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.

A Prospective Observational Study of Active Surveillance in Primary Desmoid Fibromatosis.

PURPOSE: To prospectively assess the behavior of primary sporadic (not familial adenomatous polyposis-associated) desmoid fibromatosis (DF) managed by active surveillance (AS). DESIGN: This is an Italian prospective, multicenter, observational study (NCT02547831) including patients ≥16 years with primary sporadic DF at any site. Patients were assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Primary endpoint was progression-free survival (PFS) at 3 years. Treatment-free survival (TFS) was also analyzed. PFS and TFS were calculated by Kaplan-Meier plots and compared by log-rank test. Cox proportional hazard multivariable regression analyses were performed. RESULTS: From 2013 to 2018, 108 consecutive patients were included (82% female); median age was 39 years; median size was 51 mm. CTNNB1 mutations were T41A (50%), S45F (12%), other (19%), wild-type (19%). At 32.3-month median follow-up, 42 of 108 (39%) showed RECIST progression. Spontaneous regression was initially observed in 27 of 108 (25%), while it followed dimensional progression in another 33 of 108 (31%). PFS at 36 months was 54.5% [95% confidence interval (CI), 44.9%-66.1%]. Thirty-five of 108 (32%) patients received active treatment, 18 of 108 (17%) after RECIST progression and 17 of 108 (15%) after symptomatic progression. TFS at 36 months was 65.9% (95% CI, 57.3%-75.9%). Larger tumor size and extremity location were associated to shorter TFS and a trend for S45F mutation was also observed (P = 0.06), while none of the mentioned variables was significantly associated with PFS. CONCLUSIONS: In primary DF, AS can be proposed, because disease stabilization and spontaneous regression frequently occur. However, extra care should be taken for patients with tumors of larger size, extremity location, and S45F mutation. See related commentary by Greene and Van Tine, p. 3911.

Desmoid fibromatosis: is the current picture changing?

Desmoid fibromatosis is a locally aggressive tumor with an unpredictable clinical course. Surgery was once the mainstay of treatment, but the treatment protocol has been constantly evolving and currently active surveillance is the front-line approach. There have been significant insights into the molecular biology with the addition of mutational analysis of CTNNB1 adding to prognostic information. We present a review of the literature with current practice guidelines, also including novel therapeutic targets and ongoing clinical trials, to unravel the next step in the management of sporadic desmoid fibromatosis.

Lay abstract Desmoid fibromatosis is an aggressive local tumor with continuously changing treatment paradigms. It requires MRI with biopsy for diagnosis and follow-up. Usually the tumor responds to a 'wait and watch' approach in most patients with either stable disease or regression on follow-up; a surgical plan is made only after multidisciplinary discussion, as surgery does not provide additional benefit in most patients. After a period of wait and watch, if there is disease progression, patients can be kept on medical management such as chemotherapy. Currently we have novel drugs for medical management like tyrosine kinase inhibitors, which result in disease stabilization in a majority of patients. In order to reduce the morbidity of treatment, it is essential for the patient to be on continuous follow-up and for clinicians to be updated with the continuously changing management of this disease.

Extra-abdominal desmoid tumor fibromatosis: a multicenter EMSOS study.

BACKGROUND: Extra-abdominal desmoid tumor fibromatosis (DTF) is a rare, locally aggressive soft tissue tumour. The best treatment modality for this patient cohort is still object of debate. QUESTIONS/PURPOSE: This paper aimed to (1) to compare the outcomes of DTF after different treatment modalities, (2) to assess prognostic factors for recurrence following surgical excision, and (3) to assess prognostic factors for progression during observation. METHODS: This was a retrospective multicenter study under the patronage of the European Musculoskeletal Oncology Society (EMSOS). All seven centres involved were tertiary referral centres for soft tissue tumours. Baseline demographic data was collected for all patients as well as data on the diagnosis, tumour characteristics, clinical features, treatment modalities and whether they had any predisposing factors for DTF. RESULTS: Three hundred eighty-eight patients (240 female, 140 male) with a mean age of 37.6 (±18.8 SD, range: 3-85) were included in the study. Two hundred fifty-seven patients (66%) underwent surgical excision of ADF, 70 patients (18%) were observed without therapy, the residual patients had different conservative treatments. There were no significant differences in terms of tumour recurrence or progression between the different treatment groups. After surgical excision, younger age, recurrent disease and larger tumour size were risk factors for recurrence, while tumours around the shoulder girdle and painful lesions were at risk of progression in the observational group. CONCLUSION: Local recurrence rate after surgery was similar to progression rates under observation. Hence, observation in DTF seems to be justified, considering surgery in case of dimensional progression in 2 consecutive controls (3 and 6 months) and in painful lesions, with particular attention to lesions around the shoulder girdle.

Comprehensive molecular and clinicopathological profiling of desmoid tumours.

Previous studies have not clearly identified a prognostic factor for desmoid tumours (DT). Whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics. CTNNB1 mutations with specific hotspots were identified in 56 cases (87.5%). A copy number loss in chromosome 6 (chr6) was identified in 14 cases (21.9%). Clustering based on the mRNA expression profiles was predictive of the patients' prognoses. The risk score generated by the expression of a three-gene set (IFI6, LGMN, and CKLF) was a strong prognostic marker for recurrence-free survival (RFS) in our cohort. In risk groups stratified by the expression of IFI6, the hazard ratio for recurrence-free survival in the high-risk group relative to the low-risk group was 12.12 (95% confidence interval: 1.56-94.2; p = 8.0 × 106). In conclusion, CTNNB1 mutations and a chr6 copy number loss are likely the causative mutations underlying the tumorigenesis of DT while the gene expression profiles may help to differentiate patients who would be good candidates for wait-and-see management and those who might benefit from additional systemic or radiation therapies.

Event-free survival in Desmoid-Type fibromatosis (DTF): A pre-post comparison of upfront surgery versus wait-and-see approach.

BACKGROUND: Desmoid-Type Fibromatosis (DTF) is a rare mesenchymal neoplasm with a locally invasive pattern and high risk of local recurrence after surgery. Historically, the standard treatment for DTF was surgical resection. However, considering the difficulty of achieving surgical eradication, the possible unnecessary morbidity and the unpredictability of the natural history, a wait-and-see approach has been proposed for asymptomatic DTF. METHODS: We analyzed 87 consecutive patients with histologically-proven sporadic primary DTF, first recurrence or residual disease managed at our institution between 2000 and 2018. Patients and tumor-related variables were reviewed and analyzed. Two different treatment strategies were adopted according to different time periods: in the "early period" (2000-2010) patients underwent surgical treatment irrespective of the clinical presentation, whereas in the "late period" (2012-2018) asymptomatic patients used to undergo a wait-and-see strategy. The event-free survival (EFS) was compared trough a pre-post comparison. RESULTS: In the early period, surgery was performed in 51 (94.4%) patients and watchful waiting in 3 (5.6%). In the late period, the watchful waiting group accounted for 24 (72.7%) patients and the surgical group for 9 (27.3%). No statistically independent prognostic factors were found. EFS did not show statistically significant differences between early and late period groups. CONCLUSION: Wait-and-see policy has shown to be equivalent to upfront surgery in terms of EFS; therefore, a conservative approach is recommended in asymptomatic patients diagnosed with DTF that can be followed through watchful waiting.

Long-term Outcomes of Oral Vinorelbine in Advanced, Progressive Desmoid Fibromatosis and Influence of CTNNB1 Mutational Status.

PURPOSE: Desmoid-type fibromatosis (DF) are locally aggressive neoplasms, with a need for effective systemic treatment in case of progression to avoid the short- and long-term complications of local treatments. EXPERIMENTAL DESIGN: We retrospectively analyzed the outcomes of adult patients with DF treated with oral vinorelbine (90 mg once weekly) at Gustave Roussy Cancer Institute (Villejuif, Paris, France). Only patients with documented progressive disease according to RECIST v1.1 for more than 3 months (±2 weeks) before treatment initiation were included. RESULTS: From 2009 to 2019, 90 out of 438 patients with DF were eligible for this analysis. Vinorelbine was given alone in 56 patients (62%), or concomitantly with endocrine therapy in 34 patients, for a median duration of 6.7 months. A partial response was observed in 29% and stable disease in another 57%. With a median follow-up of 52.4 months, the median time to treatment failure (TTF) was not reached. Progression-free rates at 6 and 12 months were 88.7% and 77.5%, respectively. Concomitant endocrine therapy was associated with longer TTF in women [HR, 2.16; 95% confidence interval (CI), 1.06-4.37; P = 0.03). Among 64 patients with documented CTNNB1 mutational status, p.S45F or p.S45P mutations were associated with longer TTF compared with p.T41A or wild-type tumors (HR, 2.78; 95% CI, 1.23-6.27; P = 0.04). Toxicity profile was favorable, without grade 3-4 toxicity, except for one grade 3 neutropenia. CONCLUSIONS: Oral vinorelbine is an effective, affordable, and well-tolerated regimen in patients with advanced, progressive DF. Prolonged activity was observed in patients with tumors harboring CTNNB1 p.S45F or p.S45P mutations.

Desmoid with biweekly methotrexate and vinblastine shows similar effects to weekly administration: A phase II clinical trial.

Low-dose methotrexate (MTX) plus vinblastine (VBL) chemotherapy is an effective treatment for desmoid-type fibromatosis (DF). However, previous reports have described a weekly regimen, with no reports available on a biweekly one. The aim of this study was to determine the clinical outcomes of a biweekly regimen in a cohort prospectively treated in our single institution. Since 2010, we have prospectively treated refractory DF patients with biweekly MTX (30 mg/m2 ) + VBL (6 mg/m2 ). Efficacy, progression-free survival (PFS), and correlating factors were analyzed. Adverse events (AEs) were recorded. In total, 38 patients received low-dose MTX + VBL therapy, and its efficacy was assessed in 37 of them. Nineteen (51%) patients showed partial response (PR). Clinical benefit rate was 95%. PFS at 5 y was 80.8%. In PR cases, median time to response was 10 mo. Longer duration of therapy was significantly associated with the response of PR (P = .007) by univariate analysis. There was no clear association between various clinicopathological factors, including tumor size, location, catenin beta-1 (CTNNB1) mutation status with effect. Only 3 AEs of grade 3/4 were observed. Tumor regrowth after MTX + VBL discontinuation was observed in 5 (20%) of 25 patients. Biweekly administration of MTX + VBL chemotherapy was well tolerated compared with weekly administration, and its efficacy was anticipated in DF patents, although the time needed to achieve a response may be relatively long. The treatment interval should be determined taking into account both the condition of the tumor and the patient's preference.

Risk factors of local recurrence after surgery in extraabdominal desmoid-type fibromatosis: A multicenter study in Japan.

This study was undertaken to clarify the risk factors, including the mutation status of CTNNB1, for the local recurrence after surgery of the rare disease desmoid-type fibromatosis. It was designed as a multiinstitutional joint research project with 7 major centers in Japan participating. The committee members of 7 major medical centers specializing in bone and soft tissue tumors formed this study group to develop clinical care guidelines. Of 196 cases with specimens and medical records collected from the 7 institutions, 88 surgically treated ones were analyzed regarding clinicopathologic prognostic factors including CTNNB1 mutation status. Excluding R2 cases (n = 3), 5-year local recurrence-free survival (LRFS) was 52.9%. No case had received pre- or postoperative radiotherapy. Univariate analysis revealed that extremity location (P < .001) and larger size (8 cm or more, P = .036) were significant adverse risk factors for LRFS. Multivariate analysis indicated that extremity location (P < .001) was a significantly adverse factor in addition to recurrent tumor (P = .041), S45F mutation (P = .028), and R1 surgical margin (P = .039). Preoperative drug treatment, including nonsteroidal antiinflammatory drugs, did not reduce the incidence of local recurrence (P = .199). This is the first study to analyze the factors correlating with outcomes of surgical treatment, including CTNNB1 mutation status, in a relatively large number of cases from an Asian country. Tumor location was found to be the most influential prognostic factor for local recurrence, similar to the results from Europe and North America. The development of more sensitive method(s) for determination of CTNNB1 mutation is a priority for future study.

Certain risk factors for patients with desmoid tumors warrant reconsideration of local therapy strategies.

BACKGROUND: The objective of this study was to evaluate treatment outcomes for patients with desmoid tumors (DTs) receiving local therapy with surgery alone, radiation therapy (RT) alone, or combined modality therapy (RT and surgery). METHODS: This was a cross-sectional cohort study of 412 patients with nonmesenteric DTs who received local therapy at the authors' institution between 1965 and 2018. RESULTS: The median follow-up time was 95 months (range, 1-509 months). Local recurrence occurred in 127 patients (31%) at a median time of 21 months (interquartile range, 12-38 months). The 5-year local control (LC) rate was 67%. Patient or tumor factors that were significantly associated with poorer 5-year LC in a multivariable analysis included an age ≤ 30 years (57% vs 75% for an age > 30 years; hazard ratio [HR], 1.73; P = .004), an extremity location (57% vs 71% for a nonextremity location; HR, 1.77; P = .004), and large tumors (59% for >10 cm [HR, 2.17; P = .004] and 65% for 5.1-10 cm [HR, 1.71; P = .02] vs 76% for ≤5 cm). Subset analyses of these high-risk patients revealed no local therapy strategy to be superior for young patients ≤ 30 years old (HR for surgery, 1.42; P = .33; HR for RT, 1.36; P = .38) or for large tumors > 10 cm (HR for surgery, 1.55; P = .46; HR for RT, 0.91; P = .91). However, for patients with extremity tumors, surgery alone was significantly associated with inferior LC (HR for surgery, 5.15; P < .001; HR for RT, 1.51; P = .38). CONCLUSIONS: Local therapy provides durable tumor control in the majority of patients with DTs. However, young patients, patients with an extremity location, and patients with large tumors are at increased risk of recurrence. When active treatment is indicated, systemic therapy should perhaps be considered as a first-line option in these high-risk subsets. Prospective multi-institutional studies evaluating this strategy are warranted.

Association of MRI T2 Signal Intensity With Desmoid Tumor Progression During Active Observation: A Retrospective Cohort Study.

OBJECTIVE: The aim of this study was to identify predictors of desmoid progression during observation. SUMMARY OF BACKGROUND DATA: Untreated desmoids can grow, remain stable, or regress, but reliable predictors of behavior have not been identified. METHODS: Primary or recurrent desmoid patients were identified retrospectively from an institutional database. In those managed with active observation who underwent serial magnetic resonance imaging (MRIs) with T2-weighted sequences, baseline tumor size was recorded, and 2 radiologists independently estimated the percentage of tumor volume showing hyperintense T2 signal at baseline. Associations of clinical or radiographic characteristics with progression-free survival (PFS; by RECIST) were evaluated by Cox regression and Kaplan-Meier statistics. RESULTS: Among 160 patients with desmoids, 72 were managed with observation, and 37 of these had serial MRI available for review. Among these 37 patients, median age was 35 years and median tumor size was 4.7 cm; all tumors were extra-abdominal (41% in abdominal wall). Although PFS was not associated with size, site, or age, it was strongly associated with hyperintense T2 signal in ≥90% versus <90% of baseline tumor volume (as defined by the "test" radiologist; hazard ratio = 11.3, P = 0.003). For patients in the ≥90% group (n = 20), 1-year PFS was 55%, compared with 94% in the <90% group (n = 17). The percentage of baseline tumor volume with hyperintense T2 signal defined by a validation radiologist correlated with results of the test radiologist (ρ = 0.75). CONCLUSION: The percent tumor volume characterized by hyperintense T2 signal is associated with desmoid progression during observation and may help distinguish patients who would benefit from early intervention from those who may be reliably observed.

Clinicopathological characteristics, treatment, and survival outcomes of retroperitoneal desmoid-type fibromatosis: A single-institution experience in China.

Retroperitoneal desmoid-type fibromatosis (RPDF) is a rare mesenchymal neoplasm, and it covers a broad spectrum of aggressive monoclonal, fibroblastic proliferation. There is no evidence-based or established optimal treatment available for this intriguing disease yet. Therefore, we here investigated the clinicopathological characteristics, surgical, and survival outcomes in RPDF among Chinese patients.Patients with histologically confirmed RPDF were retrospectively studied from 2010 to 2018 within the West China Hospital of Sichuan University. Demographics, clinicopathological characteristics, treatment, and survival outcome data were collected.Of the 29 cases of RPDF, 19 were females. Tumor diameter ranged from 4 to 40 cm, with a median of 10 cm. Of these patients, surgical resection was the primary treatment adopted for RPDF in 26 cases; while 3 patients underwent watchful waiting. In surgical group, complete and incomplete macroscopic resection was achieved in 21 (80.77%) and 6 (19.23%) cases, respectively. Totally, 21 (80.77%) cases underwent multi-visceral resection. With a median follow-up duration of 48 months, 11 patients experienced tumor progression for the entire cohort. Tumor progression was observed for those patients with incomplete and complete macroscopic resection in 2/5 (40.0%) and 6/21 (28.6%) cases, respectively. In the watchful waiting group, there were no documented cases of RPDF regression. The progression-free survival rate was 86.1%, 71.5%, and 62.3% at 1-, 2-, and 3-years, respectively.RPDFs are rare types of tumor, which have characteristically varied natural histories. Surgical resection had a relative favorable outcome, but some patients were associated with burden of significant surgical complications.

Clinical features and treatment outcome of desmoid-type fibromatosis: based on a bone and soft tissue tumor registry in Japan.

BACKGROUND: Treatment modality of desmoid-type fibromatosis (DF) has changed from surgery with a wide surgical margin to conservative treatment. In this study, tumor characteristics of DF, transition of the treatment modality, and clinical outcome of surgical treatment were analyzed based on data obtained from the bone and soft tissue tumor registry established in Japan. METHODS: Data were collected as registration data and follow-up data. Five hundred and thirty registered cases of DF were identified, including 223 cases with follow-up data with or without surgical treatment. RESULTS: The number of registered patients increased gradually. The frequency of surgical treatment was gradually reduced year by year. The 3-year local recurrence free survival (LRFS) was 77.7%, with tumor location and size tending to correlate with LRFS. Interestingly, there was no significant difference in LRFS between wide and marginal margin (P = 0.34). CONCLUSIONS: The treatment modality has shifted from surgical to conservative treatment, with risk factors for surgical treatment similar to those noted in previous studies. The National registry system is crucial for a rare disease such as DF, and in the future, a population based registry system should be established to better comprehend the actual status of DF.

Clinical benefit of methotrexate plus vinorelbine chemotherapy for desmoid fibromatosis (DF) and correlation of treatment response with MRI.

BACKGROUND: Desmoid fibromatosis (DF) is a rare fibroblastic proliferation that was historically treated with surgery. We report (a) outcomes using low-dose chemotherapy, methotrexate (MTX), and vinorelbine (VNL) for patients with progressing disease (PD) and (b) whether tumor volume (Vtumor ) and T2 signal on magnetic resonance imaging (MRI) are more reflective of treatment response compared with maximum tumor dimension (Dmax ) defined by RECIST1.1. METHODS: Patients with biopsy-proven DF, treated with MTX/VNL from 1997 to 2015 were reviewed. MRI for a subset of patients was independently re-evaluated for response by RECIST, Vtumor , and quantitative T2 hyperintensity. RESULTS: Among 48 patients treated for a median 19 months MTX/VNL, only nine (19%) had previous surgery. RECIST-based overall response rate was complete response (CR) 20 (42%) + partial response (PR) 19 (39%), stable disease (SD) 8 (17%), for a clinical benefit rate of 98%. The median progression-free survival (PFS) was 120 months, (95%CI 84-155 months). Thirty-six (75%) patients had not progressed at a median 38 months from treatment completion. Most common grade 1/2 toxicities included nausea (n = 12, 25%) and fatigue (n = 9,19%) with no grade 3/4 toxicities. In 22 patients with serial MRIs, there was a decrease in Dmax mean by 30%, Vtumor by 76%, and in 19/22 (86%) a decrease in T2 signal intensity. CONCLUSION: Low-dose MTX/VNL for a defined duration has high efficacy with sustained benefit and minimal toxicity for treating DF. Vtumor and T2 signal might better predict treatment response than RECIST.

Long-Term Outcomes for Patients With Desmoid Fibromatosis Treated With Radiation Therapy: A 10-Year Update and Re-evaluation of the Role of Radiation Therapy for Younger Patients.

PURPOSE: To update our experience with long-term outcomes in patients with desmoid fibromatosis treated with radiation therapy (RT) and to characterize factors associated with increased risk of local recurrence. METHODS AND MATERIALS: We reviewed the records of 209 consecutive patients with desmoid fibromatosis treated with RT, either alone or as combined-modality therapy (CMT) with surgery, at our institution from 1965 to 2015. RESULTS: Median follow-up time was 98 months (range, 1-509 months). The 5- and 10-year local control (LC) was 71% and 69%, respectively. Fifty-nine patients (28%) experienced a local recurrence at a median time of 23 months (interquartile range, 15-38 months). Among all patients, on multivariable analysis, adjusting for anatomic site, size, age, treatment era (>2005 vs ≤2005), treatment approach (RT alone vs CMT), and an interaction between age and treatment, we found only age ≤30 years (hazard ratio [HR], 2.94; P = .005; 95% confidence interval [CI], 1.38-6.27) and large tumor size >10 cm (HR, 2.51; P = .03; 95% CI, 1.09-5.78) to be correlated with poorer LC. Notably, for patients receiving RT alone, the 5-year LC was 43% for patients ≤30 years old versus 75% for >30 years old (P < .001). On multivariable analyses, for patients receiving RT alone, the only factor associated with inferior LC was age ≤30 years (HR, 2.87; P = .001; 95% CI, 1.51-5.47). The same was true for patients treated with CMT; age ≤30 years was the only factor associated with inferior LC (HR, 5.36; P = .01; 95% CI, 1.40-20.58). CONCLUSIONS: Among all patients with desmoid fibromatosis, RT is an effective local therapy for tumor control. However, young patients ≤ 30 years have notably high rates of local recurrence regardless of treatment strategy, which requires further study. Treatment decisions should be risk-adapted by large referral centers with multidisciplinary expertise in desmoid management.

Clinical prognostic factors for pediatric extra-abdominal desmoid tumor: analyses of 66 patients at a single institution.

BACKGROUND AND PURPOSE: Pediatric desmoid tumor (PDT) is rare and has a high local recurrence rate. The purpose of the present study was to analyze clinical risk factors of local recurrence in PDT patients. MATERIALS AND METHODS: We reviewed clinical data of 66 PDT patients from 2004 to 2015. All patients underwent macroscopically complete resection, and some recurrent tumors were prescribed radiotherapy. Factors such as sex, age at presentation, location, and proximity to nerves or vasculature were analyzed. The local recurrence rate and recurrence-free survival were analyzed with these factors. RESULTS: All patients in the present study were children and had extra-abdominal tumors. The median follow-up time was 6.6 years. Thirty-six (55%) patients had local recurrence. Age, sex, tumor site, tumor size, and proximity to nerves/vasculature had a significant impact on prognosis in univariate analysis. Radiotherapy decreased the local recurrence rate. In multivariate analysis, younger age, tumor location in buttocks, larger tumor, and proximity to important nerves/vasculature were independent risk factors for poor prognosis. CONCLUSIONS: Favorable therapeutic strategies could be selected according to the preoperative prognostic risk factors. Radiotherapy should be considered for local recurrence of PDT.

Sorafenib for Advanced and Refractory Desmoid Tumors.

BACKGROUND: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care. METHODS: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated. RESULTS: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). CONCLUSIONS: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).

Oncologic Resection and Reconstruction of the Chest Wall: A 19-Year Experience in a Single Center.

BACKGROUND: The aim of this study was to analyze chest wall reconstruction following oncologic resection performed by a single surgeon over a 19-year period. METHODS: A retrospective review was performed for 135 patients who underwent oncologic chest wall resection from 1997 to 2015. RESULTS: Average patient age was 57.8 years. Indications for resection were advanced breast cancer (n = 44), soft-tissue sarcoma (n = 38), bone sarcoma or chondrosarcoma (n = 28), desmoid tumor (n = 11), metastasis from other cancers (n = 7), and other primary tumors (n = 7). There were 72 full-thickness and 63 partial-thickness resections (34 soft-tissue resections only and 29 skeletal bone resections only). Resection margins were wide (n = 29), marginal (n = 82), and intralesional (n = 24). Reconstruction was warranted in 118 cases: chest wall stabilization and flap coverage in 57, chest wall stabilization only in 36, and soft-tissue flap coverage only in 25 cases. In total, 82 flaps were performed (17 free flaps and 65 pedicled/local flaps). There were no perioperative mortalities or flap losses. Complications occurred in 29 operations (Clavien-Dindo classifications grade II, n = 12; grade IIIa, n = 4; grade IIIb, n = 10; and grade IVa, n = 3) and 19 reoperations were necessary. Median follow-up was 49 months. Survival was calculated by the Kaplan-Meier method. One-, 2-, and 5-year survival rates were 84, 82, and 70 percent, respectively. CONCLUSION: With careful patient selection, appropriate perioperative and postoperative care, and accurate surgical technique, even extensive chest wall resections and reconstructions are safe. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Radiation Therapy for Aggressive Fibromatosis: The Association Between Local Control and Age.

PURPOSE: Radiation therapy (RT) is often used in the treatment of unresectable or recurrent aggressive fibromatosis (also known as desmoid tumor) typically with excellent local control. Prior reports have suggested that local control in pediatric patients with aggressive fibromatosis is poor. We aimed to report a long-term single-institution experience with the radiotherapeutic treatment of these tumors with a focus on age-dependent outcomes. METHODS AND MATERIALS: A total of 101 patients treated with RT for aggressive fibromatosis between 1975 and 2015 at a single institution were identified. A variety of demographic and treatment-related variables were abstracted from patients' medical records. Kaplan-Meier analyses were performed to investigate the relationship between these variables and local control. RESULTS: Overall survival was excellent (98% and 95% at 5 and 10 years, respectively); local control was likewise excellent (82% and 78% at 5 and 10 years, respectively). Patients aged <20 years at diagnosis had significantly worse 5-year local control than those aged >40 years at diagnosis (72% vs 97%; hazard ratio, 9.0; P = .009). Patients treated with once-daily fractionation had significantly improved 5-year local control compared with those treated with twice-daily fractionation (90% vs 73%; hazard ratio, 0.3; P = .008). Neither the presence of gross versus microscopic residual disease, initial versus recurrent presentation, number of prior surgical procedures, nor tumor size had any effect on 5-year local control. In a total of 36.6% of patients, Common Terminology Criteria for Adverse Events grade 3 or 4 toxicity developed following treatment; the frequency of toxicities was reduced in patients treated during or after 1995 (24.5%) relative to those treated prior to 1995 (51.9%, P = .02). CONCLUSIONS: RT for aggressive fibromatosis offers excellent local control and should remain the standard of care for patients with unresectable or recurrent disease. Younger patients have diminished local control relative to older patients, suggesting possible biological differences contributing to radioresistance in the pediatric and young adult population.

Desmoid Tumours of the extremity and trunk. A retrospective study of 44 patients.

BACKGROUND: Desmoid-type fibromatosis (DF) is a aggressive (myo)fibroblastic neoplasm with an infiltrative growth and a tendency to local recurrence. Resection of the tumour and/or radiation were proposed as principal treatment. The aim of this retrospective study was to analyze the local control rates focusing on the effect of surgical margins and radiotherapy. METHODS: From 1981 to 2014, 44 patients had been treated. Fifty four therapies had been applied, in 50 cases surgery +/- radiation therapy, NSAIDs or chemotherapy. In 4 cases a conservative approach was chosen. Thirty seven patients had primary, 17 recurrent disease. Endpoint was either local recurrence (LR), progression of residual disease or rare non-metastatic secondary lesions at the same extremity. RESULTS: The mean age was 39,4 years. In 17 cases a R0, in 27 a R1 and in 6 cases a R2 resection was achieved. Four patients were treated conservatively. All together in 21 cases radiotherapy, in 5 NSAIDs, in 3 imatinib and in 2 cases each tamoxifen or chemotherapy had been applied. The median follow-up was 119 months. 5-year recurrence free survival after resection was 78%. 10 (20.4%) patients developed LR between 5 and 42 months after therapy. Recurrent disease was a negative factor on LR. Margins, radiotherapy, sex, or size of the tumour had no significant impact on LR. Patients younger than 40 years had a significant higher risk of LR. CONCLUSIONS: Surgical margins are less important than keeping function. Radiotherapy might be an option in unresectable lesions, the role of adjuvant radiotherapy is controversially discussed.