Desmoid final
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1) Aggressive fibromatosis is a rare soft tissue tumor that typically affects young adults. Surgery is the main treatment but recurrence is common. 2) New evidence shows systemic therapies like sorafenib, hormonal therapies, and chemotherapy can control the disease. A large trial found sorafenib significantly reduced recurrence compared to placebo. 3) Further research is still needed to determine optimal chemotherapy regimens and biomarkers to predict response to various treatments. "Wait and watch" may be suitable for less aggressive cases. Management of fibromatosis remains challenging due to the lack of high-quality data from India and validated patient-reported outcome measures.
Desmoid final
- 1. Aggressive Fibromatosis (desmoid) – Recent advances and the evidence Dr Sameer Rastogi Assistant Professor, Medical Oncology(Sarcoma Clinic) AIIMS, New Delhi Email- [email protected]
- 2. Why this topic? • No takers for the disease being extremely rare 1 in million! • Happens in young adults and typically coincides with the time of independent living • Pain, deformity, contractures in extremity and rest depends upon sites • Long term opioid use, isolation, depression, interruption of education, employment 1 J Clin Oncol 2017; 35: Suppl: 11022. abstract.
- 3. Epidemiology of fibromatosis • Age Group – 15 to 60 years (peak age 30-40 years) • Female predominance – 2 to 3 folds • Desmoid type fibromatosis develops in 5 to 30% of patients of FAP 1,2 • FAP asscociated desmoid accounts for 2-10% of all Desmoids 1.Desmoid tumors characterization of patients seen at Mayo Clinic 1976-1999. Fam Cancer. 2006;5(2):191-194. 2.A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses. Int J Cancer. 2011;129(1):256-261.
- 4. • With aggressive follow up and in those receiving prophylactic colectomy, DTF has been reported to be the most common cause of death
- 6. Aggressive fibromatosis and the evidence • Molecular Biology • Pathology and molecular testing relevance • Treatment options • Surgery • Wait and watch • Hormonal/ tyrosine kinase/ chemotherapy • IRCH Data
- 7. Biology and treatment of Aggressive fibromatosis Mayo Clin Proc. n June 2017;92(6):947-964
- 8. Mayo Clin Proc. n June 2017;92(6):947-964
- 9. Aggressive fibromatosis and the evidence • Molecular Biology • Pathology and molecular testing relevance • Treatment options • Surgery • Wait and watch • Hormonal/ tyrosine kinase/ chemotherapy • IRCH Data
- 10. Diagnosis • Histopathology confirmation mandatory by expert soft tissue pathologist1 • On immunostaining – • Nuclear accumulation of β catenin (though non specific) • 85-90% harbor mutations in β catenin gene leading to accumulation of β catenin in nucleus. 1. Eur J Cancer 2016; 58: 90–96.
- 11. β catenin Courtesy – Dr Rimli/ Dr Adarsh Barwad
- 12. 8 year old boy progressing to tam/celecoxib/ surgery β catenin negative fibromatosis Courtesy – Dr Rimli/ Dr Adarsh Barwad
- 13. Molecular analysis • Activating mutation in CTNNB1 must be done in all the cases if there is doubt about the diagnosis or in equivocal cases. • β catenin and APC mutation are mutually exclusive • Negative β catenin in desmoid should raise the suspicion of familial or some other diagnosis • T41A and S45F are by far the most common mutations in DF accounting for roughly 50% and 25%, respectively S45P is the third most common mutation at around 9% • In 4 independent series S45F has been shown to be independent factor for the recurrence. Annals of Oncology 28: 2399–2408, 2017 Am J Pathol 2008; 173: 1518–1527 Br J Cancer 2010; 102: 1032–1036.
- 14. Aggressive fibromatosis and the evidence • Molecular Biology • Pathology and molecular testing relevance • Treatment options • Surgery • Wait and watch • Hormonal/ tyrosine kinase/ chemotherapy • IRCH Data
- 15. Options in treatment of fibromatosis • Surgery • Wait and watch • Systemic hormonal therapy and NSAIDs • Tyrosine kinase inhibitors – imatinib, sorafenib and pazopanib • Chemotherapy methotrexate, vbl, doxorubicin
- 16. Treatment for fibromatosis • Primary surgery – Eurpean consensus – EORTC, SPAEN, STBSG Annals of Oncology 28: 2399–2408, 2017 Clinical Cancer Research 2011
- 17. Why STS paradigm might not fit-- • Margin positivity is of doubtful relevance for local recurrence1 • 25 to 50% recurrences after first surgery while 90% chances after 2nd surgery • There is discrepancy between the number of recurrent surgeries they go ahead but the amputation that is hardly reported in literature2 Extremity and trunk desmoid tumors: a multifactorial analysis of outcome, Cancer 1999, vol. 86 10. 2045-2052 S. Bonvalot et al. Annals of Oncology, Volume 23, Issue suppl_10, 1 September 2012
- 18. Wait and Watch • Spontaneous regression has been reported in 5% of patients in retrospective series • Probably it is undercalculation • At that time surgery was done for resectable fibromatosis while those with multiple recurrences were kept for watch and see Br J Surg, 2004 vol. 91 1624-1629
- 19. • Two centre retrospective data • Primary end point was cumulative probability of dropping out from wait and watch policy J Bone Joint Surg Am. 2014 Apr 16;96(8):631-8
- 20. J Bone Joint Surg Am. 2014 Apr 16;96(8):631-8
- 21. If done nothing what will be the course J Bone Joint Surg Am. 2014 Apr 16;96(8):631-8
- 22. Tamoxifen and NSAIDS • In an analysis (n=40) 100 % expression of estrogen receptor β1 • NSAIDs act through Wnt pathway • No clear cut benefit of using the combination or hormonal agents • Limited toxicity • Low cost • Low response rates Oncol Res Treat 2015;38:244-248 1. Cancer. 2006 Jan 1;106(1):208-13.
- 23. Skapek et al. PBC 2013
- 24. EORTC Guidelines Eurpean consensus – EORTC, SPAEN, STBSG Annals of Oncology 28: 2399–2408, 2017
- 25. Imatinib • Largest data comes from SARC phase 2 trial • N=51 • Imatinib was used at 300mg twice a day • RECIST response rate was 6% Clin Cancer Res. 2010 Oct 1;16(19):4884-91
- 26. • Double blind phase 3 trial • n =87 •Randomized to sorafenib (400mg per day or matching placebo) Gounder et al. NEJM 2018
- 27. 2 year PFR- 81% vs 36%
- 28. Sorafenib for advanced desmoid tumors • Objective response rates were 33% vs 20% (sorafenib arm vs placebo arm) • In the patients who had response – Median time to response was 9.6 months
- 29. Chemotherapy regimen used in fibromatosis • Low dose vinblastine and methotrexate – single phase 2 trial in adults • Weekly mtx 30mg/m2 and vinblastine 6mg/m2 • N=30 (inoperable recurrent patients) • PR -40% and Stable disease 60% on treatment • 4 (13%) patients received less than 15 cycles due to toxicity Azarelli ACancer. 2001 Sep 1;92(5):1259-64
- 30. • N=62 • Methotrexate and vbl –n=21 • Anthracyclines – n=13 • ORR was 21% and PD was 19% and rest SD • Response rate was higher in anthracyclines as compared to methotrexate and vbl (54% vs 12%) • Median PFS was 40 months Annals of Oncology 23: 182–186, 2012
- 31. • Randomization between pazopanib 800mg to methotrexate vinblastine ASCO 2018 abs
- 33. Aggressive fibromatosis and the evidence • Molecular Biology • Pathology and molecular testing relevance • Treatment options • Surgery • Wait and watch • Hormonal/ tyrosine kinase/ chemotherapy • IRCH Data
- 34. Take home message • Till now no PRO tools validated only progression free survival or response • Beta catenin mutations to be considered for difficult diagnosis and prognosticating • Wait and watch policy for less aggressive disease • For aggressive tumors and symptomatic • Extremity – sorafenib • Abdomen and head and neck – chemotherapy • Lot of work – Best chemotherapy options, hormonal therapy role, pazopanib, biomarkers need to be done • Data from India except case reports needs to come soon
Editor's Notes
- #3: As for such rare cancer a high level of uncertainity exist! Both at regulatory level and clinical decision making
- #9: Four genesda disintegrin and metalloproteinase gene 12 (ADAM12), fibroblast activation protein 1a (Fap-1a), Wnt 1 inducible signaling pathway protein-1 (WISP1), and SRY-box 11 (SOX11)dhave been reported to be overexpressed in DTF compared with 16 nonneoplastic tissues,
- #11: Due to rarity and histologic mimics there can be a discrepancy rate of 40% in non experienced centres.
- #17: Treatment paradigm which was followed was from soft tissue sarcoma..
- #18: This suggests that in many of the cases as the patient and surgeon gives up the disease become stable