Abstract Background Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma, marked by NR4A3 rearrangement. Herein we report on the activity of sunitinib in a series of 10 patients, ...strengthening what initially observed in two cases. Patients and methods From July 2011, 10 patients with progressive metastatic translocated EMC have been consecutively treated with sunitinib 37.5 mg/day, on a named-use basis. In an attempt to interpret the activity of sunitinib in EMC, genotype/phenotype correlations were carried out by fluorescence in situ hybridization (FISH) analyses. Moreover, transcriptome, immunohistochemical and biochemical analyses of a limited set of samples were performed focusing on some putative targets of sunitinib. Results Eight of 10 patients are still on therapy. Six patients had a Response Evaluation Criteria in Solid Tumours (RECIST) partial response (PR), two were stable, two progressed. Positron emission tomography (PET) was consistent in 6/6 evaluable cases. One patient underwent surgery after sunitinib, with evidence of a pathologic response. At a median follow-up of 8.5 months (range 2–28), no secondary resistance was detected. Median progression free survival (PFS) has not been reached. Interestingly, all responsive cases turned out to express the typical EWSR1 – NR4A3 fusion, while refractory cases carried the alternative TAF15 – NR4A3 fusion. Among putative sunitinib targets, only RET was expressed and activated in analysed samples. Conclusions This report confirms the therapeutic activity of sunitinib in EMC. Genotype/phenotype analyses support a correlation between response and EWSR1 – NR4A3 fusion. Involvement of RET deserves further investigation.
The equivalence of a short full-dose regimen of neoadjuvant CT with anthracycline-ifosfamide compared with standard dosing in localized high-risk soft tissue sarcoma is confirmed at a long FU. ...Likewise the association of response with better OS and the importance of the concurrent neoadjuvant administration of CT and RT when preservation of function is goal are confirmed.
To report on long-term results of a phase 3 trial comparing three versus five cycles of adjuvant chemotherapy (CT) with full-dose epirubicin+ifosfamide in high-risk soft tissue sarcomas (STS).
Patients (pts) were randomized to receive three preoperative cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 (Arm A) or to receive the same three preoperative cycles plus two postoperative cycles (Arm B). Radiotherapy could be either delivered in the preoperative or in the postoperative setting. Non-inferiority of the primary end point, OS, was assessed by the confidence interval of the hazard ratio (HR; Arm A/Arm B) derived from Cox model.
Between January 2002 and April 2007, 164 pts were assigned to arm A and 164 to arm B. At a median follow-up (FU) of 117 months (IQ range 103–135 months), 123 deaths were recorded: 58 in Arm A and 65 in Arm B. Ten-year OS was 61% for the entire group of patients: 64% in Arm A and 59% in Arm B. The intention-to-treat analysis confirmed that three cycles were not inferior to five cycles (one-sided 95% upper confidence limit was 1.24). A per protocol analysis was consistent with these results. Pts with leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS) had the lowest, and the highest response rates, respectively. Consistently, Leiomyosarcoma and UPS had the worse and the best prognosis, respectively.
At a longer FU, the non-inferiority of three cycles of a full-dose conventional CT in comparison to five is confirmed. Response to therapy is also confirmed to be associated with better survival. This regimen is currently tested within an ongoing international trial against three cycles of a neoadjuvant histology-tailored CT (ClinicalTrials.gov Identifier: NCT01710176).
Sarcomas represent a heterogeneous group of tumors. Accurate determination of histological diagnosis and prognostic factors is critical for the delineation of treatment strategies. The contribution ...of second opinion (SO) to improve diagnostic accuracy has been suggested for sarcoma but has never been established in population-based studies.
Histological data of patients diagnosed with sarcoma in Rhone-Alpes (France), Veneto (Italy) and Aquitaine (France) over a 2-year period were collected. Initial diagnoses were systematically compared with SO from regional and national experts.
Of 2016 selected patients, 1463 (73%) matched the inclusion criteria and were analyzed. Full concordance between primary diagnosis and SO (the first pathologist and the expert reached identical conclusions) was observed in 824 (56%) cases, partial concordance (identical diagnosis of connective tumor but different grade or histological subtype) in 518 (35%) cases and complete discordance (benign versus malignant, different histological type or invalidation of the diagnosis of sarcoma) in 121 (8%) cases. The major discrepancies were related to histological grade (n = 274, 43%), histological type (n = 144, 24%), subtype (n = 18, 3%) and grade plus subtype or grade plus histological type (n = 178, 29%).
More than 40% of first histological diagnoses were modified at second reading, possibly resulting in different treatment decisions.
Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation of myofibroblasts lacking metastatic capacity. It may be observed in nearly every part of the body. Considering ...the variable clinical presentations, anatomic locations, and biologic behaviors, an individualized treatment approach is required. The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/&bgr;-catenin pathway. No established and evidence-based approach for the treatment of this neoplasm is available as of today. Considering the unpredictable behavior and the heterogeneity of this disease, we propose a treatment algorithm approved by the French and the Italian Sarcoma Group, based on a front-line wait and see approach and subsequent therapy in the case of progression. A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis.
To report on sunitinib activity in a retrospective series of 35 solitary fibrous tumor (SFT) treated at a single institution.
From April 2008, 35 patients with progressive advanced SFT (male/female: ...20/15; mean age: 58 years; meningeal/extrameningeal: 6/29; locally advanced/metastatic: 15/20; prior chemotherapy: 25) were treated, on an individual use basis, with continuous-dosing sunitinib 37.5 mg/day. Platelet-derived growth factor receptor beta (PDGFRB) and vascular endothelial growth factor receptor 2 (VEGFR2) status were assessed by immunohistochemistry and, in a subgroup of patients, by real time PCR.
Thirty-one patients were assessable for response by RECIST (one early death; three early interruptions). Best responses were 2 partial response (PR), 16 stable disease, 13 progressive disease. A <30% decrease in size was observed in three patients. Fourteen of 29 patients assessable by Choi criteria had a PR. Median progression-free survival by RECIST was 6 months (range 1–22). In two of six patients, resistance to sunitinib was overcome by increasing sunitinib to 50 mg/day. PDGFRB and/or VEGFR2 were positive in all cases and not predictive of response; a less aggressive morphology corresponded to an increased response rate (53% PR by Choi in the malignant SFT, 20% PR in the pleomorphic/dedifferentiated SFT).
Sunitinib is active in SFT. Response can be long-lasting.
Angiosarcoma is a highly aggressive soft tissue sarcoma. Responses to anthracyclines plus/minus ifosfamide, and taxanes alone or in combination with gemcitabine are well documented. Very few data are ...available on gemcitabine as a single agent.
We retrospectively reviewed all cases of advanced progressive angiosarcoma treated with gemcitabine as a single agent (1000 mg/m2 i.v. every week for 3 weeks every 4 weeks), at Istituto Nazionale Tumori and within the Italian Rare Cancers Network from January 2008 to November 2010.
Twenty-five patients mean age: 52 years; radiation therapy (RT)-related: 8 received gemcitabine. Best tumor response by RECIST was as follows: complete response = 2, partial response = 14, stable disease = 2, progressive disease = 7 cases, for an overall response rate (PR + CR) of 68%. Six of eight post-RT angiosarcomas responded to treatment. Median overall survival (OS) was 17 months. Median progression-free survival (PFS) was 7 months (range 1–40 months). One patient with a locally advanced thyroid angiosarcoma became resectable after 5 months of gemcitabine, with <10% residual viable tumor cells seen on surgical specimen. Overall, gemcitabine was well tolerated.
Gemcitabine is active in both RT- and non-RT-related angiosarcoma, with dimensional and possibly long-lasting responses. A formal phase II study on gemcitabine as a single agent is warranted.
To explore correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial.
In the trial, all patients received ...three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m2 and ifosfamide 9 g/m2 and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion.
Two hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45–74 months), the 5-year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT–RT and with positive surgical margins, the CI of LR was 0.
In this setting of high-risk STS treated by preoperative CT or CT–RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT–RT may be a reasonable option to maximize the chance of cure.
Abstract Background Preclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to ...be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments. Material and methods Two dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT. Results Two D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin. Conclusion Doxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.
Idiopathic retroperitoneal fibrosis (IRF) is a rare disease often causing obstructive uropathy. We evaluated the clinicopathologic features of 24 patients with IRF to characterize the histopathology ...of the disease and to provide a framework for the differential diagnosis with other retroperitoneal fibrosing conditions. Retroperitoneal specimens were analyzed by light and electron microscopy and by immunohistochemistry. Most patients presented with abdominal/lumbar pain, constitutional symptoms, and high acute-phase reactants. Overall, 20 had ureteral involvement and 13 developed acute renal failure. The retroperitoneal tissue consisted of a fibrous component and a chronic inflammatory infiltrate with the former characterized by myofibroblasts within a type-I collagen matrix. The infiltrate displayed perivascular and diffuse patterns containing lymphocytes, macrophages, plasma cells, and eosinophils. The perivascular aggregates had a central core of CD20+ cells and a mantle of CD3+ cells in equal proportions. In the areas of diffuse infiltrate, CD3+ cells outnumbered the CD20+ cells. Most plasma cells were positive for the IgG4 isotype. Small vessel vasculitis was found in the specimens of 11 patients. Our study indicates that a sclerotic background with myofibroblasts associated with a diffuse and perivascular infiltrate mainly consisting of T and B lymphocytes may be a pathological hallmark of IRF.
Abstract Background To report on anthracycline-based chemotherapy in a retrospective case-series analysis of solitary fibrous tumour (SFT) patients treated within the Italian Rare Cancer Network. ...Patients and methods We reviewed a set of SFT treated with chemotherapy since 2002, focusing on anthracycline, administered alone or in combination with ifosfamide. Responses to ifosfamide as a single agent were also evaluated. Pathologic diagnosis was centrally reviewed, distinguishing typical, malignant (MSFT) and dedifferentiated (DSFT) subtypes. Results Among 42 SFT patients treated with chemotherapy, we selected 31 cases (mean age: 62 years; locally advanced/metastatic: 13/18; front-line/further line: 25/6; typical/MSFT/DSFT/not assessable: 1/17/12/1) who received anthracycline-based chemotherapy (anthracycline monotherapy: eight; anthracycline + ifosfamide: 23). 30 patients are evaluable for response. Best response by Response Evaluation Criteria in Solid Tumours (RECIST) was: partial response (PR): 6 (20%), stable disease (SD): eight (27%), progressive disease (PD): 16 (53%) cases. Responses were confirmed after 3 months. Median progression-free survival (PFS) was 4 (range 2–15) months, with 20% of patients being progression-free at 6 months. PR was found in 2/18 (11%) MSFT and 4/12 (30%) DSFT, with a median PFS of 3.5 and 5 months in MSFT and DSFT, respectively. 19 patients received high-dose prolonged-infusion ifosfamide (front-line/further line: 11/8; typical/MSFT/DSFT: 0/15/4) with two (10%) PR, five (26%) SD, 12 (63%) PD. Conclusions This retrospective series suggests that in SFT anthracyclines have a degree of antitumour activity in the range of soft tissue sarcoma chemotherapy. Ifosfamide monotherapy seemed to have lower activity. A higher response rate was observed in DSFT in comparison to MSFT. Studies on targeted therapies are ongoing.
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