Desmoid fibromatosis (DF) is an exceedingly rare disease that is caused by monoclonal fibroblastic proliferation and has variable and unpredictable trajectory . Despite lacking metastatic potential it might be locally invasive and associated with high local recurrence rates. The treatment paradigm has recently shifted from primary surgery with negative margins to non operative approach. Non operative approaches include observation, tamoxifen, NSAIDS, tyrosine kinase inhibitors (imatinib and sorafenib) and chemotherapy. This review will focus on the current advances in fibromatosis, their critical analysis and ongoing challenges in the treatment of fibromatosis.
Desmoid type fibromatosis (DF) happens in 15 to 60 years age group with the peak at 30 to 35 years of age [2,3]. Majority of DF occur sporadically (>90%) while 5-10% arise in the backdrop of familial adenomatous polyposis. It may affect all body parts and has differential distribution in sporadic cases as compared to familial cases. Sporadic cases have more of extremity location while familial are distributed mostly localized to abdomen.
Though the clear approach to desmoid tumor still remains elusive but it should be managed by multidisciplinary team in an experience centre. The pathology is clearly the most important and the most fundamental aspect of treatment of desmoid tumor. As stated in the rare diseases like DF, diagnosis should be made by expert soft tissue histopathologist [4,5]. Immunostaining for beta catenin with nuclear positivity is helpful in establishing the diagnosis.
Mutational testing is not universally used in fibromatosis. Sporadic tumors have mutation positivity in 80 to 90 percent of cases. It may have diagnostic implications in patients with doubtful histopathology and prognostic relevance though the latter is not conclusively proven. Along with that b-catenin wild type status in DF should raise doubt for Familial Adenomatous polyposis syndrome requiring more extensive diagnostic clinical work-up(e.g. colonoscopy).
Why surgery might not be the ideal choice
Unlike soft tissue sarcoma the relevance of negative margins in soft tissue sarcoma is controversial. The recurrence rates after first surgery and second surgeries are disproportionately high as compared to soft tissue sarcoma. Similarly the number of patients who undergo amputations are far too less in literature as compared to the number of patients who have been reported on treatment. This might be due to the fact many of the lesions burn out without amputation. Recent guidelines have shifted from surgery and thus removal of the disease to preservation of the function and maintaining the quality of life in the decision making. Spontaneous regression might be seen in 20 to 30 percent of patients with DF in various series [6,7]
There is not much evidence for the frequent use of anti hormonal therapy in fibromatosis. It has been used alone or in combination with NSAIDS like sulindac or celecoxib. Widespread use is mostly due to low toxicity and easy availability. Most studies have shown low response rates as compared to other agents [8,9]
In a phase 2 study in patients with unresectable and progressive desmoids treated with with imatinib 400mg (n=40). Of 35 patients in whom response assessment was done, RECIST response was seen in 4 patients (11%) patients. Two year progression free survival rates were 55%. Imatinib had modest activity in non randomized studies and thus making it pertinent to search for more active drugs.
In the recently published phase 3, double blind trial by Gounder et al 87 patients with progressive, symptomatic or recurrent desmoids tumors were randomized to either sorafenib (400mg/ day) or placebo . Primary end point of this trial was progression free survival (PFS). After a median follow up of 27 months the 2 year PFS rate was 81% vs 36% (sorafenib group vs placebo). Prior to cross over the objective response rates were 33% in sorafenib group as compared to 20% in the placebo. The response rates in placebo arm is an indicator that even with observation a fraction of patients have decrease in the disease albeit with short follow up.
Chemotherapy might be used in case of failure of systemic agents like hormonal therapy and sorafenib in patients in which site anatomic site might be critical issue or have overt symptoms. Low dose methotrexate and vinblastine might be used once the disease doesn’t respond to observation and tyrosine kinase inhibitiors. Conventional chemotherapeutic agents like doxorubicin, liposomal doxorubicin might also be used for critical sites like head and neck, paraspinal and abdominal fibromatosis where immediate response is required.
Toulmonde et al in phase 2 randomized study compared pazopanib with chemotherapy( methotrexate and vinblastine) in adult patients with progressive fibromatosis . Primary end point was the proportion of patients who had not progressed at 6 months of start of therapy. In the first 43 patients randomized to pazopanib, proportion of patients who had not progressed was 83.7% as compared to 45% in methotrexate and vinblastin group. This trial shows promising activity of pazopanib in fibromatosis.
Other modalities like radiation therapies are seldom used in fibromatosis owing to potential risk of secondary malignancies.
Future agents and current ongoing trials
Of targeted therapies like pazopanib and sorafenib, it is still not known which agent has better activity in fibromatosis. Recently, the FDA has granted nirogacestat (PF-03084014), an investigational gamma-secretase inhibitor, with breakthrough therapy designation for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. This open-label, single-center phase II trial of nirogacestat enrolled 17 patients with desmoid tumors who were ineligible for surgery or definitive radiation therapy and who had experienced disease progression after at least 1 prior treatment regimen 
The median age of patients was 34 years (range, 19-69), 82% of the patients were female, and 53% of patients had a CTNNB1 T41A somatic missense mutation. The median number of prior therapies was 4 (range, 1-9), which included cytotoxic chemotherapy in 71% and a tyrosine kinase inhibitor in 59%. Sixteen patients were evaluable for response. After a median follow-up of more than 25 months, 5 patients (29%) achieved a partial response and 11 (65%) had stable disease, for a disease control rate of 100%. Ten patients (59%) remained on treatment with nirogacestat for more than 2 years.
Though it is seemingly benign disease but it happens in young and productive age group. This frequently leads to depression and anxiety in the patients. Simultaneously its rarity makes it difficult to understand among peers. Many a times misdiagnosis and search for expert becomes an arduous task for patients. In developing countries like India there are hardly any published data, desmoid support groups and research funding for such disease . The research is also painfully slow due to lack of awareness amongst physicians and patients. However collaboration, raising awareness, adherence to latest guidelines and teamwork is the key to success as in other rare diseases.
This article is contributed by
Author- Dr. Sameer Rastogi
Associate Professor, Sarcoma Medical Oncology
AIIMS, New Delhi
Author has no conflict of interest
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