Real-life experience with sorafenib for advanced and refractory desmoid-type fibromatosis.

BACKGROUND: In recent years, there has been a change in the therapeutic landscape of desmoid-type fibromatosis (DF). Watchful waiting is now preferred over initial local treatments such as surgery and radiotherapy. Systemic treatment is considered for progressive or symptomatic disease. The aim of this study is to review real-life data on the use of sorafenib in DF. METHODS: We established a retrospective dataset of patients treated with sorafenib in our centre, Ghent University Hospital, for progressive DF. Patient demographics, disease characteristics, response to therapy using Response Evaluation Criteria in Solid Tumours 1.1 criteria and toxicity according to CTCAE v5.0 were assessed. RESULTS: Eleven patients with DF were treated with sorafenib between 2020 and 2024. Median treatment duration was 20.4 months (95% confidence interval [CI], 10.0-NR). 36.4% achieved partial response, 54.5% stable disease and 9.1% progressive disease. For three patients, the treatment is ongoing. The median time to objective response rate is 15.0 months (95% CI, 8.8-NR). The majority (81.8%) experienced grade 2 toxicity, and one third of patients grade 3 toxicity (36.4%). The most common all-grade adverse event was skin toxicity (hand-foot syndrome, pruritus and rash) (90.9%). Nine patients (81.8%) needed dose reduction with a median time to first reduction of 1.1 months (95% CI, 0.5-NR). One patient stopped treatment due to toxicity. INTERPRETATION: Real-life data on the use of sorafenib in the treatment of DF is consistent with published data in clinical trial setting. Sorafenib is an effective treatment option for progressive DF although associated with significant toxicity and the need for rapid dose reduction.

Current Management of Desmoid Tumors: A Review.

Importance: Desmoid tumor (DT) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Previously, surgery was the standard primary treatment modality; however, within the past decade, a paradigm shift toward less-invasive management has been introduced and an effort to harmonize the strategy among clinicians has been made. To update the 2020 global evidence-based consensus guideline on the management of patients with DT, the Desmoid Tumor Working Group convened a 1-day consensus meeting in Milan, Italy, on June 30, 2023, under the auspices of the European Reference Network on Rare Adult Solid Cancers and Sarcoma Patient Advocacy Global Network, the Desmoid Foundation Italy, and the Desmoid Tumor Research Foundation. The meeting brought together over 90 adult and pediatric sarcoma experts from different disciplines as well as patients and patient advocates from around the world. Observations: The 2023 update of the global evidence-based consensus guideline focused on the positioning of local therapies alongside surgery and radiotherapy in the treatment algorithm as well as the positioning of the newest class of medical agents, such as γ-secretase inhibitors. Literature searches of MEDLINE and Embase databases were performed for English-language randomized clinical trials (RCTs) of systemic therapies to obtain data to support the consensus recommendations. Of the 18 full-text articles retrieved, only 4 articles met the inclusion criteria. The 2023 consensus guideline is informed by a number of new aspects, including data for local ablative therapies such as cryotherapy; other indications for surgery; and the γ-secretase inhibitor nirogacestat, the first representative of the newest class of medical agents and first approved drug for DT. Management of DT is complex and should be carried out exclusively in designated DT referral centers equipped with a multidisciplinary tumor board. Selection of the appropriate strategy should consider DT-related symptoms, associated risks, tumor location, disease morbidities, available treatment options, and preferences of individual patients. Conclusions and Relevance: The therapeutic armamentarium of DT therapy is continually expanding. It is imperative to carefully select the management strategy for each patient with DT to optimize tumor control and enhance quality of life.

Active surveillance and emerging medical treatment options for desmoid: when and for whom?

PURPOSE OF REVIEW: This article discusses the evolving approaches to desmoid tumors management, shedding light on recent developments. RECENT FINDINGS: Active surveillance has become the primary approach for managing primary peripheral desmoid tumors. This strategy was initially based on evidence from retrospective studies. Roughly 50% of cases managed with active surveillance show spontaneous stabilization or regression. Recent prospective trials conducted in Italy, The Netherlands, and France (2022-2023) confirm the efficacy of active surveillance, revealing 3-year progression-free survival rates ranging from 53.4 to 58%. For the patients under active surveillance, decisions regarding treatment are based on significant tumor growth or progressive symptoms. Moreover, three contemporary randomized trials investigated medical treatments for progressive or recurrent desmoid tumors. Sorafenib, pazopanib, and nirogacestat demonstrated clinical activity, as evidenced by favorable progression-free survival and objective response rates. SUMMARY: Active surveillance has solidified its position as the primary management approach for desmoid tumors, validated by three robust prospective studies. Three recent randomized trials explored medical treatment for progressive or recurrent desmoid tumors, revealing promising clinical activities.

Real-word experience of pazopanib and sorafenib in patients with desmoid tumors: A CanSaRCC multi-center study.

BACKGROUND: Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is available on long-term outcomes of patients who progressed on, stopped, or continued TKIs. METHODS: Patients diagnosed with DTs and treated with sorafenib or pazopanib between 2011 and 2022 at 11 institutions were reviewed. Patient history, response to therapy and toxicity were recorded. Statistical analyses utilized Kaplan-Meier and log-rank tests. RESULTS: 142 patients with DT treated with sorafenib (n = 126, 88.7 %) or pazopanib (n = 16, 11.3 %) were analyzed. The median treatment duration was 10.8 months (range: 0.07- 73.9). The overall response rate and the disease control rate were 26.0 % and 95.1 %, respectively. The median tumor shrinkage was - 8.5 % (range -100.0 %- +72.5 %). Among responders, the median time to an objective response was 15.2 months (range: 1.1 to 33.1). The 1-year and 2-year progression-free survival rates were 82 % and 80 %. Dose reductions were necessary in 34 (23.9 %) patients. Grade 3 or higher adverse events were reported in 36 (25.4 %) patients. On the last follow-up, 55 (38.7 %) patients continued treatment. Treatment discontinuation (n = 85, 59.9 %) was mainly for toxicity (n = 35, 45.9 %) or radiological or clinical progression (n = 30, 35.3 %). For the entire cohort, 36 (25.4 %) patients required subsequent treatment. In the 32 responders, only 1 (3.1 %) patient required a subsequent treatment. In patients who discontinued TKI, 25 (44.6 %) with stable disease received subsequent treatment compared to 0 (0.0 %) of responders. CONCLUSION: This retrospective study represents the largest cohort of DT patients treated with sorafenib or pazopanib to date. Discontinuation of treatment in responders is safe. The optimal treatment duration in patients with stable disease remains to be defined.

Onset and resolution of ovarian toxicity with nirogacestat treatment in females with desmoid tumors: Updated safety analyses from the DeFi phase 3 study.

INTRODUCTION: Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of nirogacestat, ovarian toxicity (OT) was identified as a safety signal among females of reproductive potential (FORP). This analysis further describes the incidence, presentation, and resolution of OT. METHODS: Patients were randomized to twice-daily oral nirogacestat (150 mg) or placebo, taken in continuous 28-day cycles. Investigator-identified OT in FORP was based on abnormal reproductive hormone values or perimenopausal symptoms (or both). Adverse event follow-up was conducted to assess OT resolution. Post hoc analyses included return of menstruation and return of follicle-stimulating hormone (FSH) to within normal limits (WNL) (≤20.4 mIU/mL). RESULTS: Of 92 randomized females, 73 in the safety population were FORP (n = 36 nirogacestat, n = 37 placebo). OT was identified in 75% (27 of 36) receiving nirogacestat and 0% (0 of 37) receiving placebo. As of October 24, 2022, investigators reported OT resolution in 78% (21 of 27) of patients, with median OT duration of 19.1 weeks. Off-treatment resolution was reported in all 11 patients (100%) who stopped nirogacestat treatment; of these, all nine with available menstruation information experienced return of menstruation and eight had FSH WNL at last reported assessment. Resolution was reported in 10 of 14 (71%) while on nirogacestat; of these, all 10 experienced return of menstruation and seven had FSH WNL. Two patients were lost to follow-up. CONCLUSION: Most FORP treated with nirogacestat experienced OT, with the majority resolving, including all who stopped treatment, suggesting that OT is transient.

Building the Evidence for Systemic Treatment in Desmoid Fibromatosis: Is a New Metronomic Regimen Another Layer in the Foundation?

@Thalcin explains how a metronomic regimen for desmoid tumors fits in the current treatment landscape.

Evaluation of Metronomic Therapy as a Low-Cost, Sustainable, Standard-of-Care Option in Desmoid Fibromatosis: Real-World Data From a Tertiary Care Center in India.

PURPOSE: Desmoid fibromatosis (DF) is a locally aggressive tumor with low mortality but significant morbidity. There is a lack of standard of care, and existing therapies are associated with significant barriers including access, cost, and toxicities. This study aimed to explore the efficacy and safety of the metronomic therapy (MT) in DF in a large, homogenous cohort from India. PATIENTS AND METHODS: This study involved histologically confirmed DF cases treated with MT comprising vinblastine (6 mg) and methotrexate (15 mg) both once a week, and tamoxifen (40 mg/m2) in two divided doses once daily between 2002 and 2018. RESULTS: There were 315 patients with a median age of 27 years; the commonest site was extremity (142 of 315; 45.0%). There were 159 (50.1%) male patients. Of the 123 (39.0%) prior treated patients, 119 had surgery. Of 315 patients, 263 (83.5%) received treatment at our institute (MT-151, 77-local treatment, 9-tyrosine kinase inhibitor, and 26 were observed). Among the MT cohort (n = 163, 61.2%), at a median follow-up of 36 (0.5-186) months, the 3-year progression-free and overall survival were 81.1% (95% CI, 74.3 to 88.4) and 99.2% (95% CI, 97.6 to 100), respectively. There were 35% partial responses. Ninety-two patients (56.4%) completed 1-year therapy, which was an independent prognosticator (P < .0001; hazard ratio, 0.177 [95% CI, 0.083 to 0.377]). MT was well tolerated. Predominant grade ≥3 toxicities were febrile neutropenia, 12 (7.4%) without any chemotoxicity-related death. The annual cost of MT was $130 US dollars. CONCLUSION: The novel, low-cost MT qualifies as one of the effective, less toxic, sustainable, standard-of-care options for the treatment of DF with global reach and merits wide recognition.

Favorable clinical efficacy of cytotoxic chemotherapy in patients with progressive desmoid tumors: a retrospective real-world study.

BACKGROUND: The real-world evidence about the efficacy of cytotoxic chemotherapy in desmoid tumors is still limited. We investigated the efficacy of chemotherapy in the treatment of recurrent or progressive desmoid tumors. METHODS: The patients with desmoid tumors who had received cytotoxic chemotherapy between November 2007 and June 2020 in two tertiary hospitals in Korea were reviewed. RESULTS: A total of 25 patients were included in the analysis. The most common primary tumor site was the intra-abdominal or pelvic cavity (56%), followed by the trunk and abdominal wall (24%), extremities (16%), and head and neck (4%). Sixty percent of the patients had familial adenomatous polyposis and 76% received doxorubicin plus dacarbazine. The objective response rate and disease control rate was 64% (95% confidence interval [CI]: 40.7-82.8) and 96% (95% CI: 77.2-99.9), respectively. With the median follow-up time of 55 months (95% CI: 41.0-68.2), the 3-year PFS rate was 65% (95% CI: 41.1-80.5), and the 3-year OS rate was 89% (95% CI: 63.8-97.3). Grade 3 or 4 hematologic adverse events were reported in 14 patients, all of which were manageable. CONCLUSION: Our real-world evidence suggests that doxorubicin-based cytotoxic chemotherapy can be an effective treatment option for recurrent and progressive desmoid tumors with respect to favorable clinical outcomes.

Clinical Activity of TGF-ß Inhibitor Vactosertib in Combination with Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study.

PURPOSE: The study was to determine the activity and safety of the TGF-ß inhibitor vactosertib in combination with imatinib in patients with desmoid tumors. PATIENTS AND METHODS: In this investigator-initiated, open-label, multicenter, phase Ib/II trial, patients with desmoid tumors not amenable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase Ib, the vactosertib dose was set at 100 mg (level -1) and 200 mg (level 1) to determine the recommended phase II dose (RP2D). Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. RESULTS: No dose-limiting toxicities were observed during phase Ib; therefore RP2D was defined at doses of 400 mg imatinib daily in combination with 200 mg vactosertib. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. Most toxicities were mild to moderate myalgia (n = 10, 37%), anemia (n = 10, 37%), and nausea (n = 9, 33.3%). Common grade 3 to 4 toxicities included neutropenia (n = 6, 22.2%) and anemia (n = 5, 18.5%). CONCLUSIONS: The vactosertib and imatinib combination was well tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-ß inhibitor, in this rare and difficult-to-treat desmoid tumor.

PDGFRß Signaling Cooperates with ß-Catenin to Modulate c-Abl and Biologic Behavior of Desmoid-Type Fibromatosis.

PURPOSE: This study sought to identify ß-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFRß), affect these targets to alter natural history or treatment response in patients. EXPERIMENTAL DESIGN: In vitro experiments utilized primary desmoid cell lines to examine regulation of ß-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies. RESULTS: CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α protein. ChIP-seq identified ABL1 as a ß-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1A inhibited desmoid cell-induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRß signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRß and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRß/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment. CONCLUSIONS: The ß-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.

Desmoid-type fibromatosis: Current therapeutic strategies and future perspectives.

Desmoid tumors (DT) are rare, slow-growing, locally invasive soft tissue tumors that often pose significant therapeutic challenges. Traditional management strategies including active surveillance, surgery, radiotherapy, and systemic therapy which are associated with varying recurrence rates and high morbidity. Given the challenging nature of DT and the modest outcomes associated with current treatment strategies, there has been a growing interest in the field of γ-secretase inhibitors as a result of its action on the Wnt/ß-catenin signaling pathway. In this review article, we will shed the light on the pathogenesis and molecular biology of DT, discuss its symptoms and diagnosis, and provide a comprehensive review of the traditional therapeutic approaches. We will also delve into the mechanisms of action of γ-secretase inhibitors, its efficacy, and the existing preclinical and clinical data available to date on the use of these agents, as well as the potential challenges and future prospects in the treatment landscape of these tumors.

New treatments for desmoid tumors.

PURPOSE OF REVIEW: Desmoid tumor is a rare disease of intermediate malignancy characterized by a locally aggressive monoclonal, fibroblastic proliferation and accompanied by a variable and often unpredictable clinical course. The purpose of this review is to give an overview on the emerging new systemic treatment options for this intriguing disease for which no established or approved drugs are available yet. RECENT FINDINGS: Over decades, surgical resection has been the established initial treatment approach; however, more recently, a paradigm shift has been introduced towards a more conservative treatment strategy. Almost 10 years ago, The Desmoid Tumor Working Group has initiated a consensus process initially in Europe and then globally with the intention to harmonize the therapeutic strategy amongst clinicians and set up management recommendations for desmoid tumor patients. SUMMARY: This review will summarize and focus on the latest emerging impressive data on the use of gamma secretase inhibitors in this disease paving a possible future perspective in the treatment armamentarium for desmoid tumor patients.

Oral vinorelbine in young patients with desmoid-type fibromatosis.

BACKGROUND: Desmoid-type fibromatosis are rare intermediate tumors in children and adolescents. Owing to local aggressiveness and relapse, systemic treatment for symptomatic advanced or progressive forms is recommended. Following promising results in adult patients, oral vinorelbine is investigated in young patients. METHODS: A retrospective review of young patients (<25 years old) with advanced or progressive desmoid type fibromatosis treated with oral vinorelbine in eight large centers of the Société Française des Cancers de l'Enfant was performed. In addition to tumor assessment according to RECIST 1.1, pre-treatment and during-treatment imagery were reviewed centrally to assess tumor volume and estimate fibrosis score through the change in percentage in hypoT2 signal intensity. RESULTS: From 2005 to 2020, 24 patients (median age 13.9 years [range, 1.0-23.0]) received oral vinorelbine. Median number of prior systemic lines of treatment was 1 (range, 0-2), mainly based on intravenous low dose methotrexate and vinblastine. Before vinorelbine initiation, all patients had a progressive disease: radiological for 19, radiological and clinical (pain) for three and only clinical for two. Oral vinorelbine was delivered for a median duration of 12 months (range, 1-42). The toxicity profile was favorable, with no grade 3-4 event. Overall response estimated on 23 evaluable patients according to RECIST 1.1 criteria was three partial responses (13%), 18 stabilization (78%) and two progressive disease (9%). Overall progression-free survival was 89.3% (95% confidential intervals 75.2-100) at 24 months. Four stable tumors according to standard RECIST criteria displayed a partial response with > 65% tumor volume reduction. Among 21 informative patients, the estimated fibrosis score decreased for 15 patients, was stable for four patients and increased for two patients. CONCLUSION: Oral vinorelbine seems to be effective to control advanced or progressive desmoid type fibromatosis in young patients, with a well-tolerated profile. These results support testing this drug as first-line alone or in combination to improve response rate while preserving quality of life.

Efficacy and tolerability of sorafenib in desmoid-type fibromatosis: A need to review dose.

BACKGROUND: Sorafenib is currently one of the recommended treatments for symptomatic patients with desmoid-type fibromatosis (DTF). In this study, we aim to assess the clinical efficacy and tolerability of sorafenib in DTF patients. METHODOLOGY: Patients aged>18 years with a histological diagnosis of DTF and who have received sorafenib were enroled in this prospective observational study. Demographic data, clinical profile, the initial dose of sorafenib, treatment-related toxicities, dose modifications, and responses were recorded. The primary objective was to assess the objective response rate (ORR). The secondary objectives were to evaluate progression-free survival (PFS), tolerability, and adverse effects of sorafenib. Response assessment was based on response evaluation criteria in solid tumours 1.1 criteria. Adverse effects were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 criteria. Time to event was calculated by Kaplan-Meier analysis, and survival was compared by log-rank test. Univariate and multivariable cox regression analysis were used to find independent predictors of relapse. RESULTS: A total of 104 patients were enroled in the study. The median age of the study population was 32 (range, 18-81) years, and 66.35% of patients were females. On response assessment, ORR was 46.1% and stable disease was observed in 31.7% patients. ORR was higher in the appendicular site (51.7%) compared to the abdominal site (27.2%). PFS at 1 and 2 years was 86.6% (79.6-92.7%) and 73.7% (62.4-82.8%), respectively. Two-thirds (66.6%) of patients had already received some form of treatment. At the time of analysis, 70 (67.3%) patients were continuing sorafenib. Only 4.8% stopped sorafenib due to progression, 10.5% due to intolerable adverse effects, and 17.3% due to other reasons. The common treatment-related toxicities were hand-foot skin reaction (HFSR) (89.4%), fatigue (79.8%), alopecia (70.1%), and diarrhoea (48.0%). In the patients with a starting dose of ≥400 mg (48.0% of patients), discontinuation was necessitated in 12% of patients, and further dose reduction was required in 58%, while only about 13% required dose reduction or discontinuation at a starting dose of 200 mg (51.9% of patients). Responses were not compromised due to lower starting doses. CONCLUSIONS: Sorafenib has good activity in DTF, but it is associated with significant toxicity. The adverse effect profile is distinct in Indian patients with higher HFSR and alopecia. Due to the high rate of dose reduction/discontinuation with a starting dose of 400 mg, a starting dose of 200 mg may be recommended in Indian patients.

[A Case of Long-Term Survival with Tumor Resection and DOX plus DTIC Therapy for Desmoid Tumor after FAP Surgery].

The patient is a 22-year-old, female. She had a family history of familial adenomatous polyposis(FAP)and a prophylactic total colorectal resection was performed for FAP at age of 18. She presented with fever and abdominal distention and palpated a mass with tenderness in the right lower abdomen. Contrast-enhanced CT scan of the abdomen showed a heterogeneous contrast effect around the tumor margins. With the diagnosis of intra-abdominal desmoid tumor, a partial duodenal resection, small bowel mass resection, and right fallopian tube resection were performed along with the tumor, and an artificial anus was created with the jejunum. Contrast-enhanced CT scan of the abdomen 16 months after resection of desmoid tumor showed a 6.5 cm long desmoid tumor recurrence in the mesentery. She received 5 courses of doxorubicin (DOX)plus dacarbazine(DTIC)therapy followed by continued NSAIDs. Seven years after the operation, she has been able to maintain the shrinkage of the recurrent tumor and is still on medication. Long-term surveillance is necessary because of the possibility of the appearance of other associated lesions in the future.

Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.

BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

Oral Losartan After Limited Mandibulectomy for Treatment of Desmoid-Type Fibromatosis.

Desmoid-type fibromatosis (DF) is a rare soft tissue lesion with an annual incidence of 2 to 4 per million population and peak incidence occurring at approximately 4.5 years of age. While benign, the tumor has a locally aggressive infiltrative growth pattern and a high rate of recurrence. Given the functional and aesthetic implications of excision and reconstruction in the facial skeleton, novel medical treatment options are highly desirable. We describe the case of a 3-year-old boy who presented with an enlarging, asymptomatic mass involving the left mandible. Biopsy revealed an immunohistochemical profile consistent with DF. Despite the high likelihood of recurrence, conservative, mandible-sparing en bloc resection and limited mandibulectomy were performed. Pathological and immunohistochemical analysis of the resection specimen revealed DF with grossly positive margins and elevated expression of angiotensin II type 1 receptor. Postoperative medical treatment with the angiotensin receptor blocker losartan was initiated. The patient remains medically stable and disease progression-free on repeat imaging at 20 months post-resection. We describe for the first time the successful use of the angiotensin blocker losartan following conservative surgery for management of DF.

A cost analysis of sorafenib for desmoid tumors.

INTRODUCTION: A recent randomized trial demonstrated that sorafenib improved progression free survival (PFS) in patients with desmoid tumors despite many patients experiencing stable disease or spontaneous regression without treatment. Utilizing these trial data, we performed a cost analysis of sorafenib efficacy through two years of treatment. METHODS: Current Medicare Part D rates for sorafenib were utilized (dose 400 mg/day, cost $309/day). Annual costs per progression and objective response were calculated. Radiologic progression and response were defined using RECIST criteria. Patients with disease progression were separately analyzed in two groups: both clinical and radiologic (CAR), and radiologic alone. RESULTS: 84 previously randomized patients were analyzed (placebo: 35, sorafenib: 49). At one year, sorafenib was associated with a 43% absolute risk reduction (ARR) of CAR progression and number-needed-to-treat (NNT) of 2.3 patients/year, costing $259,406. At two years, ARR was 48% and NNT of 2.1 patients/year, costing $473,697. When evaluating only patients with RECIST defined radiologic progression, sorafenib patients experienced ARR of 13.9% with NNT 7.2 and estimated costs of $812,052 at one year. Two-year ARR was 17.5% with NNT 5.7 and estimated costs $1,285,052. Sorafenib patients experienced improved RECIST partial response rates at 1 and 2 years of 14.7% and 14.3%, with NNT 6.8 and 6.9, and costs of $766,938 and $1,556,433; respectively. CONCLUSION: For the treatment of desmoid tumors, Sorafenib led to improved PFS, but at a significant cost per patient. Favorable RECIST outcomes were less likely and costlier. Patients should be informed of possible benefits of treatment versus potential financial burden.

Clinical outcomes of medical treatments for progressive desmoid tumors following active surveillance: a systematic review.

Approximately 80% of desmoid tumors (DTs) show spontaneous regression or disease stabilization during first-line active surveillance. Medical treatment can be considered in cases of disease progression. This systematic review aimed to evaluate the effectiveness and toxicity of each medical treatment by reviewing only the studies that included progressive disease as the inclusion criterion. We searched the EMBASE, PubMed, and CENTRAL databases to identify published studies for progressive DTs. The disease control rates of the medical treatments, such as low-dose chemotherapy with methotrexate plus vinblastine or vinorelbine, imatinib, sorafenib, pazopanib, nilotinib, anlotinib, doxorubicin-based agents, liposomal doxorubicin, hydroxyurea, and oral vinorelbine for progressive DTs were 71-100%, 78-92%, 67-96%, 84%, 88%, 86%, 89-100%, 90-100%, 75%, and 64%, respectively. Low-dose chemotherapy, sorafenib, pazopanib, nilotinib, anlotinib, and liposomal doxorubicin had similar toxicities. Sorafenib and pazopanib were less toxic than imatinib. Doxorubicin-based chemotherapy was associated with the highest toxicity. Hydroxyurea and oral vinorelbine exhibited the lowest toxicity. Stepwise therapy escalation from an initial, less toxic treatment to more toxic agents is recommended for progressive DTs. Sorafenib and pazopanib had limited on-treatment side effects but had the possibility to induce long-term treatment-related side effects. In contrast, low-dose chemotherapy has some on-treatment side effects and is known to have very low long-term toxicity. Thus, for progressive DTs following active surveillance, low-dose chemotherapy is recommended in young patients as long-term side effects are minor, whereas therapies such as sorafenib and pazopanib is recommended for older patients as early side effects are minor.