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AGGRESSIVE FIBROMATOSIS TREATMENT Imatinib challenges Literature review

AGGRESSIVE FIBROMATOSIS TREATMENT Imatinib challenges Literature review. Gordana Damjanovska ¹, Nikola Labacevski² ¹REPLEK FARM Ltd, g_damjanovska@yahoo.com ²Institute for preclinical and clinical pharmacology and toxicology, Medical faculty, University”St Ciryl and Metodius”,.

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AGGRESSIVE FIBROMATOSIS TREATMENT Imatinib challenges Literature review

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  1. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challengesLiterature review Gordana Damjanovska ¹, Nikola Labacevski² ¹REPLEK FARM Ltd, g_damjanovska@yahoo.com ²Institute for preclinical and clinical pharmacology and toxicology, Medical faculty, University”St Ciryl and Metodius”,

  2. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • INTRODUCTION • WHO Definition: ” Clonal fibroblastic proliferations that arise in the deep soft tissues and are characterized by infiltrative growth and a tendency toward local recurrence but an inability to metastasize” • Incidence and prevalence • Aetiology • Molecular issues • Clinical presentation • Diagnosis/DD • Treatment

  3. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • PURPOSE Purpose of this review was to overview effectiveness of treatment options for AF and the role of imatinib mesylate (Glivec™; Novartis), in AF that has been accumulated over the past decade.

  4. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • MATERIAL AND METHODS • Review and analysis of all available data on the topic AF in the English language literature. • Search of the electronic databases PubMed/ Medline for published trials, studies and series. • Keywords ‘desmoid tumors’ ‘aggressive fibromatosis treatment’, and ‘imatinib’ • Cross-referencing used in addition to the computerised searches. • Inclusion criteria : information about patients’ age and sex, tumor status (primary versus recurrent), previous therapy, type of therapy, response and duration of response.

  5. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • RESULTS • SURGERY • Mainstay treatment for patients with primarily resectable and localized tumors: R0 resection. • R0 resection is not always possible • Nuytens et al. tumor-free and tumor-positive margins, local control rates of 94% and 75% • Bonvalot et al. R0 debated: long-term follow-up of 89 patients-event-free survival ratebetween R0 and nonsurgical treatment similar • despite the use of surgery 20–36% of patients will show local recurrence • spontaneous regressions reported supporting wait-and-see policy after resection without wide margins

  6. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • RESULTS • RADIOTHERAPY • Treatment as adjuvant therapy to surgery not R0 or as primary therapy for unresectable tumors. • Nuytens et al. Comparative review of 22 articles(1983-1998): s/s+rt/rt: local control rate: 61%, 75%,78%. RT(10-75Gy)-780 patients • Complication rate - 22.8%, fibrosis, malignancy • Gluck et al. Retrospective study( 1984-2008)-95 patients: s/s+rt/rt equivalent local control rates • Novel approach: preoperative rt • EORTC pilot study 62991- 40 AF patients- 56 Gy

  7. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • RESULTS • NONCYTOTOXIC AGENTS • Antiinflamatory agents • NSAIDs alone or with hormonal agent • NSAIDs inhibit prostaglandin production, which interferes with β-catenin/TCF-dependent transcription • Pharmacologic blockade of COX 2 resulting in decreased cell proliferation in desmoid cell cultures • Hansmann et al. Sulindac or Indomethacin, demonstrated 37%–57% positive responses(PR, CR, SD) • Tsukada et al. -14 patients Sulindac- 57% positive response • Francis et al.- 16 patients Cereblex + Tamoxifen-50% positive response • Nishida et al. -20 patients Meloxicam 10mg daily – 95% positive response(CR 4,5 % PR 32%, SD 45%).

  8. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • RESULTS • NONCYTOTOXIC AGENTS • Hormonal agents • Antiestrogen binding sites modulating or mediating the action of antiestrogens • Tamoxifen 20-80mg daily: PR or SD in many case reports • Hansmann Aet al. - 25 patients Tamoxifen 120-200mg +Sulindac 300mg daily- 52% positive response • Higher doses: risk for second cancers and deep venous thrombosisalone or with hormonal agent • Brooks et al.- 20patients Toremifene 200mg daily- 50 % positive response • Waddell and Kirsch- 17 patients Testolactone 750mg daily – 40% positive response.

  9. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • RESULTS • CYTOTOXIC AGENTS • Appropriate choice for unresectable, rapidly growing highly symptomatic and/or life-threatening desmoid tumor • Garbay et al. Several combination chemotherapy regimens are active with DOX, lDOX, DTIC, IFO, and MTX plus VNR, VCR,VBL producing significant responses ranging from 50% to 80% (partial responses or stable disease for at least 6 months) • Constantinidou A at al.-12 patients LDOX 50mg/m2 -33%PR, 58%SD • Camargo et al. -35 patients Anthracyclines comb.- 37%PR, 51% SD • Azarrelli et al. -27 patients MTX + VBL- 15%PR, 70% SD • Cumulative toxicity, slow response( 12-18 mth treatment)

  10. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • RESULTS • IMATINIB • Imatinib mesylate is a selective protein-tyrosine kinase inhibitor that inhibits the bcr-abl tyrosine kinase and is also an inhibitor of other class 3 receptor tyrosine kinases: receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF),c-kit (CD117), and inhibits PDGF and SCF mediated cellular events. Lately it was reported that imatinib inhibits macrophage-colony stimulating factor receptor (M-CSFR) too. This agent blocks ligand activated receptor phosphorylation and mitogen-activated kinase activation and proliferation, resulting in the inhibition of cellular growth and proliferation.

  11. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • STUDIES • Mace at al. 2002 reported two patients dramatic responses to imatinib, amputation as final surgical solution avoided. • Several case reports with positive responses to imatinib 400-600mg daily in patients pretreated with recurrent AF • Heinrich et al. 2006- 19 patients imatinib 800mg daily- 15.7% PR, 21% SD. • Heinrich et al. 2008 - Phase II, open-label study 20 patients imatinib 800mg daily: 10%PR, 40% SD. • Chugh R et al. 2010- SARC Phase II Multicenter trial - 51 patient imatinib 200-600mg daily: 6% PR, 17.6% SD • Penel et al.2011- FNCLCC/French Sarcoma Group phase II trial – 40 patients 400mg imatinib daily: 2,9%CR, 8,6%PR, 80%SD

  12. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • IDENTIFICATION OF THE MOLECULAR BASIS OF RESPONSE/NONRESPONSE TO IMATINIB: expression/ mutation of c-Kit, PDGFR-A, PDGFR-B • Heinrich et al. 2006- 19 patients- not found any mutations of c-KIT, PDGFR-A, or PDGFR-B • Heinrich et al. 2008 - 20 patients- all c-kit negative and PDGFR-B positive • Chugh R et al. 2010- 51 patients- immunohistochemical positivity for c-kit, PDGFR-a, PDGFR-b, AKT, phosphatase and beta-catenin, and slight mutational changes for c-kit, PDGFR-a, PDGFR-b and beta-catetin. • Penel et al.2011- 40 patients-currently performing biological studies on plasma

  13. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challengesTable 1. Imatinib treatment in patients with AF

  14. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challengesTable 2. Immunohistochemistry/immunoblotting evaluations

  15. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • DISCUSION AND CONCLUSION • Reviewed literature included case reports, case series, retrospective studies and several small phase II trials. According to the review NSAIDs treatment performed positive response range of 37%-57%, COX 2 treatment (Meloxicam) up to 90% response, treatment with hormonal agents response ratio between 40%-50%, positive responses for chemotherapy against AF of almost 50% and response rate for Imatinib ~10%. • Reviewed literature presents evidence that citotoxic and non-citotoxic systemic therapies other that surgery are effective against AF.

  16. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • However several questions need to be answered: • which is the most suitable treatment at certain AF condition, • what is the optimal dose and duration of treatment since the lack of sufficient patient numbers and randomized trials compromises the validity of the reported results. • Main issue that has to be processed is stronger validation of results by further investigation with properly designed prospective studies including larger patient numbers, with main end points to include not only tumor response rate and survival but also quality-of-life issues.

  17. AGGRESSIVE FIBROMATOSIS TREATMENTImatinib challenges • DISCLOSURE • Authors declare no conflicts of interest • ACKNOWLEDGEMENTS • Todo Sobre Mi Madre • REFERENCES

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