bluuebunny/crossref_metadata_2025 huggingface dataset:
Imatinib failure-free survival (IFS) in patients with localized gastrointestinal stromal tumors (GIST) treated with adjuvant imatinib (IM): The EORTC/AGITG/FSG/GEIS/ISG randomized controlled phase III trial.
Authors: Casali Paolo Giovanni , Le Cesne Axel , Poveda Velasco Andres , Kotasek Dusan , Rutkowski Piotr , Hohenberger Peter , Fumagalli Elena , Judson Ian Robert , Italiano Antoine , Martin Broto Javier , Gronchi Alessandro , Dei Tos Angelo Paolo , Marreaud Sandrine , Van Der Graaf Winette T.A. , Zalcberg John Raymond , Litière Saskia , Blay Jean-Yves ,   EORTC Soft Tissue and Bone Sarcoma Group (EORTC STBSG), French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), Grupo Español de Investigación en Sarcomas (GEIS), Australasian Gastro-Intestinal Trials Group (AGITG)
Published: March 2020

10500

Background: In 2004 we launched an open-label randomized trial with adjuvant IM for 2 yrs in localized, surgically resected, high/intermediate-risk GIST. Methods: Pts were randomized between 2 yrs of IM, 400 mg daily, and no further therapy after surgery. The primary end-point was OS, while RFS, RFI and toxicity were secondary end-points. Main eligibility criteria were: age >18 yrs, PS 0-2, localized CD117-positive GIST, intermediate or high risk according to the 2002 Consensus classification, R0 or R1 surgical margins, no previous medical therapy. Pts were stratified by risk, tumor site and margins. An accrual of 400 pts was planned, then escalated to 900. Given the prognostic improvement of advanced GIST pts, in 2009 the study IDMC authorized to change the primary end-point into IFS, whose failure was defined as the time when a different tyrosine kinase inhibitor (TKI) is started. We report on a planned interim analysis carried out after 115 events according to the new primary end-point, with a significance level of 1.5%. Hazard ratios (HR) and p-values were adjusted for stratification factors. Results: 908 pts were randomized between 2005 and 2008, 454 to IM and 454 to observation arm; 835 pts were eligible. 17% of pts treated with IM stopped early due to toxicity or refusal. With a median follow-up of 4.7 yrs, 5-yr IFS was 87% in the IM-arm vs 84% in the control arm (HR=0.80, 98.5% CI [0.51; 1.26], p=0.23); RFS was 84% vs 66% at 3 yrs, and 69% vs 63% at 5 yrs (p<0.001); 5-yr OS was 100% vs 99%. Among 528 pts with high-risk GIST by local pathology, 5-yr IFS was 79% vs 73% (p=0.11), and 77% vs 73% (p=0.44) amongst 336 high-risk GIST pts by centrally reviewed pathology. Conclusions: This study confirms that adjuvant IM has an overt impact on short-term freedom from relapse. In the high-risk subgroup, a non-statistically significant trend in favor of the adjuvant arm was observed in terms of IFS. This new end-point for the adjuvant setting, i.e. survival free from any failure of the first employed TKI, was designed to incorporate secondary resistance, i.e. the currently main factor adversely affecting prognosis of advanced GIST pts. Clinical trial information: NCT00103168.
SARC006: Phase II trial of chemotherapy in sporadic and neurofibromatosis type 1 (NF1)-associated high-grade malignant peripheral nerve sheath tumors (MPNSTs).
Authors: Widemann Brigitte C. , Reinke Denise K. , Helman Lee J. , Ludwig Joseph A. , Schuetze Scott , Staddon Arthur P. , Milhem Mohammed M. , Rushing Daniel A , Moertel Christopher L. , Goldman Stewart , Livingston Michael B. , Wagner Lars M. , Rodler Eve T. , Dombi Eva , Perry Arie , Annunziata Christina M. , Long Lauren , Viskochil David , Steinberg Seth M. , Baker Laurence H.
Published: March 2020

10522

Background: MPNSTs occur in 10% of the NF1 population, and retrospective, pooled analyses have reported worse chemotherapy response for NF1 (9-18%) compared to sporadic MPNSTs (39-55%). Methods: We prospectively evaluated the objective response (OR) rate, [complete responses (CR) and partial responses (PR) WHO criteria] of children and adults with high-grade, unresectable or metastatic chemotherapy naive NF1 associated versus sporadic MPNST after 2 cycles of ifosfamide and doxorubicin (IA) followed by 2 cycles of ifosfamide and etoposide (IE) as primary endpoint. This was followed by surgery and/or radiation for local control and up to 2 more cycles of IA and IE each. Pathology was centrally confirmed. A Simon optimal two-stage design was used with a target response rate of 40% and 17 patients per stratum in the first stage. With 4+/17 ORs, enrollment was to be expanded to 37 patients per stratum, and 11+/37 ORs would be potentially consistent with a 40% OR rate. Results: Both initial stages met criteria for enrollment expansion with 4/17 PRs in NF1 and 4/12 PRs in sporadic MPNSTs, but only 1 additional PR was observed in the expanded NF1 stratum. Of the 9 PRs, 5 were first observed after 2 cycles IA, and additional 4 after 2 cycles IE. Enrollment was slower than expected and the trial was closed before full accrual. Conclusions: While the primary trial objective was not reached due to slow enrollment, with only 5/29 ORs in the NF1 stratum the desired OR rate of 11+/37 would have unlikely been met even if accrual had been completed. We observed a lower OR rate in NF1 compared to sporadic MPNSTs similar to retrospective literature reports. However, our trial was not powered to detect a difference in response rates between the two strata. In addition to PRs after both IA and IE, disease stabilization was achieved in most patients. Novel strategies including the evaluation of targeted agents in combination with chemotherapy should be considered. Clinical trial information: NCT00304083. [Table: see text]
Association of circulating VEGF-A levels with outcome in patients with vascular sarcomas receiving sorafenib (Sor): Exploratory analysis from AngioNext study.
Authors: Bal-Mahieu Christine , Fournier Charles , Ray-Coquard Isabelle , Chevreau Christine , Le Cesne Axel , Italiano Antoine , Bompas Emmanuelle , Robin Yves Marie , Bay Jacques-Olivier , Piperno-Neumann Sophie , Isambert Nicolas , Baldeyrou Brigitte , Lansiaux Amelie , Blay Jean-Yves , Clisant Stephanie , Penel Nicolas ,   French Sarcoma Group
Published: March 2020

10525

Background: We have carried out a stratified phase II study of Sor in pts with advanced angiosarcoma (AA, n=32), malignant solitary tumour (SFT, n=4) & epithelioid hemangioendothelioma (EE, n=13). We report here the correlative analysis of predictive value of circulating pro/anti-angiogenetic biomarkers. Methods: Using ELISA method (R&D SYSTEMS) Circulating biomarkers (VEGF-A [pg/mL], Thrombospondin-1 (TSP1) [µg/mL], Stem Cell Factor (SCF) [pg/mL], Placental growth factor (PlGF) [pg/mL], VEGF-C [pg/mL] & E-selectin [ng/mL]) have been measured before Sor treatment & after 7 days. We analyze the correlation with histological subtypes, presence of metastases, best response and occurrence of hemorrhage and Gr3-4 arterial hypertension. Results: VEGF-A (mean value 475 vs 541 pg/mL, p=0.002), TSP1 (16 vs 24 µg/mL, p=0.0002), PlGF (20.9 vs 40.7 pg/mL, p=0.0001) significantly increased during the treatment. Sor treatment did not affect the levels of SCF, VEGF-C & E-selectin. The distributions of all biomarkers were similar across the histological subtypes, whatever the presence of metastasis, the occurrence of hemorrhage or arterial hypertension. 2 biomarkers were associated with better outcome:VEGF-A & PlGF. Best objective response and non-progression at 180 days were associated with low level of VEGF-A at baseline (p=0.04 and p= 0,03 respectively). There was a correlation between circulating level of VEGF-A & time to progression (TTP) (r=-0.47, p=0.001). Best objective response and non-progression at 180 days were not associated with baseline level of PlIGF (p=0.34 and 0.07), but there was a correlation between circulating level of PlIGF at baseline and TTP (-0.31, p=0.02). Conclusions: In pts with vascular sarcomas receiving Sor, we have observed a significant decrease in circulating level of VEGF-A. Low level of VEGF-A at baseline (<500 pg/mL) was significantly associated with better outcome, especially best objective response rate, non-progression at 180 days and time to progression. Clinical trial information: 2007-004651-10.
Prognostic significance of Wnt signaling pathway molecules in nongastric GIST patients: A tissue microarray-based (TMA) analysis.
Authors: Martin Broto Javier , Ramos Rafael , Martinez-Trufero Javier , Calabuig Silvia , Horndler Carlos , Casado Antonio , Ortega Luis , Gonzalez de Sande Luis Miguel , Izquierdo Francisco , Gutierrez Antonio , Sala Angeles , Ugalde Aitziber , Valverde Claudia María , de Torres Ines , Losa Ferran , Blanco Remei , Gomez Rosa Maria Sanchez , Cubedo Ricardo , Carrasco Juan Antonio , Balañá Carmen ,   Spanish Group for Research on Sarcomas (GEIS)
Published: March 2020

10529

Background: Pathogenesis in GIST could be related to cancer stem cell hypothesis (highly chemo resistant, very uncommon complete responses, kit is stem cell marker) even though no stem cell component in GIST has been yet demonstrated. Wnt signaling regulates proliferation in some normal and cancer stem cells as it occurs with intestinal epithelium. We have explored the prognostic significance of several Wnt signaling pathway and related molecules. To investigate the prognostic significance of β-Catenin, CDC25A, ROR2, p53, CUL4A, AKT-p and VEGFR-3 by immunohistochemical (IHC) analysis in TMA specimens of 101 non-gastric GIST. Methods: Data of diagnostic, therapeutic and follow-up procedures stem from the GIST Registry of GEIS. Cytoplasmic and/or membrane staining was deemed positive for ROR-2, VEGFR-3 and p-AKT antibodies whereas nuclear staining was positive for β-Catenin, CDC25A, CUL4A and p53 antibodies. IHC positive cases were considered if they displayed staining in at least 10% of cells. Statistical analyses for correlation of protein expression with known prognostic variables (mitoses, size) were performed with Mann-Whitney U test. Results: A subset of 101 non-gastric localized GIST patients was selected (90 intestinal, 15 others: mainly rectum and omentum). The median age was 62 y with gender distribution of 59M/42F and the median of follow-up was 36 months. The positivity for each protein was distributed as follows: ROR-2 63%, p-AKT 55%, β-Catenin 53%, VEGFR-3 22%, CDC25A 20%, p53 8% and CUL4A 7%. A statistically significant correlation was found between mitoses and β-Catenin (median 5 if negative/ 10 if positive, p=0.028); VEGFR-3 (median 5 if negative/21 if positive, p=0.002); CUL4A (median 6 if negative/60 if positive, p= 0.027). Additionally, tumor size was statistically correlated with VEGFR-3 (median 7 if negative/11 if positive, p=0.007). Conclusions: VEGFR-3, β-Catenin and CUL4A are correlated with the highest proliferative non-gastric GIST. These findings deserve further analysis and lead to potential new molecular therapeutic targets in GIST. This study was partially granted by Buesa Grant of GEIS.
Switching chemotherapy in adult osteosarcoma patients with poor necrosis rates post neoadjuvant methotrexate, cisplatin, and doxorubicin (MAP).
Authors: O'Kane Grainne , Cadoo Karen Anne , Walsh Elaine , O'Keane Conor , O'Toole Gary , Dudney Sean , Carney Desmond
Published: March 2020

10530

Background: Chemotherapy in the treatment of osteosarcoma has improved 5 year overall survival (OS) from 20% with surgery alone to 60-70%. However, poor tumor necrosis following neoadjuvant chemotherapy (NAC) is associated with decreased survival, therefore strategies to improve outcomes are required for these patients. Methods: Records from all adult patients diagnosed with osteosarcoma between 1986 and 2012 were retrospectively reviewed. Patients were stratified according to age at diagnosis (<40yrs and >40yrs), stage (localised or metastatic) and tumor necrosis post NAC (<90% and >90%). All patients received 2 cycles of methotrexate alternating with cisplatin/doxorubicin (MAP) preoperatively. Following surgery, patients with >90% tumor necrosis continued MAP whilst those with <90% necrosis switched to 4 cycles of ifosfamide and etoposide (IE). Results: 105 patients were identified and 98 who received systemic chemotherapy were included. Median age was 23yrs (Range 15-75yrs); 68% of patients were male. Limb sparing surgery was performed in 76% of applicable patients. Of the patients with localised disease (N=85), 5 year OS, with a median follow up of 8 years (1-26 yrs) was 68% (p=0.002). Patients <40 yrs with localised disease had a 5yr OS of 71% (N=73) compared to 40% in those >40 yrs (N=12) (p=0.05). 2/13 patients with metastatic disease at diagnosis are disease free >10 years post diagnosis. 65 of 73 patients with localised disease < 40 yrs had histology reviewed post neoadjuvant MAP. 34/65 (52%) had >90% tumor necrosis and continued on MAP, 5 yr OS 79%, 31 patients (48%) had <90% necrosis and received adjuvant IE, 5 yr OS 68% (P=0.10). Conclusions: Age and stage are important prognostic factors in patients with osteosarcoma treated with chemotherapy and surgery. Historically, patients with <90% tumor necrosis post NAC are considered to have a poorer prognosis. Switching from MAP to IE is an appropriate salvage regimen in such patients and appears to improve long term survival.
Ten-year prospective experience of gastrointestinal stromal tumors (GISTS) from the Cambridge GIST Study Group, United Kingdom.
Authors: Bulusu Venkata Ramesh , Hatcher Helen , Hardwick Richard , Carroll Nicholas , Pursglove Stephanie , Save Vicki , Safranek Peter , Earl Helena Margaret ,   Cambridge GIST Study Group
Published: March 2020

10541

Background: Cambridge GIST study group was formed in 2003. GIST specialist multidisciplinary team (MDT) and GIST clinic were established with central review of histology/pathology and management plans. We present our 10 year experience of a prospective database which formed the template for the United Kingdom national GIST registry. Methods: All patients (pts) who have been referred to the GIST MDT were included in the study. The following data was prospectively collected: patient demographics, presenting symptoms, site, size, histology including mutational data (where available) risk stratification of the GISTS, surgical interventions, systemic therapies, other tumours occurring in GIST pts. Results: 260 patients (pts) were reviewed in the GIST MDT. 29 pts had endoscopic/imaging diagnosis of a GIST and were not included in the final analysis. 41 pts had other tumours diagnosed when GIST was initially suspected. Histologically confirmed GISTS N=190. Male: Female 52%:48%. Median age 64 years (range 14-94), 4% <40years. 84% had surgical intervention (primary or metastatectomy), 9% had resections on imatinib/sunitinib. Tumour characteristics: Site: Stomach-73%, small bowel-16%, EGIST-4%, colorectal-3%, duodenum-3% and oesophagus-1%. Size 0.1-40 cm. Histology subtype: Spindle cell =84%, mixed=12% and epitheloid=4%. Miettinen risk stratification groups: High risk=27%, intermediate risk=16% and very low risk/low risk=57%. Mutational status results in 36 pts: exon 11=64%, PDGFRA= 14%, wild type=11%, exon 9=5.5%, exon 13=5.5%. 14% of GIST pts had other tumour either prior to diagnosis or during treatment/follow up of GISTS. Conclusions: This is the first prospective regional GIST registry data from UK. Our results mirror other large prospective series. GISTS should be managed by an experienced multidisciplinary specialist team to provide a high quality patient centred service.
Quality of life (QoL) and content validity in objective tumor response.
Authors: Twelves Christopher , Awada Ahmad , Kaufman Peter Andrew , Yelle Louise , Perez Edith A. , Velikova Galina , Wanders Jantien , Olivo Martin S. , He Yi , Dutcus Corina , Simons W. Robert , Cortes Javier
Published: March 2020

1055^

Background: Key properties of QoL instruments in a clinical trial setting are reliability, the ability to detect a change, and content validity. Using data from the Study 301 phase III breast cancer trial, we report here content validity and ability to detect a change for the EORTC QLQ-C30 and breast cancer-specific QLQ-BR23 questionnaires. Methods: Patients with locally advanced or metastatic breast cancer were randomized to 21-day cycles of either eribulin mesylate 1.4 mg/m2 given on Days 1 and 8, or capecitabine 1.25 g/m2BID orally on Days 1-14. QoL questionnaires were completed at baseline and at 6 weeks, 3, 6, 12, 18, and 24 months. Objective tumor response was evaluated (complete response [CR]; partial response [PR]; stable disease [SD]; progressive disease [PD]). Univariate and multivariate longitudinal analyses using weighted generalized estimating equations were employed to assess the responsiveness of the QoL scales to objective tumor response. Results: 1,102 patients were randomized (554 eribulin, 548 capecitabine). Global health status (GHS)/QoL scores were low at baseline (55). GHS/QoL scores were highest for patients with CR (70.8), followed by those patients with PR (63.5), SD (60.5), and PD (58.1). Physical functioning followed the same pattern: CR (98.3); PR (79.1); SD (72.8); PD (71.0). Role and social functioning scores were also responsive. Pain increased, while fatigue and body image worsened, with poorer tumor responses. Using the weighted generalized estimating equations, there were improvements in physical (34.78; p<0.01), cognitive (27.29; p<0.01), and social (22.04; p<0.01) functioning, and future perspective 11.47 (p<0.01), in patients who responded (CR and PR) to treatment compared with non-responders. Pain decreased significantly by 28.62 (p<0.01) on a 0-100 scale. Patients who responded also gained appetite and had fewer breast symptoms. Conclusions: These results suggest content validity of the EORTC QLQ-30 and QLQ-BR23 questionnaires as they correlate with changes in objective tumor assessments. Clinical trial information: NCT00337103.
Clinicopathologic predictors (CP) of survival in patients with endometrial stromal sarcomas (ESS) treated with multi-modality therapy.
Authors: Dalia Samir , Conley Anthony Paul , Fisher Kate , Lee Ji-Hyun , Wenham Robert Michael , Apte Sachin , Gonzalez Ricardo Jorge
Published: March 2020

10556

Background: ESS is a rare uterine neoplasm in which there is minimal data about CP prognostic markers. Our study aims to determine the association of CP variables on overall survival (OS). Methods: Patients at Moffitt Cancer Center between January 1, 1990 and April 30, 2012 with the diagnosis of ESS were identified using our institutional database. Vital status, demographics, and therapeutic information were recorded. Survival time was estimated using the Kaplan-Meier method, and Cox proportional hazard model was used to identify potential risk factors for the time to event data. A p value < 0.05 was significant. Results: 64 patients were identified. 11 were excluded for incomplete records or inaccurate pathology, and 53 patients were analyzed. Median OS was 214 months (95% Confidence Interval (CI) 60-338). Median follow up was 133 months (95% CI 84-182). Mean age was 53±14 years, 45 (85%) underwent oophorectomy at or prior to diagnosis, 12 (23%) were diagnosed with metastatic disease, 37 (70%) were low grade, 19 (36%) were FIGO stage III-IV. Mean BMI was 29±8 kg/m2, 23 (43%) received adjuvant therapy (adjT) of any type (hormonal, chemotherapy, or radiation) and 16 (30%) received hormonal therapy at any time (HRT). 27 (51%) patients had ER or PR testing and 19 (70%) were ER(+), 20 (74%) were PR (+). The sample size was too small for multi-variable analysis. The Table shows the results of select univariable analysis and OS. Conclusions: Age, initial tumor size, ER and PR status had the greatest impact on survival while BMI, FIGO stage, AdjT or HRT did not. The association between survival and ER or PR status was seen independent of if a patient received HRT. Multicenter collaborative efforts are needed in order to further study the effects of ER and PR status on survival in ESS. [Table: see text]
Recombinant adenoviral human p53 gene combined with radiotherapy in treatment-advanced sarcoma.
Authors: Geng Jianhao , Xiao Shaowen , Zhang Shenwen
Published: March 2020

10557

Background: Advanced soft tissue sarcoma generally are resistant both chemo- and radiotherapy. P53 gene has multiple anti-tumor functions including sensitizing tumor cells to chemo- or radiotherapy. Methods: Thirty-six patients with advanced, unresectable soft tissue sarcoma, with an age of 48.3±19.1 years old, 19 males and 17 females, were treated with combination of p53 gene and radiotherapy. Recombinant adenoviral human p53 gene (rAd-p53) was given through intratumoral injection at a dose of 2 x 1012 rAd-p53 viral particles (VP) once per week for 4-9 times. If tumors spread to the peritoneal cavity with or without malignant peritoneal effusions, 2 x 1012 VP diluted into 500 ml of physiological saline was infused into abdominal cavity, once a week for 4 times. Intensity modulated radiation therapy were given at a total dose of 20 – 70 Gy in 2-7 weeks. Results: The overall response rate at 3 months after treatment was 44.4% (16/36, 2/36 in CR and 14/36 in PR). Twenty patients (55.5%) were stable. The tumor in two patients was successfully resected after the combined therapy. Medium overall survival and progress free survival time were 17.8 and 13.5 months, respectively. The survival rates of one year, two years three years, and 5 years were 58.3%, 25.0%, 13.9%, and 8.3%, respectively. Mild or medium fever was observed in all patients after application of rAd-p53. No serious adverse events or complications observed. Conclusions: Combination of local p53 gene and radio-therapy is effective and safe treatment regimen for advanced soft tissue sarcoma.
Expression of neurotrophins and their receptors in adult sarcomas.
Authors: Malenke Elke , Dorn Christiane , Wirths Stefan , Mueller Martin Rudolf , Kanz Lothar , Kopp Hans-Georg
Published: March 2020

10562

Background: Neurotrophins (NT) influence proliferation, survival, death, and differentiation by binding Tropomyosin-related kinase (Trk) receptors and p75NTR(CD271). While the three Trk-receptors TrkA, TrkB, and TrkC display specific binding to their ligands, i.e. TrkA to NGF (nerve growth factor), TrkB to BDNF (brain-derived neurotrophic factor), NT4/5 (neurotrophin 4/5) and TrkC to NT3 (neurotrophin 3), CD271 shows low affinity to all neurotrophins. Notably, CD271 has been suggested as marker for the prospective isolation of bone marrow mesenchymal stromal cells (MSC), and rhabdomyosarcomas have previously been found to express neurotrophins and NT receptors. Methods: RNA was isolated from sarcoma cell lines and freshly obtained sarcoma (src) cells from patients after surgical resection. RNA was reverse transcribed and cDNA products underwent PCR analysis with specific primers. Furthermore, cell lines from the same primary tissues were established and treated with doxorubicin. Effects of K252a (Trk receptor inhibitor), Pep5 (CD271-Inhibitor), and neurotrophins on sarcoma cell proliferation and survival were analyzed. Results: An array of freshly obtained clinical src samples (n=10 each subtype) was screened for expression of NT3, NT4/5, BDNF, NGF as well as TrkA, TrkB, TrkC, and CD271. Interestingly, src subtype-specific expression patterns were observed. In the established cell lines, K252a increased doxorubicin-induced tumor cell death, while CD271-Inhibitor Pep5 enhanced proliferation in doxorubicin treated cells, especially under serum free conditions and when combined with BDNF and NGF. Conclusions: NT and NT receptors are expressed on all adult src samples screened in this study. Chemotherapy resistant liposrc as well as myxofibrosrc samples displayed the strongest expression of NT3 as well as TrkB, TrkC, and CD271. The concomitant expression of NT and their receptors suggests autocrine self-stimulation, which may propagate survival, proliferation, and treatment resistance. NT receptor tyrosine kinases may represent an interesting therapeutic target in adult src.
Two doses of NGR-hTNF (N) given alone or in combination with doxorubicin (D) in soft tissue sarcomas (STS).
Authors: Ferrari Stefano , Casali Paolo Giovanni , Blay Jean-Yves , Tonini Giuseppe , Le Cesne Axel , Ali Nasim , Perfetti Vittorio , Palmerini Emanuela , Palassini Elena , Ray-Coquard Isabelle , Vincenzi Bruno , Domont Julien , Marchesi Emanuela , Marrari Andrea , Cassier Philippe Alexandre , Silletta Marianna , Stacchiotti Silvia , Lambiase Antonio , Bordignon Claudio
Published: March 2020

10568

Background: N, a tumor-targeted antivascular agent, displays a biphasic dose response curve with activity shown at low dose (LD) or high dose (HD). Vascular effects involve at LD an early vessel stabilization that enhances intratumor D uptake followed by late vessel damage and at HD a rapid vessel disruption. Methods: STS patients (pts), stratified by prior D dose (> vs ≤ 300 mg/m2), were randomized to N alone given at LD (0.8 μg/m2) in arm A and at HD (45 μg/m2/d1/q1w) in B, or combined with D (60 mg/m2/d1/q3w/6 cycles) at LD in arm C and at HD in D. Primary aim of this 4-arm phase II trial was progression free survival (PFS) with CT scans performed q6w until progressive disease (PD). Using 2-stage design, each regimen was rejected if ≤ 2/14 and ≤ 7/24 pts were PD free at 3 months after 1st and 2nd stage, respectively (β=20%, α=10%, n=96). Secondary aims: adverse events (AEs), response rate by RECIST criteria and early metabolic response (MR), as quantified by fractional change in SUV using FDG-PET according to EORTC criteria Results: 66 pts have been enrolled and 55 were included in 1st study stage analysis: median age: 57 yrs; male: 30; PS ≥ 1: 26; leiomyosarcomas: 12; median prior lines: 3 (range, 0-7). In all, 488 weekly cycles were given (mean, 9; range, 1-45). Main grade 3/4 AEs were: neutropenia 18%, chills 7%. After first study stage, primary endpoint was met only in arm C (LD N + D), with 7/14 pts PD free at 3 months. Median PFS was 1.3 months (95% CI, 1.1-1.5) for arm A, 1.5 (1.1-1.8) for B, 4.5 (3.6-5.4) for C and 1.3 (1.1-1.5) for D (p=.01 for trend). By RECIST, there were no objective responses and 20/48 (42%) evaluable pts had stable disease (SD), including 1/12 in arm A, 6/12 in B, 9/12 in C and 4/12 in D. Median SD duration in arm C was 5.5 months (95% CI, 3.7-7.3). By FDG-PET imaging done after 3 weeks, 7/30 (23%) assessable pts had partial MR (4 SD/3 PD per RECIST), with mean change in SUV of -34% (SD, ± 12), while 18 pts (60%) had stable MR (7 SD/11 PD per RECIST), with mean change in SUV of 2% (± 11). Median PFS was 4.2 months in pts who achieved partial MR and 1.5 months in pts who did not (HR=0.67). Complete follow-up for arm C and central histology/radiology review are under way. Conclusions: LD NGR-hTNF plus D is safe, with promising activity as measured by FDG-PET. Clinical trial information: NCT00484341.
Epithelioid haemangioendothelioma.
Authors: Yousaf Nadia , Benson Charlotte , Al-muderis Omar , Fisher Cyril , Judson Ian Robert
Published: March 2020

10569

Background: Epithelioid haemangioendothelioma (EHE) is a rare vascular tumour which can arise in any site. There is little published data about the clinical behaviour and management of these tumours. Methods: A retrospective review of the management of patients with histologically proven EHE presenting to the Royal Marsden Hospital from January 1999 to January 2012. Demographics, site, treatment and survival outcomes were collected. Results: 28 patients (21 females) were identified with a mean (SD) age of 44 (17). 20 patients presented with diffuse disease involving one or more organs at presentation. The predominant site of disease was identified as liver n=8, mediastinum n=6, lung n= 2, limb n=1, pancreas n=1, spleen n=1, back n=1, abdominal wall n=1, oesophagus n=1, neck n=1, pelvis n=1, not known n=2. Median overall survival (Interquartile range) [OS (IQR)] in months was the longest in 10 patients who had localised operable disease at presentation, 116 (71). Amongst those with inoperable disease (n=16), patients with liver disease had the longest OS (IQR), 18 (43) months and those with lung and mediastinal disease had the shortest OS (IQR), 10 (2.5) and 11 (17) months respectively. A variety of treatment modalities were used for patients with inoperable disease and these are summarised in the Table. Conclusions: The clinical behaviour of EHE can vary depending on the site of disease. Surgery, if feasible, has the best outcome. In those with inoperable disease a period of observation to assess the clinical behaviour of the tumour is recommended. Non-steroidal anti-inflammatory drugs are a reasonable, relatively non-toxic first line treatment option. The use of anti-angiogenic drugs merits further exploration. [Table: see text]
Identification of potential molecular biomarkers for response of soft tissue sarcoma to eribulin: Translational results of EORTC trial 62052.
Authors: Wozniak Agnieszka , Wiemer Erik A.C. , Burger Herman , Allemeersch Joke , van Eijsden Rudy , Mathijssen Ron H.J. , Sleijfer Stefan , Smid Marcel , Floris Giuseppe , Marreaud Sandrine , Nzokirantevye Axelle , Sciot Raf , Schoffski Patrick
Published: March 2020

10573

Background: The phase II study EORTC 62052 demonstrated potential antitumor activity of eribulin, a tubulin-interacting cytotoxic agent, which is a synthetic analogue of the natural compound halichondrin B, in patients with various subtypes of metastatic soft tissue sarcoma (STS) including leiomyo- (LMS) and adipocytic (ADI) sarcomas, but not synovial sarcomas (SYN) and other sarcoma histotypes (OTH) (Schöffski P et al. Lancet Oncol. 2011;12:1045). In addition to histotypes, we aimed to identify potential biomarkers responsible for eribulin sensitivity or resistance to eribulin using gene expression and miRNA profiling. Methods: From 68 consenting patients archived tumor tissue was collected, including 22 LMS, 15 ADI, 10 SYN and 21 OTH sarcoma histotypes. Total RNA was isolated from 65 samples and analyzed using GeneChip Human Exon ST Array (for mRNA expression) and Taqman Low Density Array (for miRNA). Progression free survival (PFS) at week 12 (RECIST 1.0) was the primary endpoint of the clinical trial and used for correlative studies. Eighteen out of 56 (32.1%) evaluable patients in this analyzed subset had non progressive disease at week 12 (“responders”). Results: Overall expression of 62 transcripts including ALS2CR11 (uncorrected p<0.001) and 26 miRNAs (p<0.05) differed significantly between non-responders and responders. Additional transcripts and miRNAs were identified when considering the different histological groups (Table). Conclusions: The level of (mi)RNA expression in soft tissue sarcoma samples may predict response of soft tissue sarcoma to eribulin. Further validation studies are required. [Table: see text]
Incidence and predictive factors of late relapse in patients with soft tissue sarcomas: Implications for prolonged follow-up.
Authors: Toulmonde Maud , Le Cesne Axel , Mendiboure Jean , Blay Jean-Yves , Piperno-Neumann Sophie , Chevreau Christine , Delcambre Corinne , Penel Nicolas , Terrier Philippe , Ranchere-Vince Dominique , Lae Marick , Le Guellec Sophie , Michels Jean-Jacques , Robin Yves Marie , Italiano Antoine
Published: March 2020

10574

Background: There is no consensus on how to follow soft-tissue sarcoma (STS) patients after their initial management. In particular, the incidence of late relapse which would justify prolonged surveillance is unknown. Methods: Follow-up data were reviewed from 719 patients with localized STS, included in the French Sarcoma Group database from January 1990 to June 2005, and who achieved complete remission maintained for at least five years after their initial management. The outcomes of interest were the cumulative probabilities of late (> 5 years) local and metastatic relapse with death as a competing event. Estimations and 95% confidence intervals (CIs) were computed with the cumulative incidence function. Patients who did not experience the event of interest or death over the course of the study were censored at their last follow-up. Results: 67 (9.3%) and 42 (5.8%) patients had late local and metastatic relapse respectively. On univariate analysis, internal trunk location, liposarcoma histological subtype, tumor size > 10 cm, R1 margins, no adjuvant radiotherapy were significantly associated with increased risk of late local relapse. On multivariate analysis, internal trunk location (HR= 3.9, 95% CI 2.2-6.7, p<0.001) and tumor size > 10 cm (HR= 2.1, 95% CI 1.1-4, p=0.03) were the two factors independently associated with local relapse. On univariate analysis, leiomyosarcoma histological subtype, and grade > 1 were significantly associated with increased risk of late metastatic relapse. On multivariate analysis, grade > 1 (HR= 4.7, 95% CI 1.1-21, p=0.04) was the sole factor independently associated with the risk of late metastatic relapse. Conclusions: Late relapse of STS (> 5 years after initial management) is relatively uncommon. However, its existence and our results emphasize the critical role of long-term follow-up to detect late local recurrence in patients with retroperitoneal or very large STS and late metastatic recurrence in patients with high grade disease.
Safety of trabectedin (T) in elderly patients (pts) with advanced soft tissue sarcoma (STS).
Authors: Sanfilippo Roberta , Baldi Giacomo Giulio , Fumagalli Elena , Marrari Andrea , Bertulli Rossella , Palassini Elena , Stacchiotti Silvia , Libertini Michela , Casali Paolo Giovanni
Published: March 2020

10576

Background: T is a marine-derived cytoxic alkaloid approved in the European Union for further-line chemotherapy of advanced STS. Most common side effects are fatigue, neutropenia and transient transaminitis. Overall the drug is well tolerated with no cumulative toxicity. Studies in elderly pts are lacking. Methods: We retrospectively reviewed all pts ≥65 year-old, with pre-treated advanced STS, who received T at our Institution from January 2002 to January 2013, focusing on tolerability. All patients received premedication with dexamethasone 4 mg p.o. bid 24 hours prior to T administration. Treatment toxicity was graded according to CTCAE (v 4.0). Results: Fourty-two pts were identified (males = 22, females = 20; median age = 69 years, range 65-82; ECOG PS 0 = 1 pt, 1= 38 pts and 2-3= 3 pts; main histotypes = 22 liposarcoma: 12 myxoid-round cell liposarcoma, 10 well/dedifferentiated liposarcoma, 17 leiomyosarcoma, 2 synovial sarcoma, 4 others; disease extent = 34 metastatic and 8 locally advanced; median line of administration of T= 3rd, range 1st-5th; median T dose = 2.2 mg, range = 2.7-1.7 mg). A total of 319 cycles were administered (median 6, range = 1-23). Starting dose was 1.3 mg/mq in 37 pts and 1.1 mg in 5 pts. The most common side effects were: fatigue (all grades: 19% of cycles), reversible myelosuppression, mainly neutropenia (grade 3-4: 50%), transient transaminitis (grade 3-4: 21%). Eighteen pts needed a dose reduction: inter-cycle transient transaminitis (3 pts), neutropenia ( 13 pts), asthenia (2 pts). In 7 patients, cycles needed to be delayed as well. Three pts interrupted T due to toxicity: grade 3 thrombocytopenia in 1 pt and grade 4 neutropenia in 2 pts. Conclusions: This retrospective analysis confirms that T is well tolerated in elderly pts. No major differences were found in the safety profile compared to historical controls, except a higher incidence of myelosuppression, which however was not influential on subsequent T administration.
Targeted radiofrequency ablation of metastatic posterior vertebral body lesions in patients with soft tissue sarcomas.
Authors: Ley Jessica C. , Jennings Jack , Baker Jonathan C , Hillen Travis , Van Tine Brian Andrew
Published: March 2020

10585

Background: Metastatic spinal lesions can be debilitating with significant impact on patients quality of life. Concern for damage to adjacent neural elements during treatment exist due to high radiation doses required to treat certain radioresistant spinal lesions such as soft tissue sarcoma. Radiofrequency ablation (RFA) of metastatic lesions has been shown to be effective in bone. Spine anatomy presents challenges for minimally invasive (MI) treatment of posterior vertebral body lesions. Targeted RFA (t-RFA) using a novel tumor ablation system, designed for spinal anatomy is evaluated in patients with symptomatic posterior vertebral wall spinal lesions. Methods: Five patients with metastatic leiomyosarcoma or liposarcoma and posterior vertebral body spine lesions, treated by prior radiation with continued progression of lesion size and pain received t-RFA, using a novel spinal tumor ablation system (STAR, DFINE), which contains an articulating bipolar, extensible electrode for navigation. Device thermocouples (TC) permit real time monitoring of the ablation zones to determine size. Sequential post-procedural pain scores, PET and contrast enhanced magnetic resonance imaging, and histopathology of treated area was performed. Results: No complications or thermal injury occurred. Intra-procedural imaging demonstrated the articulated, bipolar instrument was able to navigate to posterior lesions. Post-ablation MRI demonstrated lesion necrosis within a discrete ablation zone. No evidence of malignancy by PET or histopathology was noted through 10 months. All patients reported post procedural pain relief. Systemic therapy was not interrupted. Conclusions: Navigational t-RFA proved a safe and effective, non-ionizing palliative therapy alternative for radio-resistant lesions . Post-ablation imaging and histology confirmed metastatic lesions were necrotic and included in ablation zone with tumor control 10 mos post treatment. Ablation zone was very consistent with real time temperature readings. t-RFA permitted MI targeted treatment of lesions within close proximity of spinal cord, not controlled by systemic therapy. Prospective clinical trial is under preparation.
Nuclear SMAD4 as a predictor of survival in patientes with extremity soft tissue sarcomas submitted to neoadjuvant chemotherapy.
Authors: Cunha Isabela Werneck , Batista Ranyell Spencer Sobreira , Stevanato Paulo Roberto , Aguiar Samuel , Lopes Ademar , Mello Celso Abdon , Costa Wilson Luiz da
Published: March 2020

10586

Background: Neoadjuvant chemotherapy for locally advanced soft tissue sarcomas, although not standard, represents a promising option for resectable tumours. The discovery of biological predictors of chemotherapy response highlights the possibility to develop individualised therapeutic approaches in selected group of patients or predict survival also. The SMAD4 protein, a member of TGFβ superfamily has a role in progression and tumor metastasis and may be involved sarcomas recurrence. Methods: 30 patients with soft tissue sarcomas (STS) of high-grade located in extremities treated with neoadjuvant doxorubicin and ifosfamide chemotherapy were observed prospectively since January 2005 to June 2011. All patients were submitted to radiation therapy adjuvant. Surgical specimens after neoadjuvant treatment were evaluated of SMAD4 nuclear expression by immuno-histochemistry and percentage of viable cells Results: The median follow-up time was 42 months. The overall survival (OS) was 91.7% in patients with low expression SMAD4 nuclear protein associated with ≤10% of viable cells (n=12) in the surgical specimen and 68.9% in the remaining patients. Likewise, the disease free survival (DSF) was 91.7% versus 38.6% (p 0.01) respectively. Conclusions: The combination of nuclear SMAD4 low expression and 10% or less of viable cells in the surgical specimen was statistically significant in better DFS in patients with locally advanced extremity STS treated with neoajuvant chemotherapy with benefit in OS.
Met and HGF inhibition in triple-negative breast cancer cell lines.
Authors: Gaule Patricia Brid , Collins Denis , Walsh Naomi , Duffy Michael J. , Crown John , O'Donovan Norma
Published: March 2020

1066

Background: Basal-like breast cancer (BLBC) is associated with high expression of c-Met. c-Met and its ligand HGF may be rational therapeutic targets for BLBC. We evaluated expression of c-Met and response to c-Met/HGF inhibition alone/in combination with other targeted therapies in triple-negative breast cancer (TNBC) cell lines. Methods: Expression and phosphorylation of c-Met was measured by immunoblotting. qRT-PCR was used to measure HGF mRNA. Cell proliferation was measured by acid phosphatase assay after 5 day treatment with a c-Met inhibitor (CpdA), HGF monoclonal antibody, rilotumamab, a panHER inhibitor (neratinib) and a SRC kinase inhibitor, (saracatinib). Invasion through 0.4 μm Matrigel coated membranes was measured for two cell lines. Results: c-Met and p-Met were detected in 7 and 4 of the 7 TNBC cell lines tested, respectively. HGF mRNA was not detectable in any of the TN cell lines. CpdA inhibited growth in 4 TN cell lines with IC50values ranging from 2.1-7.6 μM. Rilotumumab did not inhibit growth, however combined treatment with CpdA and rilotumumab resulted in significantly increased growth inhibition in 3 of 5 cell lines (Table). CpdA in combination with neratinib significantly improved growth inhibition in MDA-MB-468 cells, and in combination with saracatinib significantly improved growth inhibition in 3 of 5 cell lines (Table). CpdA also inhibited invasion of CAL-85-1 cells by 21.4% (± 10.4%) but not HDQ-P1cells. Conclusions: c-Met may represent a viable molecular target in TNBC. Dual targeting of Met and HGF and/or with EGFR or SRC may increase the efficacy of c-Met inhibition in TNBC. [Table: see text]
Pathologic complete response (pCR) with weekly nanoparticle albumin bound (nab-P) plus carboplatin (C) followed by doxorubicin plus cyclophosphamide (AC) with concurrent bevacizumab (B) for triple-negative breast cancer (TNBC).
Authors: Snider Jessica Nicole , Sachdev Jasgit C. , Allen Jeffrey Warren , Schwartzberg Lee Steven , Young Robyn R. , Javed Ahmed Yasir , Yunus Furhan , Verrier Carmel S. , Jahanzeb Mohammad
Published: March 2020

1068

Background: TNBC are mostly “basal-like” tumors, that have been shown to overexpress Secreted Protein Acidic and Rich in Cysteine (SPARC). Endothelial transcytosis of nab-P via albumin- gp60 -cav1 and binding of albumin to SPARC results in high intratumoral levels of nab-P. Exploiting this and the dysfunctional DNA repair in basal tumors, we hypothesized that nab-P + C would produce high rates of pCR in TNBC, further enhanced by antiangiogenesis properties of B. Methods: Eligible women had operable TNBC ≥ 2 cm. pCR in the breast and pCR in the breast + nodes were primary & secondary end points respectively. We needed 57 evaluable patients to demonstrate 40% pCR vs. 25% (P0) in a single stage phase II design (α: 0.05, β: 0.2).Schema: C AUC 6 d1 + nab-P 100mg/m2d 1, 8 & 15 Q 28 d x 4 cycles followed by AC d1, Q14d x 4 cycles preoperatively with B 10mg/kg Q 14d for the first 6 cycles of preoperative chemotherapy, resuming postoperatively to complete 1 year of treatment.Baseline tumor biopsies & serial serum/blood samples were collected. Results: Due to slow accrual, study was closed after 42 patients. They were women between 35 and 68 years of age (median 52); 51% were African American and 46% were node positive. Safety population: N=41. Four patients came off study prior to surgery while 7 are still on pre-op treatment. Grade ¾ hematologic AEs: neutropenia (Gr3: 56%; Gr4:24%) febrile neutropenia (4%), thrombocytopenia (32%), anemia (22%). 7 patients had SAEs, with 1 grade 5 event. To date, thirty of 31 patients who had surgery (efficacy population) are considered evaluable per protocol. In-breast pCR rates are 55% (17/31) and 56% (17/30) and the rates of pCR breast + nodes are 52% (16/31) and 53% (16/30), for the efficacy and evaluable populations respectively. Conclusions: Majority of the patients in our study achieved a pCR, which is among the highest rates reported compared to anthracyclines+ taxanes without B in TNBC. Correlative analyses are planned. An ongoing randomized intergroup study is evaluating the individual contributions of carboplatin & bevacizumab to pCR in TNBC. Clinical trial information: NCT00777673.
Claudin 1, 3, 4, and 7 expression in triple-negative breast cancer.
Authors: Ko Beom Seok , Kim Hee Jeong , Yu Jong Han , Lee jong Won , Sohn Byung Ho , Kim Sung-Bae , Gong Gyungyub , Ahn Sei-Hyun
Published: March 2020

1070

Background: Triple negative breast cancer (TNBC) often grows rapidly and has poor prognosis, with a high recurrence rate. Because conventional endocrine treatment and HER2 targeted therapy for TNBC is invalid, chemotherapy is the only systemic treatment for TNBC. It is known that several subtypes within the TNBC show different responses to chemotherapy, depending on the subtypes. Recently, a claudin (CLDN) low breast cancer has been identified, exhibiting low expressions of CLDNs 1, 3, 4 and 7. CLDNs are transmembrane proteins that seal tight junctions and are critical for maintaining cell-to-cell adhesion in epithelial cell sheets. However, their role in cancer progression remains largely unexplored. Methods: Surgically removed, formalin-fixed, paraffin-embedded breast cancers from 341 TNBC patients were analyzed to identify CLDN expression.They underwent wide local excision or mastectomy between March, 2004 and December, 2007 at the breast surgery unit of Asan Medical Central Hospital. Results: In our tumor series, we found 45.0% (153/339) of high expressing cases for CLDN1, 57.0% (192/337) for CLDN3, 57.6% (194/337) for CLDN4 and 44.0% (149/339) for CLDN7. Overall, we found 20.5% (70/341) of cases were within the low CLDN expression group and 79.5% (271/341) of tumors were within the high expression group of CLDN1, 3, 4 ,7. Although the high CLDN expression group was significantly associated with positive lymph node status and higher stage, there were no significant differences between CLDN low and high groups in disease free survival (p=0.477) or overall survival (p=0.253). Conclusions: CLDN high tumors are associated with poor prognosis features, but they are not an independent prognostic factor in TNBC patients. However, the mechanisms underlying the different roles of CLDNs in tumorigenesis are largely unclear. Studying the associations of these CLDNs with the TNBC subgroup of breast cancers might provide us with potential diagnostic biomarkers or therapeutic targets for cancer cells.
Clinical impact of febrile neutropenia (FN) increase among patients receiving adjuvant docetaxel/cyclophosphamide (TC) chemotherapy compared to TC plus pegfilgrastim for breast cancer.
Authors: Hamilton Erika Paige , Topping Donna L. , Peppercorn Jeffrey M. , Marcom P. Kelly , Kimmick Gretchen Genevieve , Duff Erin , Cirrincione Constance T. , Blackwell Kimberly L.
Published: March 2020

1076

Background: The FN rate for the approved regimen of TC is 5% in pivotal studies. Other small retrospective reports have reported FN rates as high as 20-35%. We report the incidence of FN from a large retrospective series of breast cancer patients receiving TC with or without pegfilgrastim (PF) for adjuvant therapy. Methods: We reviewed records of 240 sequential patients who had received adjuvant TC (75 and 600 mg/m2) between Mar ’07 and Nov ’12 for FN, upfront PF use, and adverse events by treatment cohort. FN was defined as T> 100.4°F and ANC <500, while upfront PF was defined as PF given at physician discretion 24-48h after 1stcycle of TC administration. Comparisons between two proportions used exact binomial methods; effect of PF on FN after adjusting for baseline characteristics was tested using multivariate logistic regression. Results: 153 (63.7%) patients received upfront PF, while 87 (36.3%) did not (Table). Patients receiving upfront PF were older (57 vs. 52 yrs, p=0.02). Other baseline characteristics (size of primary tumor, hormone receptor status, and nodal status) were no different between groups. FN, fever, antibiotic use, hospitalization, and dose delay were significantly higher when upfront PF was not used (Table). The average length of hospital stay was 2.9 days for TC + PF, and 3.8 days for TC pts. 31/87 (35.6%) of patients without upfront PF went on to receive PF after the 1st cycle. Conclusions: FN for adjuvant TC meets clinical practice threshold and ASCO guidelines for upfront use of PF. FN-related outcomes such as fever, antibiotic use, dose delays, and number of hospitalizations, and were significantly increased without upfront PF. The cost-effectiveness of these findings will be presented and have major clinical implications for routine care. [Table: see text]