To determine whether the administration of histology-tailored neoadjuvant chemotherapy (HT) was superior to the administration of standard anthracycline plus ifosfamide neoadjuvant chemotherapy (A+I) ...in high-risk soft tissue sarcoma (STS) of an extremity or the trunk wall.
This was a randomized, open-label, phase III trial. Patients had localized high-risk STS (grade 3; size, ≥ 5 cm) of an extremity or trunk wall, belonging to one of the following five histologic subtypes: high-grade myxoid liposarcoma (HG-MLPS); leiomyosarcoma (LMS), synovial sarcoma (SS), malignant peripheral nerve sheath tumor (MPNST), and undifferentiated pleomorphic sarcoma (UPS). Patients were randomly assigned in a 1:1 ratio to receive three cycles of A+I or HT. The HT regimens were as follows: trabectedin in HG-MLPS; gemcitabine plus dacarbazine in LMS; high-dose prolonged-infusion ifosfamide in SS; etoposide plus ifosfamide in MPNST; and gemcitabine plus docetaxel in UPS. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), estimated using the Kaplan-Meier method and compared using Cox models adjusted for treatment and stratification factors. The study is registered at ClinicalTrials.gov (identifier NCT01710176).
Between May 2011 and May 2016, 287 patients (UPS: n = 97 33.8%; HG-MLPS: n = 65 22.6%; SS: n = 70 24.4%; MPNST: n = 27 9.4%; and LMS: n = 28 9.8%) were randomly assigned to either A+I or HT. At the final analysis, with a median follow-up of 52 months, the projected DFS and OS probabilities were 0.55 and 0.47 (log-rank
= .323) and 0.76 and 0.66 (log-rank
= .018) at 60 months in the A+I arm and HT arm, respectively. No treatment-related deaths were observed.
In a population of patients with localized high-risk STS, HT was not associated with a better DFS or OS, suggesting that A+I should remain the regimen to choose whenever neoadjuvant chemotherapy is used in patients with high-risk STS.
To prospectively assess the behaviour of primary sporadic (not FAP associated) desmoid fibromatosis (DF) managed by active surveillance (AS).
This is an Italian prospective, multicenter, ...observational study (NCT02547831) including patients {greater than or equal to}16 years with primary sporadic DF at any site. Patients were assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 . Primary end-point 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.
From 2013 to 2018 108 consecutive patients were included (82% female); median age was 39-yr; median size was 51 mm. CTNNB1 mutations were: T41A (50%); S45F (12%); other (19%); WT (19%). At 32.3-month median-FU, 42/108 (39%) showed RECIST progression. Spontaneous regression (SR) was initially observed in 27/108 (25%), while it followed dimensional progression in other 33/108 (31%). PFS at 36 months was 54.5% (95% CI, 44.9%-66.1%). Thirty-five/108 (32%) patients received active treatments, 18/108 (17%) after RECIST progression and 17/108 (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 above variables was significantly associated to PFS.
In primary DF, AS can be proposed, since disease stabilization and SR frequently occur. However extra care should be taken for patients with tumors of larger size, extremity location and S45F mutation.
Purpose
The need for systematic reexcision in patients who underwent unplanned excision (UE) for extremity and superficial trunk soft tissue sarcoma (ESTSTS) has been questioned. We investigated the ...outcome of patients who underwent reexcision for ESTSTS compared with primarily resected at our institution and the prognostic impact of microscopic residual disease (MR) in the reexcision specimen.
Methods
Primary ESTSTS patients surgically treated at our institution between 1997 and 2017 were divided in three groups: primarily resected (A), reexcised after macroscopically complete UE (B), and incomplete UE (C). Weighted overall survival (OS), crude cumulative incidence of local relapse (CCI-LR), and distant metastasis (CCI-DM) were calculated and compared. In group B, multivariable models were performed to assess factors associated with the outcomes.
Results
A total of 1962 patients were identified: 1076, 697 and 189 in groups A, B, and C, respectively. Overall median follow-up was 85 months. Seven-year weighted-OS was 73.8%, 84.1%, and 80.7% (
p
< 0.001) for groups A, B, and C respectively. Seven-year CCI-LR and DM were 5.0% and 25.3%, 12.1% and 15.8%, and 13.6% and 29.4% (both
p
< 0.001) for groups A, B, and C, respectively. At multivariable analysis, the presence MR was associated with LR (
p
< 0.001) but not with OS nor CCI-DM.
Conclusions
UE and the presence of MR at pathology in reexcision specimen are associated to a higher risk of LR but not to a higher risk of DM or lower OS. After macroscopic complete UE, postponing reexcision until a LR occurs may be considered on an individualized basis.
Abstract Introduction Imatinib showed activity in 50 chordoma patients treated within a Phase II study. In that study, 70% of patients remained with stable disease (SD), median progression free ...survival (PFS) was 9 months and median overall survival (OS) was 34 months. We now report on a retrospective series of PDGFB/PDGFRB positive advanced chordoma patients treated with imatinib as a single agent within a compassionate-use programme at Istituto Nazionale Tumori, Milan, Italy (INT) between August 2002 and November 2010, when the programme was closed. Methods 48 patients were consecutively treated with imatinib 800 mg/d. All patients had inoperable and progressive disease before starting imatinib. Demographics, treatment duration, toxicity and response rate by Response Evaluation Criteria in Solid Tumors (RECIST) were retrospectively recorded. Results The median duration of therapy was 7 months (1–46.5). No patient is on therapy at present. 46 patients were evaluable for response. No partial responses were detected. Best response was: stable disease 34 (74%), progressive disease 12 (26%). At a median follow-up of 24.5 months (0.5–117), median PFS was 9.9 months (95% confidence interval (CI) 6.7–13). Eight patients (16.5%) remained on therapy >18 months and 10 patients (21%) remained progression-free >18 months. Median OS was 30 months (95% CI 20–40), with 24 (50%) patients dead at the time of the present analysis. Conclusions We confirm the activity of imatinib in locally advanced and metastatic chordoma, in terms of >70% tumour growth arrest in previously progressive patients. Median duration of response lasted almost 10 months, with >20% of patients progression-free at 18+ months.
Today, surgery and radiation therapy have a limited role in desmoid-type fibromatosis. Different systemic treatments were shown to be effective. Herein, we report on our institutional experience with ...low-dose methotrexate (MTX) + vinca alkaloids in this disease over the last 25 years.
We retrospectively reviewed data from all adult patients with sporadic desmoid-type fibromatosis treated with MTX and vinca alkaloids at our institution between 1989 and 2014.
We identified 75 patients treated with MTX + vinblastine (40%), MTX + vinorelbine (57%), and vinorelbine alone (3%). All patients had progressive disease before chemotherapy; 72%, 10%, and 48% of patients had received previous surgery, radiation therapy, and/or systemic treatments, respectively. Chemotherapy was administered for a median duration of 14 months and a median number of 37.5 cycles. Eight patients interrupted chemotherapy because of toxicity. According to RECIST (Response Evaluation Criteria in Solid Tumors) complete response, partial response, stable disease, and progressive disease were observed in 1%, 47%, 51%, and 1% of patients, respectively. Symptomatic relief was obtained in 80% of symptomatic cases. The median progression-free survival (PFS) was 75 months; it was 136 months in responding patients. Upon progression, after chemotherapy withdrawal, MTX plus vinblastine/vinorelbine was offered to 11 patients with partial response, stable disease, and progressive disease in 4, 6, and 1 cases, resulting in a median PFS of 53 months.
In this series, chemotherapy with MTX and vinca alkaloids is confirmed to be active and effective, with a remarkable PFS, higher in responding patients, and limited toxicity. Even progression can be successfully rechallenged.
To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (DFSP)/fibrosarcomatous (FS)-DFSP and on the impact of the treatment on tumor biology.
Ten consecutive ...patients treated with IM from 2007 to 2015 for a metastatic relapse from DFSP/FS-DFSP were identified. FISH analysis for COL1A1-PDGFB was performed. Two IM-treated and 4 naïve FS-DFSP were transcriptionally profiled by RNAseq on HiScanSQ platform. Differential gene expression was analyzed with edgeR (Bioconductor), followed by hierarchical clustering and Principal Component Analysis.
All cases featured fibrosarcomatous in the metastasis and retained the COL1A1-PDGFB. Best RECIST response was: 8 partial response, 1 stable disease, and 1 progressive disease. Median progression-free survival was 11 months. Five patients received surgery after IM and all relapsed. IM was restored in 4 patients with a new response. After IM, the most upregulated genes included those encoding for immunoglobulins and those affecting functions and differentiation of endothelial cells. Pathway enrichment analysis revealed upregulation in genes involved in antigen processing and presentation, natural killer-mediated cytotoxicity, and drug and xenobiotics metabolism. Conversely, a significant down-regulation of kinase signaling pathways was detected.
All metastatic cases were fibrosarcomatous. Most patients responded to IM, but PFS was shorter than reported in published series which included both DFSP and FS-DFSP. All patients operated after IM had a relapse, suggesting that IM cannot eradicate metastatic cases and that the role of surgery is limited. Transcriptional profile of naïve and posttreatment samples pointed the contribution of immune infiltrates in sustaining the response to IM.
Background
The improved outcome of extremity soft tissue sarcoma patients surgically treated until 2007 at the authors’ institution was previously reported. This study updates the analysis at a later ...follow-up and extends the patients’ cohort to assess changes in outcomes over time for extremity and superficial trunk soft tissue sarcoma (ESTSTS) treated at a single referral center.
Methods
All consecutive patients with primary localized adult-type ESTSTS surgically treated at the authors’ institution between 1987 and 2017 were included and divided into group 1 (1987–2002) and group 2 (2003–2017) according to primary surgery year. Crude cumulative incidence (CCI) of sarcoma-specific mortality (SSM), local recurrence (LR), and distant metastases (DM) were calculated in a competing-risks framework. DM-free survival (DMFS) and post-DM survival were also assessed.
Results
The study identified 2382 patients. The median follow-up was 104 months (range, 63–127 months), and the post-DM follow-up was 76 months (range, 37–126 months). Since 2003, an increased adoption of preoperative treatments was observed: the use of chemotherapy, radiotherapy and combined chemoradiotherapy went from 10.5% to 23.7%, from 1.7% to 17.8%, and from 1% to 11.8% respectively. This change in treatment strategies was associated to an improvement in CCI-SSM (27.8% vs 19.5%;
P
< 0.001), CCI-LR (14.1 vs 7.5%;
P
< 0.001), DMFS (57.9% vs 65.8%;
P
= 0.004), and post-DM (12.2% vs 20.1%;
P
= 0.012), but not in CCI-DM.
Conclusions
Increased adoption of preoperative treatments and greater availability of medical agents in the recent years were associated to better outcomes. New treatments are eagerly awaited for further improvement of outcome for ESTSTS patients because no major changes have been observed since 2003.
Background
The aim of this study was to report on sirolimus activity in a series of patients with hemangioendothelioma (HE) treated at the National Cancer Institute, Milan (Istituto Nazionale Tumori; ...INT) and within the Italian Rare Cancer Network (“Rete Tumori Rari”; RTR).
Methods
We retrospectively reviewed patients with advanced and progressing epithelioid hemangioendothelioma (EHE) treated with sirolimus at the INT and/or within the RTR. Pathologic review and molecular analysis for
WWTR1
rearrangement were performed. Sirolimus was administered until unacceptable toxicity or progression, with the dose being adjusted to reach target plasma levels of 15–20 ng/dL. Responses were assessed using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
Results
Since 2005, 18 patients (17 EHE, 1 retiform HE; 1 locally advanced, 17 metastatic;
WWTR1
rearrangement: 16) have been identified, with 17/18 patients being evaluable for response. Mean sirolimus daily dose was 4.5 mg. According to RECIST, best responses in EHE were 1 partial response (PR), 12 stable disease (SD), and 3 progressive disease (PD); the patient with retiform HE also achieved a PR, lasting >2 years. Four patients with a reversed interval progression on interruption were observed. Median overall survival was 16 months, and median progression-free survival was 12 months (range 1–45), with four patients progression-free at 24 months. The clinical benefit (complete response CR + PR + SD
>
6 months) was 56 %. Seven patients receiving sirolimus experienced an increase in pleural/peritoneal effusion plus worsening of tumor-related symptoms; six of these patients died within 1–8 months from evidence of effusion progression, while a RECIST PD was assessed in two of seven patients.
Conclusions
A clinical benefit was achieved in 56 % of patients receiving sirolimus, which lasted >24 months in four patients. Most patients with pleural effusion did not benefit from sirolimus and had a poor outcome.
Background
Chordoma is a rare tumor, and its natural history is still not well known.
Materials and Methods
All patients affected by localized chordoma surgically treated at Istituto Ortopedico ...Rizzoli, Bologna, and Istituto Nazionale Tumori, Milan, Italy, between 1980 and 2008 were reviewed. Local recurrence, distant metastasis, and overall survival (OS) were analyzed both from time of diagnosis and from time of local recurrence/distant metastasis. A multivariable analysis to identify independent prognostic factors was carried out.
Results
A total of 138 consecutive patients were identified (sacrum 78%, lumbar spine 15%, cervical-dorsal spine 7%). Of these, 130 underwent surgical resection. Median follow-up was 142 months. The 5- and 10-year OS, local relapse-free survival (LRFS), and distant relapse-free survival (DRFS) were, respectively, 78% and 54%, 52% and 33%, and 86% and 72%. Size was an independent prognostic factor for OS (
P
value < .001), LRFS (
P
value: .038), and DRFS (
P
value: .004), while surgical margins independently predicted LRFS (
P
value: .003) with a trend for OS. The 5- and 10-year OS, LRFS, and DRFS after the first local relapse were 50% and 26%, 47% and 31%, and 64% and 61%. The size of the recurrence and quality of surgical margins did not influence postrelapse OS. The 5-year OS after the second local relapse was 19%. 22% of patients developed distant metastases with a 5-year post-metastases OS of 33%.
Conclusions
Tumor size and surgical margins affected outcome only on initial presentation. However, wide surgery was feasible in a minority of cases. Most patients died of local–regional disease even when metastases occurred. Indeed, long-term prognosis was such that disease-free survival at 10 years was only 26%.
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