Intermediate-risk endometrial cancer treated with adjuvant brachytherapy using single dosimetric planning: long-term outcome and toxicity assessment.

OBJECTIVE: Brachytherapy of the vaginal dome is the recommended adjuvant treatment for intermediate-risk endometrial cancer. This study assessed the results of dosimetric planning of high-dose-rate brachytherapy exclusively in the first treatment session. STUDY DESIGN: This retrospective study included all patients who underwent hysterectomy for endometrial cancer followed by adjuvant brachytherapy of the vaginal dome between 2012 and 2015. Local recurrence rates, overall survival (OS) rates, recurrence-free survival (RFS) rates, and related acute and late toxicity rates were evaluated. RESULTS: This analysis included 250 patients, of whom 208 were considered to be at high-intermediate risk of disease recurrence. After a median follow-up of 56 months, the cumulative incidence of local recurrence was 4.8% at 3 years [95% confidence interval (CI) 2.8-8.3] and 7.8% at 5 years (95% CI 4.8-12.6). The 5-year OS rate was 86.2% (95% CI 80.6-90.3), and the 5-year RFS rate was 77.5% (95% CI 71.1-82.7). Acute toxicity occurred in 20 (8%) patients, of which two patients had grade ≥3 toxicity. Only one patient (0.4%) presented with late grade ≥3 toxicity. CONCLUSION: These findings confirm the tolerability of this brachytherapy approach, indicating minimal cases of late grade ≥3 toxicity, associated with a good 5-year OS rate. With the advent of molecular prognostic factors, the current focus revolves around discerning those individuals who gain the greatest benefit from adjuvant therapy, and tailoring treatment more effectively.

Initial Active Surveillance Strategy for Patients with Peripheral Sporadic Primary Desmoid-Type Fibromatosis: A Multicentric Phase II Observational Trial.

BACKGROUND: Stabilization or spontaneous regressions are demonstrated in more than half of patients affected by primary desmoid-type fibromatosis (DF) in retrospective studies. The objective of this phase II study was to prospectively assess the behavior of primary sporadic DT managed by active surveillance (AS). METHODS: This prospective, multicenter, observational study (NCT01801176) included patients ≥18 years of age with primary sporadic DF located in an extremity or the abdominal/thoracic wall. At inclusion, all patients were initially placed on AS. Follow-up was based on clinical and radiological evaluation by magnetic resonance imaging (MRI) performed at 1, 3, 6, 9, and 12 months, and then every 6 months for 3 years. The primary endpoint was progression-free survival (PFS) at 3 years according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as evaluated by a Central Review Board. RESULTS: Between 2012 and 2015, 100 patients were enrolled. The female/male ratio was 8 and the median age was 34 years (interquartile range [IQR] 30.8-43.9). Median follow-up was 46.6 months (IQR 36.8-61.1) and the 3-year PFS was 53.4% (95% confidence interval 43.5-63.1%). At progression (48 patients), 23 patients received active treatment. Fifty-eight patients (58%) presented with spontaneous tumor regression (decrease > 0% compared with the initial size) during the first 3 months (n = 35, 35%) or after an initial progression (n = 23, 23%), of whom 26 (26%) had partial responses (PRs). The median time to PR was 31.7 months (25.3-not available). CONCLUSIONS: These data support the use of AS as the primary approach to select patients with peripheral DF who require aggressive treatment.

[Contribution of whole-body MRI to the initial assessment of myxoid liposarcoma]. / Apport de l'IRM corps entier au bilan initial du liposarcome myxoïde.

INTRODUCTION: Myxoid liposarcoma is a soft tissue sarcoma associated with multifocal metastases at diagnosis. These metastases are asymptomatic and occult on CT and FDG-PET and can alter the therapeutic management and prognosis. In this context, we evaluated the contribution of whole-body MRI to the initial workup of patients with myxoid liposarcoma. METHOD: This retrospective study was conducted between January 2015 and December 2020 at the Oscar Lambret Center. We enrolled 22 patients who were diagnosed with myxoid liposarcoma and underwent whole-body MRI at diagnosis. The number of metastases at diagnosis, their location, and the visibility of these lesions on CT were evaluated. Associations between clinical features, presence of metastasis, and their impact on management were assessed. RESULTS: Sixteen patients (72.7%) had non-metastatic disease at the initial diagnosis, and 15 of these patients were managed using local treatment. Six patients (27.3%) had metastases at multiple locations and received chemotherapy. The main locations were the bones (n=5) and lungs (n=3). In five patients with metastases, whole-body MRI demonstrated additional lesions that were not visible on CT (bone and soft tissue lesions). Only the presence of a round cell contingent (P=0.009) was found as a criterion associated with the presence of metastases. CONCLUSION: The patients' young age, absence of reliable prognostic factors at diagnosis, asymptomatic nature of the lesions, and the benefits of early and targeted therapeutic management encourage the use of whole-body MRI as part of the initial work-up as it seems to provide a better initial staging compared with conventional imaging.

Diagnostic Value of the Texture Analysis Parameters of Retroperitoneal Residual Masses on Computed Tomographic Scan after Chemotherapy in Non-Seminomatous Germ Cell Tumors.

After chemotherapy, patients with non-seminomatous germ cell tumors (NSGCTs) with residual masses >1 cm on computed tomography (CT) undergo surgery. However, in approximately 50% of cases, these masses only consist of necrosis/fibrosis. We aimed to develop a radiomics score to predict the malignant character of residual masses to avoid surgical overtreatment. Patients with NSGCTs who underwent surgery for residual masses between September 2007 and July 2020 were retrospectively identified from a unicenter database. Residual masses were delineated on post-chemotherapy contrast-enhanced CT scans. Tumor textures were obtained using the free software LifeX. We constructed a radiomics score using a penalized logistic regression model in a training dataset, and evaluated its performance on a test dataset. We included 76 patients, with 149 residual masses; 97 masses were malignant (65%). In the training dataset (n = 99 residual masses), the best model (ELASTIC-NET) led to a radiomics score based on eight texture features. In the test dataset, the area under the curve (AUC), sensibility, and specificity of this model were respectively estimated at 0.82 (95%CI, 0.69-0.95), 90.6% (75.0-98.0), and 61.1% (35.7-82.7). Our radiomics score may help in the prediction of the malignant nature of residual post-chemotherapy masses in NSGCTs before surgery, and thus limit overtreatment. However, these results are insufficient to simply select patients for surgery.

[Uterin adenosarcoma: French Guidelines of the French Sarcoma Group and the Rare Gynecologic Tumor Group]. / Adénosarcomes mullériens de l'utérus ­ référentiels de prise en charge du GSF-GETO/NETSARC+ et du groupe TMRG.

Uterine adenosarcoma is a very rare malignancy defined as a biphasic tumor composed of both benign epithelial component and a malignant sarcoma component. The stage of the disease is determined by the presence of myometrial invasion and the extent of extra-uterine disease. The most important histopronostic factors are the existence of a sarcomatous overgrowth defined by a sarcomatous contingent occupying more than 25 % of the volume of the tumor (directly correlated to the grade of the disease), the presence of a heterologous and/or a high-grade component. Stage I adenosarcomas without sarcomatous overgrowth have a good prognosis, with an overall 5-year survival of up to 80 %. In localized disease, complete surgical removal is recommended. The role of hormone therapy, chemotherapy and adjuvant radiotherapy is not established. If possible, relapses should be re-treated surgically, with the aim of achieving complete resection. In the advanced inoperable or metastatic setting, hormone therapy is an option for low-grade adenosarcomas with estrogen receptor (ER) and progesterone receptor (PR) overexpression. For high-grade tumors, the standard chemotherapies are doxorubicin-based combinations, although an integrated approach of surgery and medical treatment should also be considered in this setting.

[Uterin sarcoma, high-grade stroma, indifferenciated, referential]. / Sarcomes utérins du stroma de haut grade et sarcomes indifférenciés ­ Référentiels de prise en charge du Groupe Sarcome Français et du Groupe des Tumeurs Rares Gynécologiques.

High-grade endometrial stromal sarcoma (HGESS) and uterine undifferentiated sarcoma (UUS) are rare uterine malignancies arising from mesenchymal endometrial cells. They are characterized by aggressive behavior and poor prognosis. Median age of diagnostic is 55years. The most common symptoms are vaginal bleeding, abdominal pain, and pelvic mass. Approximately 65 % are diagnosed witch advance disease stage III or IV according to the International Federation of Gynecology and Obstetrics classification. Median overall survival is around 20months. The management of the disease must be discussed in multidisciplinary staff meetings. The standard management of HGESS and UUS is total hysterectomy with bilateral oophorectomy. Systematic lymphadenectomy is not recommended. Adjuvant therapies, such as chemotherapy and radiotherapy must be discussed. In case of oligo-metastasic disease, surgery of the primary tumor and metastasis must be discussed and if not operable the standard management is doxorubine-based chemotherapy.

[Uterine leiomyosarcoma - French guidelines from the GSF/NETSARC and TMRG groups]. / Léiomyosarcomes utérins ­ Référentiel de prise en charge du GSF-GETO/NETSARC+ et du groupe TMRG.

Uterine leiomyosarcomas represent the most common uterine sarcomas. The prognosis is poor with metastatic recurrence in more than half of the cases. The purpose of this review is to make French recommendations for the management of uterine leiomyosarcomas within the framework of the French Sarcoma Group - Bone Tumor Study Group (GSF-GETO)/NETSARC+ and Malignant Rare Gynecological Tumors (TMRG) networks in order to optimize their therapeutic management. The initial assessment includes a MRI with diffusion perfusion sequence. The diagnosis is histological with a review in an expert center (Reference Network in Sarcoma Pathology (RRePS)). Total hysterectomy with bilateral salpingectomy, en bloc without morcellation, is performed when complete resection is possible, whatever the stage. There is no indication of systematic lymph node dissection. Bilateral oophorectomy is indicated in peri-menopausal or menopausal women. Adjuvant external radiotherapy is not a standard. Adjuvant chemotherapy is not a standard. It can be an option and consists in doxorobucin based protocols. In the event of local recurrence, the therapeutic options are based on revision surgery and/or radiotherapy. Systemic treatment with chemotherapy is most often indicated. In case of metastatic disease, surgical treatment remains indicated when resecable. In cases of oligo-metastatic disease, focal treatment of metastases should be considered. In the case of stage IV, chemotherapy is indicated, and is based on first-line doxorubicin-based protocols. In the event of excessive deterioration in general condition, management by exclusive supportive care is recommended. External palliative radiotherapy can be proposed for symptomatic purposes.

[Endometrial stromal sarcoma: French Guidelines from the French Sarcoma Group and the Rare Malignant Gynecologic Tumors Group]. / Sarcomes du stroma endométrial de bas grade : référentiels de prise en charge du GSF-GETO/NETSARC+ et du groupe TMRG.

Low-grade endometrial stromal sarcoma (LG-ESS) accounts for approximately 15% of all uterine sarcomas. Median age of patients is around 50 years and half of the patients are premenopausal. In all, 60% of cases present with FIGO stage I disease. Preoperatively radiologic findings of ESS are not specific. Pathological diagnosis remains essential. This review aimed to present the French guidelines for low grade ESS treatment within the Groupe sarcome français - Groupe d'étude des tumeurs osseuse (GSF-GETO)/NETSARC+ and tumeur maligne rare gynécologique (TMRG) networks. Treatments should be validated in multidisciplinary team involved in sarcomas or rare gynecologic tumors. Hysterectomy is the cornerstone of treatment for localized ESS, and morcellation should be avoided. Systematic lymphadenectomy in ESS does not improve the outcome and is not recommended. Leaving the ovaries in situ in stage I tumors could be discussed for young women. Adjuvant hormonal treatment could be considered, for two years for stage I with morcellation or stage II and livelong for stages III or IV. Nevertheless, several questions remain, such as optimal doses, regimens (progestins or aromatase inhibitors) and duration of therapy. Tamoxifen is contraindicated. Secondary cytoreductive surgery if feasible for recurrent disease, appears to be an acceptable approach. Systemic treatment for recurrent or metastatic disease is mainly hormonal, with or without surgery.

Results of a 20 Year Retrospective Analysis of Early-Stage Cervical Cancer: Should 3 cm Be Considered the New Ariadne's Thread in Early Cervical Cancer Treatment?

(1) This study aims to evaluate the overall survival (OS) and recurrence-free survivals (RFS) and assess disease recurrence of early-stage cervical cancer (ESCC) patients treated with minimally invasive surgery (MIS). (2) This single-center retrospective analysis was performed between January 1999 and December 2018, including all patients managed with MIS for ESCC. (3) All 239 patients included in the study underwent pelvic lymphadenectomy followed by radical hysterectomy without the use of an intrauterine manipulator. Preoperative brachytherapy was performed in 125 patients with tumors measuring 2 to 4 cm. The 5-year OS and RFS rates were 92% and 86.9%, respectively. Multivariate analysis found two significant factors associated with recurrence: previous conization with HR = 0.21, p = 0.01, and tumor size > 3 cm with HR = 2.26, p = 0.031. Out of the 33 cases of disease recurrence, we witnessed 22 disease-related deaths. Recurrence rates were 7.5%, 12.9%, and 24.1% for tumors measuring ≤ 2 cm, 2 to 3 cm, and > 3 cm, respectively. Tumors ≤ 2 cm were mostly associated with local recurrences. Tumors > 2 cm were frequently associated with common iliac or presacral lymph node recurrences. (4) MIS may still be considered for tumors ≤ 2 cm subject to first conization followed by surgery with the Schautheim procedure and extended pelvic lymphadenectomy. Due to the increased rate of recurrence, a more aggressive approach might be considered for tumors > 3 cm.

Prognostic impact of tumor size reduction assessed by magnetic resonance imaging after radiochemotherapy in patients with locally advanced cervical cancer.

Objective: Pelvic magnetic resonance imaging (MRI) is a key exam used for the initial assessment of loco-regional involvement of cervical cancer. In patients with locally advanced cervical cancer, MRI is used to evaluate the early response to radiochemotherapy before image-guided brachytherapy, the prognostic impact of which we aimed to study. Methods: Patients with locally advanced cervical cancer treated using concomitant radiochemotherapy followed by closure treatment between January 2010 and December 2015 were included in this study. Clinical, anatomopathological, radiological, therapeutic, and follow-up data were evaluated. Results: After applying the inclusion and exclusion criteria to the initially chosen 310 patients, 232 were included for evaluation (median follow-up period, 5.3 years). The median age was 50 years (range, 25-83 years), and the median tumor size was 47.5 mm (range, 0-105 mm). Based on the International Federation of Gynaecology and Obstetrics classification system, 9 patients were in stage IB2; 20, IB3; 2, IIA; 63, IIB; 4, IIIA; 7, IIIB; and 127, IIIC1 or higher. The re-evaluation MRI was performed at the median dose of 55.5 Gy, and median reduction in tumor size was 55.2% (range, -20-100%). There was a difference between the disease-free and overall survival rates of the patients with a tumor response greater or lesser than 50%. The risk of recurrence or death reduced by 39% in patients with a tumor size reduction >50%. The overall 5-year survival rate of patients with a response greater and lesser than 50% were 77.7% and 61.5%, respectively. The 5-year disease-free survival rate for these two groups of patients were 68.8% and 51.5%, respectively. Conclusion: Our study confirms the prognostic impact of tumor size reduction using MRI data obtained after radiochemotherapy in patients with locally advanced cervical cancer.

[Magnetic resonance imaging of desmoid-type fibromatosis: Current evaluation criteria]. / Imagerie par résonance magnétique des tumeurs desmoïdes : critères d'évaluations actuels.

The management of desmoid-type fibromatosis has considerably evolved these last years, toward first-line active surveillance then systemic or local symptomatic treatment in case of aggressive tumor. Magnetic resonance imaging is the modality of choice in each of these treatment settings. It needs multiparametric approach taking into account mainly the tumor size, and T2-weighted signal that is correlated with histological composition and clinical behavior. A volumetric approach should be favored for the evaluation of tumor size change. The interest of paramagnetic contrast injection and tumor enhancement requires further investigation.

A double-blind placebo-controlled randomized phase II trial assessing the activity and safety of regorafenib in non-adipocytic sarcoma patients previously treated with both chemotherapy and pazopanib.

BACKGROUND: Metastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib. PATIENTS AND METHODS: This double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours-based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 (ClinicalTrials.gov, NCT01900743). RESULTS: From December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4-not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15-0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23-1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0). CONCLUSION: The present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.

Outcomes of pre-operative brachytherapy followed by hysterectomy for early cervical cancer.

OBJECTIVE: The standard of care for early cervical cancer is radical hysterectomy; however, consideration of pre-operative brachytherapy has been explored. We report our experience using pre-operative brachytherapy plus Wertheim-type hysterectomy to treat early stage cervical cancer. METHODS: This single-center study evaluated consecutive patients with histologically proven node-negative early stage cervical cancer (International Federation of Gynecology and Obstetrics 2009 stage IB1-IIB) that was treated using pre-operative brachytherapy and hysterectomy. Pre-brachytherapy staging was performed using magnetic resonance imaging (MRI) and pelvic lymph node assessment was performed using lymphadenectomy. The tumor and cervical tissues were treated using brachytherapy (total dose 60 Gy) followed by Wertheim-type hysterectomy. The study included patients from January 2000 to December 2013. RESULTS: A total of 80 patients completed a median follow-up of 6.7 years (range 5.4-8.5). The surgical specimens revealed a pathological complete response for 61 patients (76%). Patients with incomplete responses generally had less than 1 cm residual tumor at the cervix, and only one patient had lymphovascular space involvement. The estimated 5-year rates were 88% for overall survival (95% CI 78% to 94%) and 82% for disease-free survival (95% CI 71% to 89%). Toxicities were generally mild-to-moderate, including 26 cases (33%) of grade 2 late toxicity and 10 cases (13%) of grade 3 late toxicity. Univariate analyses revealed that poor disease-free survival was associated with overweight status (≥25 kg/m2, HR 3.05, 95% CI 1.20 to 7.76, p=0.019) and MRI tumor size >3 cm (HR 3.05, 95% CI 1.23 to 7.51, p=0.016). CONCLUSIONS: Pre-operative brachytherapy followed by Wertheim-type hysterectomy may be safe and effective for early stage cervical cancer, although poorer outcomes were associated with overweight status and MRI tumor size >3 cm.

Persistent response to vemurafenib in metastatic ameloblastoma with BRAF mutation: a case report.

BACKGROUND: Ameloblastomas are uncommon locally aggressive tumors of odontogenic epithelium that rarely metastasize. Currently, there is no standard of care for the metastatic forms. Several studies have shown that ameloblastomas frequently have a BRAF mutation. CASE PRESENTATION: We report a case of a 33-year-old Caucasian woman with ameloblastoma diagnosed 30 years ago who developed lung metastasis 19 years ago. Systemic oral treatment with vemurafenib, a BRAF inhibitor, was initiated 28 months ago within the AcSé French basket clinical trial of vemurafenib. CONCLUSIONS: The patient has shown a durable clinical, functional, and radiographic partial response with vemurafenib. These observations suggest the possibility of introducing neoadjuvant and/or adjuvant targeted therapy in locally advanced ameloblastoma to improve outcome. BRAF inhibition has proved to be an efficient strategy in patients with a BRAF-mutated ameloblastoma.

[French program of breast cancer screening: Radiologist viewpoint]. / Dépistage organisé du cancer du sein : point de vue du radiologue.

French program of breast cancer screening is implemented since15 years and results are in adequation with international guidelines except for participation. To answer to recurrent controversies about breast cancer screening, publications from National Institute of French cancer registry confirm the positive impact of screening on decreasing mortality for participating women. The harms of mammography (and not from screening) need to be communicated to the invited women to help them to make decision about participation but also the risk of worse prognosis in case of symptomatic cancer. The future of screening will be different and works are in progress to find new ways to select women who will beneficiate for screening and whose cancer needs to be treated. Until then, the only way to screen for breast cancer stays the mammographic process as well as other technics in case of dense breast or in case of family history of breast cancer.

Alveolar soft-part sarcoma: can MRI help discriminating from other soft-tissue tumors? A study of the French sarcoma group.

OBJECTIVES: To investigate the imaging features of alveolar soft-part sarcomas (ASPS) on pre-treatment MRI in order to identify relevant criteria to distinguish ASPS from other soft-tissue tumors. METHODS: A series of 25 patients (mean age, 18.5 years old) with histologically proven ASPS from five French comprehensive cancer centers was compared to a control cohort of 292 patients with various histologically proven benign and malignant soft-tissue tumors representative of the 10-year long activity of one center. All had a baseline MRI with contrast-agent administration. Two radiologists independently reviewed the MRIs. Features assessing location, size, signal, architecture, periphery, and vascularization were reported. Their association with the histological diagnosis of ASPS was evaluated with chi-square or Fisher's test. Their prevalence, sensitivity, specificity, odds ratio, and reproducibility were calculated. RESULTS: Eight MRI features were significantly associated with ASPS: deep location (p < 0.001), high signal intensities on T1-weighted imaging (p < 0.001), central area of necrosis (p = 0.001), absence of fibrotic component (p = 0.003), infiltrative growth pattern (p = 0.003), absence of tail sign (p = 0.001), presence of intra- and peritumoral flow-voids (p < 0.001), and number of flow-voids ≥ 5 (p < 0.001). Twenty out of the 25 (80%) ASPS showed at least 7 of these 8 features compared to only four out of 292 (1.4%) tumors of the control cohort (1 benign vascular tumor, 1 solitary fibrous tumor, 2 high-grade soft-tissue sarcomas). The five ASPS with less than 7 out of 8 features measured less than 40 mm. CONCLUSION: The striking histological uniformity of ASPS translates into imaging. However, ASPS may be misdiagnosed as benign tumors or pseudo-tumors, notably intramuscular benign vascular tumors or vascular malformations. KEY POINTS: • ASPS are rare aggressive mesenchymal tumors displaying recurrent MRI features highly reminiscent of the diagnosis. • Deep-seated tumors presenting with mainly high signal intensity on T1-weighted imaging, an absence of fibrotic component, ill-defined margins without aponeurotic extension, and more than five central and peripheral flow-voids are very likely to be ASPS. • ASPS may be misdiagnosed as intramuscular benign vascular tumor or vascular malformation, which occur in the same age group.

Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial.

BACKGROUND: Pigmented villonodular synovitis (alternatively known as diffuse-type giant cell tumour) is a rare, locally aggressive tumour driven by a specific translocation resulting in the overexpression of colony-stimulating factor 1 (CSF1). CSF1 receptor (CSF1R) inhibitors (ie, tyrosine kinase inhibitors and antibodies) induce a response in patients with pigmented villonodular synovitis. We investigated the safety and efficacy of a CSF1R tyrosine kinase inhibitor, nilotinib, in patients with locally advanced non-resectable pigmented villonodular synovitis. METHODS: In this phase 2, open-label, single-arm study, we enrolled patients from 11 cancer centres of hospitals in four countries (France, Netherlands, Italy, and Australia). Eligible patients were aged at least 18 years with a WHO performance status of 2 or less, and histologically confirmed progressive or relapsing pigmented villonodular synovitis that was inoperable, or resectable only with mutilating surgery. Patients received oral nilotinib (400 mg twice per day) until disease progression, unacceptable toxicity, or completion of 1 year of treatment. The primary endpoint was the proportion of patients who were progression free at 12 weeks, which was centrally assessed according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were by modified intention to treat (ie, all patients with no major protocol violations who were treated with nilotinib for at least 3 weeks were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT01261429, and the results presented here are the final analysis of the trial. FINDINGS: Between Dec 15, 2010, and Sept 28, 2012, we enrolled 56 patients with pigmented villonodular synovitis and treated them with nilotinib. Five (9%) patients discontinued study treatment before week 12; therefore, 51 patients were evaluable for the primary endpoint at 12 weeks. The estimated proportion of patients who were progression free at 12 weeks was 92·6% (95% credible interval 84·3-97·9). 54 (96%) of 56 patients had a treatment-related adverse event. Six (11%) of 56 patients had at least one grade 3 treatment-related adverse event (headache, dizziness, and hepatic disorders [n=1], pruritus and toxidermia [n=1], diarrhoea [n=1], increased γ-glutamyl transferase concentration [n=1], anorexia [n=1], and increased headache [n=1]). No grade 4 or 5 adverse events were reported. One patient had a treatment-related serious adverse event (toxidermia) and two patients had serious adverse events not considered to be related to the study drug (borderline ovarian tumour [n=1] and pilonidal cyst excision [n=1]). INTERPRETATION: More than 90% of patients with locally advanced unresectable progressive pigmented villonodular synovitis achieved disease control with 12 weeks of nilotinib treatment. These results indicate that CSF1R tyrosine kinase inhibitors have anti-tumour activity with manageable toxicity in patients with inoperable progressive pigmented villonodular synovitis. Randomised trials investigating the efficacy of nilotinib for patients with unresectable pigmented villonodular synovitis are warranted. FUNDING: Novartis, Institut National du Cancer, EuroSARC, French National Cancer Institute, General Directorate of Care Supply, Lyon Research Innovation for Cancer, L'Agence nationale de la recherche, Laboratory of Excellence, Fondation ARC pour la recherche sur le cancer, Ligue contre le Cancer (comité de l'Ain), Info Sarcomes, and Association DAM'S.

REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis.

BACKGROUND: In a placebo-controlled, randomized phase 2 trial (ClinicalTrials.gov identifier NCT01900743), regorafenib improved progression-free survival (PFS) for patients with doxorubicin-pretreated advanced nonadipocytic sarcoma. A quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) post hoc exploratory analysis was applied to provide an integrated measure of its clinical benefit. METHODS: In the base-case analysis, each patient's overall survival (OS) was partitioned into 3 mutually exclusive health states: the time with a grade 3 or 4 adverse event (TOX), the time without symptoms of disease or grade 3 or 4 toxicity from treatment, and the time after tumor progression or relapse. The time spent in each state was weighted with a health-state utility associated with that state and was summed to calculate the Q-TWiST. The stability of the base-case analysis was explored with several sensitivity analyses. RESULTS: In nonadipocytic sarcoma, the PFS was (4.0 months [2.6-5.5 months] with regorafenib vs 1.0 month [0.9-1.8 months] with a placebo; hazard ratio, 0.36 [0.25-0.53]; P < .0001); the OS was 13.4 months (8.6-17.3 months) with regorafenib and 9.0 months (6.8-12.5 months) with a placebo (hazard ratio, 0.67 [0.44-1.02]). With the classic definition of TOX (including all grade 3 and 4 clinical adverse events), the Q-TWiSTs were 8.0 months (7.0-9.0 months) with regorafenib and 5.7 months (4.9-6.4 months) with a placebo (P < .001). CONCLUSIONS: For patients with doxorubicin-pretreated soft-tissue sarcoma, regorafenib significantly improved quality-adjusted survival in comparison with a placebo. Cancer 2017;123:2294-2302. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.