilla. Although the disease remained constipation and neuropathy. After five months, an MRI dimensionally stable the lateral component (arrows) demonstrated showed progressive disease (PD), the tumour measuring T2 signal drop from intermediate to low indicating a reduction in cellularity. 15 × 5.9 cm. At this point, treatment with pazopanib 800 mg od was started. Shortly afterwards, the patient developed remained stable in size but with T2 changes in MRI hypertension, dysgeusia and mild palmar erythema so suggestive of response for nearly eighteen months. The the dose was reduced to 600 mg od. After two months, clinical benefit has been very clear and in particular the patient reported a significant improvement in her pain is well controlled, which was the main factor pain. Analgesic requirements were dramatically reduced impairing the patient’s quality of life. and an MRI showed no changes in size but a significant reductionintumourT2signalintensity,suggesting Patient 2 reduction in cellularity. Six months after starting pazo- Patient 2 is a female who presented at the age of 16 years panib, a further dose reduction due to diarrhoea was with a painful left axillary mass. The histological analysis needed (400 mg od). At that time, a second assessment was consistent with DT/AF. The patient did not have a MRI showed maintained SD and the drop in T2 signal in- history of Gardner´s syndrome or colonic polyps. Incom- tensity compared to baseline remained suggesting contin- plete resection was performed and for the following ten ued response (Figure 1). In the following months, further years the patient remained asymptomatic. After that time, toxicities appeared: skin rash, peripheral neuropathy and she developed pain and impairment in the abduction of worsening hypertension, dysgeusia and diarrhoea. These her left arm. An MRI confirmed tumour recurrence, with side effects led to a further dose reduction to 200 mg od involvement of the triceps and inferior deltoid muscles. and optimization of supportive treatment. Surgery was not advised and the patient was started on The patient is currently tolerating pazopanib without systemic treatment with high dose NSAIDs; three months significant side effects. Furthermore, her tumour has on MRI scan showed no significant changes and limitation Martin-Liberal et al. Clinical Sarcoma Research 2013, 3:13 Page 3 of 5 http://www.clinicalsarcomaresearch.com/content/3/1/13 in the abduction of the arm persisted. After one year of regained an almost complete range of movement in treatment, the patient became pregnant and treatment her arm. was discontinued. Unfortunately, shortly after the One year after her last operation, an MRI showed two symptoms dramatically worsened. Pegylated liposomal new sites of disease. These findings were associated with doxorubicin was initiated when the patient was in the worsening of the pain in spite of NSAIDs. Tamoxifen, to- third trimester of her pregnancy but with no radio- gether with continuation of high dose NSAIDs, was then logical nor symptomatic benefit. As there were con- prescribed. Six months on, further tumour growth and tinued significant limitations in arm movement, the worsening symptoms suggested that the treatment was patient was very keen to pursue further treatment. ineffective. Therefore, tumour resection followed by radiotherapy A new line of treatment with pazopanib 800 mg od was performed. After these procedures, the patient was started. After two weeks of treatment, significant Figure 2 Axial T2 weighted and coronal STIR MRI images of the proximal left arm at baseline (a and b) and following 11 months of pazopanib (c and d). A large focus of fibromatosis expands the triceps muscle and following 11 months of treatment reduced in size from 10.2 cm in maximum craniocaudal dimension to 8.0 cm. Predominantly intermediate/high signal tissue (a and b, arrows) showed a marked reduction in signal (c and d, arrows) indicating diminished cellularity. Martin-Liberal et al. Clinical Sarcoma Research 2013, 3:13 Page 4 of 5 http://www.clinicalsarcomaresearch.com/content/3/1/13 improvement of the pain was noticed. Moreover, the nature of this report and the small number of patients first assessment MRI after three months demonstrated this observation clearly needs to be confirmed in prospect- reduction in tumour size (from 10.2 × 4.2 cm at baseline ive studies. Thus, the French Sarcoma Group is currently to 9×3.1cm).Mild diarrhoeaand fatiguewerethe only conducting a phase II trial that assesses the efficacy and side effects. Subsequent MRIs showed further tumour tolerance of pazopanib in DT/AF (ClinicalTrials.gov shrinkageand reduction inT2signal(Figure 2).In identifier NCT01876082). This encouraging novel strat- addition, mobility of patient’s left arm progressively im- egy deserves further investigation. proved. The patient remains on full dose of pazopanib without significant toxicities and with ongoing clinical and Consent radiological benefit more than one year since starting Written informed consent was obtained from the patients pazopanib. for publication of this Case Report and any accompanying images. Copies of the written consents are available for Conclusions review by theEditor-in-Chiefofthisjournal. This report demonstrates for the first time that pazopanib Competing interests is an active treatment in DT/AF. The authors declare that they have no competing interests. The lack of effective therapeutic options and its high morbiditymakeDT/AF achallenging disease. The Authors’ contributions JML, CB, HM and IJ contributed to the conception, design and drafting of promising results observed with sorafenib suggested the manuscript. CM carried out the radiological evaluation. KT performed the that angiogenesis might play an important role in this histopathological analyses of the tumours. CB and IJ coordinated the condition . Although DT/AF is not strictly consid- manuscript drafting. All authors read and approved the final manuscript. ered a malignancy, the mechanisms that lead to uncon- Author details trolled monoclonal cellular proliferation and survival The Royal Marsden Hospital, Sarcoma Unit, Fulham Road, SW3 6JJ London, are similar to those in cancer . Angiogenesis is one UK. Belfast City Hospital, Lisburn Road, BT9 7AB Belfast, UK. of the most important processes in carcinogenesis and Received: 12 November 2013 Accepted: 21 November 2013 its relevance in soft-tissue tumours has also been dem- Published: 26 November 2013 onstrated . Several studies confirm the key role of some of its effectors such as the vascular endothelial References 1. Alman BA, Pajerski ME, Diaz-Cano S, Corboy K, Wolfe HJ: Aggressive growth factor (VEGF) and the different isoforms of its fibromatosis (desmoid tumor) is a monoclonal disorder. Diagn Mol Pathol receptor (VEGFR) [15-19]. 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Clinical Sarcoma Research – Springer Journals
Published: Nov 26, 2013
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