We report here a correlation analysis conducted along with a phase II trial assessing bevacizumab in combination with weekly paclitaxel.
Circulating pro/anti-angiogenic factors were assessed on day 1 ...(D1) and day 8 (D8). The prognostic value for progression-free survival (PFS) was evaluated using a Cox model with biomarkers as continuous variables.
Among the 51 patients enrolled and treated in this trial, biomarker analysis was performed for 42: 18 in Arm A (single-agent) and 24 in Arm B (combination). With a median follow-up of 46 months, PFS was 5.5 versus 5.7 months, respectively (p = 0.75). According to univariate analysis, factors associated with a poor PFS were as follows: visceral angiosarcoma, de novo angiosarcoma, and high PlGF and low VEGF-C baseline values. In multivariate analysis, de novo angiosarcoma (HR = 2.5; p = 0.024) and baseline VEGF-C value (HR = 0.7; p = 0.003) were significant prognostic factors. We observed a significant increase in circulating PlGF (< 0.001) and a decrease in VEGF (< 0.001) during bevacizumab treatment. An increase in FGF was associated with a poor outcome.
De novo angiosarcoma and a low baseline level of VEGF-C were found to be associated with a poor prognosis. Addition of bevacizumab induces major changes in circulating biomarkers (VEGF and PlGF) in a short timeframe without impacting PFS.
Retrospectively registered on EudraCT N° 2009-017020-59 and NCT01303497 (February 24, 2011).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Brain metastases from sarcomatous lesions pose a management challenge owing to their rarity and the histopathological heterogeneity. Prognostic indices such as the Graded Prognostic Assessment (GPA) ...index have been developed for several primary tumour types presenting with brain metastases (e.g. lung, breast, melanoma), tailored to the specifics of different primary histologies and molecular profiles. Thus far, a prognostic index to direct treatment decisions is lacking for adult sarcoma patients with brain metastases.
We performed a multicentre analysis of a national group of expert sarcoma tertiary centres (French Sarcoma Group, GSF-GETO) with the participation of one Canadian and one Swiss centre. The study cohort included adult patients with a diagnosis of a bone or soft tissue sarcoma presenting parenchymal or meningeal brain metastases, managed between January 1992 and March 2012. We assessed the validity of the original GPA index in this patient population and developed a disease-specific Sarcoma-GPA index.
The original GPA index is not prognostic for sarcoma brain metastasis patients. We have developed a dedicated Sarcoma-GPA index that identifies a sub-group of patients with particularly favourable prognosis based on histology, number of brain lesions and performance status.
The Sarcoma-GPA index provides a novel tool for sarcoma oncologists to guide clinical decision-making and outcomes research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
CIC‐rearranged sarcomas (CIC‐RS) represent the most frequent subset of “Ewing‐like” undifferentiated small round cell sarcomas. These tumors tend to be more aggressive than Ewing sarcomas. ...Moreover, treatment strategy can differ according to teams. The primary aim of this retrospective study was to describe the characteristics, treatments, and outcome for patients with CIC‐RS included in the French NETSARC+ database.
Methods
Pediatric and adult patients from 13 French centers with a diagnosis of CIC‐RS were registered from October 2008 to March 2021. Patients and tumors characteristics were collected from the national network NETSARC+ database (http://netsarc.sarcomabcb.org). CIC‐RS diagnosis was pathologically and molecularly confirmed with a central review by expert pathologists. Two groups of patients were studied: those treated as classical Ewing sarcomas (cohort EwS) and those treated as high‐grade soft tissue sarcomas (cohort STS) according to ESMO and/or EpSSG guidelines. Survival was calculated using the Kaplan–Meier method and the log‐rank test was used to compare survival.
Results
Among 79 patients, the male/female sex ratio was 0.7 and the median age at diagnosis was 27 years (range 2–87). With a median follow‐up of 37 months, 39 patients died of the disease. Median overall survival from diagnosis was 18 months, with no significant difference between both cohorts (p = 0.9). Nevertheless, when focusing on patients with metastatic disease at diagnosis (N = 21), all patients from cohort STS died of disease while some patients from cohort EwS were still alive and in complete remission.
Conclusion
FSG experience confirms the aggressive clinical course of CDS patients regardless of chemotherapy regimen.
Two groups characterized by different patterns of care were evaluated in our study. On one hand (cohort 1), patients were treated as Ewing sarcomas, and on the other hand (cohort 2), patients were treated as high‐grade soft tissue sarcomas. Overall, the prognosis was poor and there were no statistical differences in overall survival and relapse‐free survival between the two groups. Nevertheless, a significant proportion of patients with metastatic CDS from cohort 1 achieved very long‐term survival and might be cured.
The purpose was to describe first and subsequent relapses in patients from the OS2006/Sarcome-09 trial, to help future trial design. We prospectively collected and analysed relapse data of all French ...patients included in the OS2006/Sarcome-09 trial, who had achieved a first complete remission. 157 patients experienced a first relapse. The median interval from diagnosis to relapse was 1.7 year (range 0.5-7.6). The first relapse was metastatic in 83% of patients, and disease was not measurable according to RECIST 1.1 criteria in 23%. Treatment consisted in systemic therapy (74%) and surgical resection (68%). A quarter of the patients were accrued in a phase-II clinical trial. A second complete remission was obtained for 79 patients. Most of them had undergone surgery (76/79). The 3-year progression-free and overall survival rates were 21% and 37%, respectively. In patients who achieved CR2, the 3y-PFS and OS rates were 39% and 62% respectively. Individual correlation between subsequent PFS durations was poor. For osteosarcoma relapses, we recommend randomised phase-II trials, open to patients from all age categories (children, adolescents, adults), not limited to patients with measurable disease (but stratified according to disease status), with PFS as primary endpoint, response rate and surgical CR as secondary endpoints.
The aim of this retrospective study was to determine, at baseline, the prognostic value of different FDG-PET/CT quantitative parameters in a homogenous Ewing Sarcoma Family of Tumors (ESFT) adult ...population, compared with clinically relevant prognostic factors.
Adult patients from 3 oncological centers, all with proved ESFT, were retrospectively included. Quantitative FDG-PET/CT parameters (SUV (maximum, peak and mean), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of the primary lesion of each patient were recorded before treatment, as well as usual clinical prognostic factors (stage of disease, location, tumor size, gender and age). Then, their relation with progression free survival (PFS) and overall survival (OS) was evaluated.
32 patients were included. Median age was 21 years (range, 15 to 61). Nineteen patients (59%) were initially metastatic. On multivariate analysis, high SUV
remained independent predictor of worst OS (p=0.02) and PFS (p=0.019), metastatic disease of worst PFS (p=0.01) and high SUVpeak of worst OS (p=0.01). Optimal prognostic cut-off of SUV
was found at 12.5 in multivariate analyses for PFS and OS (
=0.0001).
FDG-PET/CT, recommended at ESFT diagnosis for initial staging, can be a useful tool for predicting long-term adult patients outcome through semi-quantitative parameters.
Rectal and pararectal gastrointestinal stromal tumors (GISTs) are rare. The optimal management strategy for primary localized GISTs remains poorly defined.
We conducted a retrospective analysis of 41 ...patients with localized rectal or pararectal GISTs treated between 1991 and 2011 in 13 French Sarcoma Group centers.
Of 12 patients who received preoperative imatinib therapy for a median duration of 7 (2-12) months, 8 experienced a partial response, 3 had stable disease, and 1 had a complete response. Thirty and 11 patients underwent function-sparing conservative surgery and abdominoperineal resection, respectively. Tumor resections were mostly R0 and R1 in 35 patients. Tumor rupture occurred in 12 patients. Eleven patients received postoperative imatinib with a median follow-up of 59 (2.4-186) months. The median time to disease relapse was 36 (9.8-62) months. The 5-year overall survival rate was 86.5%. Twenty patients developed local recurrence after surgery alone, two developed recurrence after resection combined with preoperative and/or postoperative imatinib, and eight developed metastases. In univariate analysis, the mitotic index (≤5) and tumor size (≤5 cm) were associated with a significantly decreased risk of local relapse. Perioperative imatinib was associated with a significantly reduced risk of overall relapse and local relapse.
Perioperative imatinib therapy was associated with improved disease-free survival. Preoperative imatinib was effective. Tumor shrinkage has a clear benefit for local excision in terms of feasibility and function preservation. Given the complexity of rectal GISTs, referral of patients with this rare disease to expert centers to undergo a multidisciplinary approach is recommended.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Leiomyosarcoma (LMS) and liposarcoma (LPS) are ultra-rare sarcomas in pediatric (0–18 years) and young adult (19−30) populations. We aimed to analyze their clinical characteristics at ...these young ages and to determine whether they should be considered with the same therapeutic strategy in both populations. Methods: National retrospective multicenter study of all young patients (0–30 years) included in the sarcoma database “ConticaBase”, treated for LMS or LPS between 2010 and 2019 via the national NETSARC+ network, with available pathology/biology review. Findings: A total of 218 patients were identified, 34 children (nine LMS, 25 LPS) and 184 young adults (58 LMS, 126 LPS). Myxoid/Round Cell LPS (M/RC-LPS) was the most frequent LPS subtype (72 %). All children had localized LMS and LPS, versus 52/58 and 116/126 respectively in adults. Clinical presentation of LMS and all LPS subtypes was comparable in both populations, except for a preferential limb location of LMS in children. The therapeutic strategy was mainly based on primary surgery in LMS (9/9 children, 52/58 adults) and for LPS (respectively 25/25 and 122/126), exclusively or with adjuvant radiotherapy and systemic treatment. With a median follow-up of 62.4 months (range, 2.5–146), 5-year overall survival was respectively 83 % 95 % CI, 58–100 in children and 73 % 61–88 in young adults for LMS, 100 % 100 vs 92 % 87–99 for M/RC-LPS and 25 % 5–100 vs 60 % 29–100 for pleomorphic LPS. Interpretation: LMS and all LPS subtypes appear to display comparable behavior in children and young adults. The authors propose that the same therapeutic strategy should be considered for both groups.
Hepatotoxicity is an important concern for nearly 40% of the patients treated with trabectedin for advanced soft tissue sarcoma (ASTS). The mechanisms underlying these liver damages have not yet been ...elucidated but they have been suggested to be related to the production of reactive metabolites. The aim of this pharmacogenetic study was to identify genetic variants of pharmacokinetic genes such as CYP450 and ABC drug transporters that could impair the trabectedin metabolism in hepatocytes. Sixty-three patients with ASTS from the TSAR clinical trial (NCT02672527) were genotyped by next-generation sequencing for 11 genes, and genotype-toxicity association analyses were performed with R package SNPassoc. Among the results,
c.1249A allele (rs2273697) and
intron variant c.-15994T (rs7699188) were associated with an increased risk of severe cytolysis, whereas
c.3563A allele had a protective effect, as well as
variants rs2032582 and rs1128503 (
-value < 0.05). Furthermore,
*1 rs776746 (c.6986A > G) increased the risk of severe overall hepatotoxicity (
= 0.012, odds ratio (OR) = 5.75), suggesting the implication of metabolites in the hepatotoxicity. However, these results did not remain significant after multiple analysis correction. These findings need to be validated on larger cohorts of patients, with mechanistic studies potentially being able to validate the functional consequences of these variants.
Desmoid type fibromatosis (DTF) are rare intermediate malignancies with unpredictable outcome. Series containing children and young adults (YA) are lacking.
The aim of this retrospective study was to ...describe the French population of patients<40 years with DTF diagnosed between 2006 and 2017.
Eighty-three children and 881 YA (18–39 years) were included (sex ratio M/F 1.3 and 0.25, respectively). Locations were abdominal wall (40.8%), trunk (23.5 %), extremities (19 %), mesentery (13.5 %) and head and neck (HN) (3.2 %).
Tumors were larger in children (7 vs 5.5 cm for YA, p < 0.001), and more frequently located in the abdomen and mesentery in YA (p < 0.001). Patients with Familial Adenomatous Polyposis condition (5.3 % of the cases) were three times more frequent in the multifocal DTF group, and in mesenteric primary (p < 0.001).
First-line strategy for 548 patients was: surgery (289 patients), active surveillance (AS, 189 patients), medical treatment (57 patients), other local treatment (radio/cryotherapy, 7 patients), or the combination of several active treatments (6 patients).
The 2-year progression free survival (PFS) rate for the whole cohort was 68.3 %, better for YA (69.2 %) than for children (59.5 %, p = 0.0106). Among 548 informative patients, AS was associated with a better PFS (HR = 0.558) and the only variables associated with worse PFS in multivariate analysis were tumor size ≥ 5 cm (HR = 1.785) and location in the extremities (HR = 1.934) or trunk (HR=1.598).
Clinical DTF presentation is more aggressive in children than YA. AS seems to be a valid first-line option preventing overtreatment, and local progression is linked to size and location, regardless of age.
•Clinical DTF presentation is more aggressive in children than young adults.•DTF were larger in children.•DTF were more frequently located in the abdomen and mesentery in young adults.•Active Surveillance seems to be a valid first-line option preventing overtreatment.•Progression is linked to size and location (extremities and trunk), regardless of age.
Regorafenib has proven activity in patients with pretreated gastrointestinal stromal tumours and colorectal and hepatocellular carcinoma. We designed REGOBONE to assess the efficacy and safety of ...regorafenib for patients with progressive metastatic osteosarcoma and other bone sarcomas. This trial comprised four parallel independent cohorts: osteosarcoma, Ewing sarcoma, chondrosarcoma, and chordoma. In this Article, we report the results of the osteosarcoma cohort.
In this non-comparative, double-blind, placebo-controlled, phase 2 trial, patients aged 10 years or older with histologically confirmed osteosarcoma whose disease had progressed after treatment with one to two previous lines of chemotherapy for metastatic disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive either oral regorafenib (160 mg/day, for 21 of 28 days) or matching placebo. Patients in both groups also received best supportive care. Randomisation was done using a web-based system and was stratified (permuted block) by age at inclusion (<18 vs ≥18 years old). Investigators and patients were masked to treatment allocation. Patients in the placebo group, after centrally confirmed progressive disease, could cross over to receive regorafenib. The primary endpoint was the proportion of patients without disease progression at 8 weeks. Analyses were done by modified intention to treat (ie, patients without any major entry criteria violation who initiated masked study drug treatment 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 NCT02389244, and the results presented here are the final analysis of the osteosarcoma cohort (others cohorts are ongoing).
Between Oct 10, 2014, and April 4, 2017, 43 adult patients were enrolled from 13 French comprehensive cancer centres. All patients received at least one dose of assigned treatment and were evaluable for safety; five patients were excluded for major protocol violations (two in the placebo group and three in the regorafenib group), leaving 38 patients who were evaluable for efficacy (12 in the placebo group and 26 in the regorafenib group). 17 of 26 patients (65%; one-sided 95% CI 47%) in the regorafenib group were non-progressive at 8 weeks compared with no patients in the placebo group. Ten patients in the placebo group crossed over to receive open-label regorafenib after centrally confirmed disease progression. 13 treatment-related serious adverse events occurred in seven (24%) of 29 patients in the regorafenib group versus none of 14 patients in the placebo group. The most common grade 3 or worse treatment-related adverse events during the double-blind period of treatment included hypertension (in seven 24% of 29 patients in the regorafenib group vs none in the placebo group), hand–foot skin reaction (three 10% vs none), fatigue (three 10% vs one 3%), hypophosphataemia (three 10% vs none), and chest pain (three 10% vs none). No treatment-related deaths occurred.
Regorafenib demonstrated clinically meaningful antitumour activity in adult patients with recurrent, progressive, metastatic osteosarcoma after failure of conventional chemotherapy, with a positive effect on delaying disease progression. Regorafenib should be further evaluated in the setting of advanced disease as well as potentially earlier in the disease course for patients at high risk of relapse. Regorafenib might have an important therapeutic role as an agent complementary to standard cytotoxic chemotherapy in the therapeutic armamentarium against osteosarcoma.
Bayer HealthCare.
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