bluuebunny/crossref_metadata_2025 huggingface dataset:
An open-label international multicentric phase II study of nilotinib in progressive pigmented villo-nodular synovitis (PVNS) not amenable to a conservative surgical treatment.
Authors: Ray-Coquard Isabelle , Gelderblom Hans , Chevreau Christine , Kroep Judith R. , Italiano Antoine , Stacchiotti Silvia , Le Cesne Axel , Piperno-Neumann Sophie , Ferraresi Virginia , Duffaud Florence , Penel Nicolas , Cassier Philippe A , Tatersall Martin , Hassan Andrew Bassim , Bui Nguyen Binh , Bourne Branchu Veronique , Guillemaut Severine , Cropet Claire , Perol David , Blay Jean-Yves
Published: March 2020

10006

Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a rare pathological entity affecting the synovium in young adults. This neoplastic disease is driven by a t(1;2) translocation which results in the fusion of COL6A3 and M-CSF genes. Nilotinib has inhibitory properties on M-CSF receptor pathway which could be of therapeutic interest in pts with non resectable PVNS. Methods: In this open-label International, multicenter, non-randomized, phase II study the primary objective is to evaluate the efficacy of nilotinib treatment in patients (pts) with progressive or relapsing PVNS not amenable to surgery or in whom surgery would be mutilating, as measured by the 12-week progression-free rate (12-w PFR) validated by an independent committee. Using a Bayesian design with a stopping rule for futility, interim analyses were planned after the inclusion of 10 pts and then every 5 pts. Results: From December 2010 to November 2011, 33 pts with progressive disease from 17 institutions from Europe and Australia were enrolled. 14 pts (median age 37 y (range: 19-68), 7 males) were analyzed in the 2nd interim analysis. Median time since diagnosis was 4.4 years (range: 0.2-26). Primary tumour was located on a knee for 10 pts (71%) and on hip (1 pt, 7%), finger (7%), foot (7%), hand (7%), respectively. 69% of pts had a inoperable PVNS and 31% had a resectable tumour but requiring mutilating surgery. All pts started nilotinib at the planned dose of 800 mg/day. At a median follow-up of 8.9 months (range: 0.6-11), 2 pts had a dose reduction and 1 pt had discontinued nilotinib after 14 days due to toxicity. Nilotinib was well tolerated, with only 2 pts experiencing grade 3 adverse events (anorexia: 1 pt; hepatic failure: 1 pt).The 12-w PFR was 85.7% (95%CI, 57.2%-98.2%), in favour of the study continuation. No OR was observed at w-12; 1 pt (7%) was in PR at w-30. Updated results will be presented after the 3rd interim analysis. Conclusions: Nilotinib treatment induces disease stabilisation in a large proportion of PVNS patients with non resectable disease or in whom resection would be mutilating.
PALETTE: Final overall survival (OS) data and predictive factors for OS of EORTC 62072/GSK VEG110727, a randomized double-blind phase III trial of pazopanib versus placebo in advanced soft tissue sarcoma (STS) patients.
Authors: Van Der Graaf Winette T.A. , Blay Jean-Yves , Chawla Sant P. , Kim Dong-Wan , Bui Nguyen Binh , Casali Paolo Giovanni , Schoffski Patrick , Aglietta Massimo , Staddon Arthur P. , Beppu Yasuo , Le Cesne Axel , Gelderblom Hans , Judson Ian Robert , Araki Nobuhito , Ouali Monia , Marreaud Sandrine , Hodge Rachel , Dewji Mohamedraza , Dei Tos Angelo Paolo , Hohenberger Peter
Published: March 2020

10009

Background: At ASCO 2011 we presented an increase in median progression-free survival (PFS) of pazopanib of 13 weeks (median 7 to 20 weeks; HR 0.31) in a randomized double-blind, placebo-controlled phase III trial in advanced non-adipocytic STS patients pretreated with chemotherapy. Now we present final OS data and predictive factors for OS, such as ethnicity, ancestry and well-known prognostic and predictive factors in STS patients treated with chemotherapy. Methods: At clinical cut-off median follow-up was 25 months. Comparison of both treatments for OS was performed using a two-sided log rank test stratified for number of prior lines of systemic therapy for advanced disease and WHO performance status (PS). HR was calculated with a 2-sided CI. A Kaplan-Meier OS curve was used. Baseline characteristics as potential predictive factors for OS were: PS (0 vs 1), number of lines of prior therapy for advanced disease (0-1 vs 2+), age (≤55 yrs vs > 55 yrs), gender, ethnicity (Hispano or Latino vs other), geographic ancestry (White Caucasian, Asian, other), tumour grade (1-2 vs 3), histology (leiomyosarcoma vs synovial sarcoma vs other). A Cox model was fitted with the investigated factor, treatment arm and associated interaction factor. Data of all 369 randomized patients (123 placebo, 246 pazopanib) were used for the analyses. Results: Median OS (95% CI) was 10.7 (8.7-12.8) in the placebo versus 12.5 (10.6-14.8) months in the pazopanib group, HR: 0.86 (0.67-1.1). Post study protocol systemic treatment was administered in 63% of placebo, and in 49% of pazopanib treated patients. None of the investigated factors showed any statistical significant predictive value for OS. Conclusions: Although pazopanib demonstrated a statically significant increase in PFS compared to placebo, final OS analysis, which showed a trend in favor of pazopanib in patients with metastatic non-adipocytic STS, did not reach statistical significance. The factors studied were not predictive for OS.
Phase I study of neoadjuvant chemoradiation (CRT) plus sorafenib (S) for high-risk extremity soft tissue sarcomas (STS).
Authors: Meyer Janelle Marie , Perlewitz Kelly Shea , Hayden James B. , Hung Arthur , Doung Yee-Cheen , Mansoor Atiya , Beckett Brooke , Holtorf Megan L. , Woodward William J. , Rodler Eve T. , Jones Robin Lewis , Huang Wei , Ryan Christopher W.
Published: March 2020

10011^

Background: We previously reported a regimen of epirubicin/ifosfamide (E/I) and hypofractionated radiation (RT) followed by surgery and postoperative E/I. We hypothesize that S + CRT is safe and augments activity through anti-angiogenic mechanisms. We performed dynamic contrast-enhanced MRI using shutter speed pharmacokinetic analysis (SSM DCE-MRI) to assess preoperative therapy effect. Methods: Subjects with >5 cm, grade 2-3 extremity STS were treated in cohorts of escalating S dose using a 3+3 design based on dose-limiting toxicity (DLT) during the first 8 weeks. Daily S was initiated 14 days prior to E/I (E 30 mg/m2/day days 1-3 and I 2.5 g/m2/day days 1-3 every 21 days for 3 pre- and 3 postoperative cycles). 28 Gy preoperative RT was administered in 8 fractions during cycle 2 (E omitted). Primary objective was to determine maximum tolerated dose (MTD). DCE-MRI was performed at baseline, after 2 weeks S, and prior to surgery. Results: 16 subjects were enrolled. Histologies included pleomorphic (5), synovial (5), liposarcoma (3), other (3). All were extremity (12 lower, 4 upper) tumors. Median tumor size was 11.7 cm. The MTD of S was 400 mg daily (see table). Most common grade 3/4 adverse events among all dose levels were neutropenia (94%), anemia (75%), hypophosphatemia (69%), thrombocytopenia (56%), neutropenic fever/infection (50%), and hypokalemia (31%). 38% developed wound complications requiring surgical intervention including amputation in 1 subject. 44% had >95% histologic necrosis at surgery. No subjects have recurred with median follow-up of 15 (6-27) months. 8 subjects underwent DCE-MRI. Changes in SSM DCE-MRI biomarkers after 2 weeks S correlated with histologic response (R2=0.71). Conclusions: The addition of S to CRT is feasible with promising activity that warrants further investigation. Rate of wound complications is similar to other reports of preoperative radiation. SSM DCE-MRI detected changes in tumor perfusion after only 2 weeks of S and may prove useful to assess early drug effect in STS. [Table: see text]
Desmoid fibromatosis and pregnancy: A multi-institutional analysis of recurrence and obstetric risk.
Authors: Fiore Marco , Coppola Sara , Colombo Chiara , Bertagnolli Monica M. , George Suzanne , Le Cesne Axel , Casali Paolo Giovanni , Gronchi Alessandro , Bonvalot Sylvie , Raut Chandrajit P.
Published: March 2020

10017

Background: Desmoid fibromatosis (DF) may be diagnosed during or after pregnancy (P). However, the risk of progression during P, or in women of child-bearing age with DF prior to P, is unknown. Furthermore, obstetric risks have not been well described. Methods: Institutional databases were reviewed at 3 sarcoma referral centers in Europe and US for women with sporadic DF from 1985 to 2011. Pregnancy and treatment data, outcomes, and obstetric complications were recorded. Results: Overall 75 women were identified. DF was diagnosed during P in 17 women (Group A) or within 6 mo after P in 10 (Group B), was in situ at the time of P in 29 women (Group C), or had been resected prior to P in 19 (Group D). Anatomic site, outcomes, and treatment for each group are in the Table. Among patients operated at diagnosis, 2/11 (18%) recurred (Group A+B). Among the entire cohort, 15 women (20%) recurred after definitive treatment and only 6 (8%) needed multiple treatments after P. Ten spontaneous regressions occurred after P (13%). Twelve women had further P following the DF-related one, and 3 (25%) needed treatment after the subsequent P. At a median follow up of 35 mo from P, 17 women did not receive any treatment (23%), and 39 remain disease-free (52%). Caesarean section was needed in 14 cases (19%), but only in 1 expressly due to DF. DF-related P was associated with abortion in 6 cases (4 spontaneous, 2 voluntary); in no case was it caused by the presence of DF. Conclusions: DF developing prior to or during P may progress during the course of P or thereafter. Spontaneous regression after P was also observed. When resected, P-related DF rarely recurs. Wait & see is an option as well. DF history is not an indication for therapeutic abortion nor a contraindication against subsequent P. [Table: see text]
Optimizing the therapy of desmoplastic small round cell tumor: Combined experience from the two major cancer centers.
Authors: Subbiah Vivek , Viny Aaron D , Anderson Peter Meade , Hayes-Jordan Andrea Anita , Qiao Wei , Benjamin Robert S. , Maki Robert G. , Ludwig Joseph A.
Published: March 2020

10021

Background: Desmoplastic small round cell tumor (DSRCT) is a rare translocation-positive (EWS-WT1)sarcoma subtype that often presents as diffuse peritoneal sarcomatosis in male adolescents and young adults. The objective of this study was to assess the survival of patients with DSRCT from the two major cancer centers. Methods: A multi-center retrospective review was performed of patients diagnosed with DSRCT treated at The University of Texas MD Anderson Cancer Center (MDACC) and Memorial Sloan-Kettering Cancer Center (MSKCC). Results: Of the 197 pts evaluated at both cancer centers (109 from MSKCC and 88 from MDACC) 87 % were male. The mean age was 25 ± 11 years; 139 (70.6%) underwent surgery; 38 ( 19.6%) had debulking surgery, 30 received radiation therapy, and 27 underwent hyperthermic chemotherapy after debulking (CHPP), 11 had a stem cell transplant. 112 patients were seen after 2003 in both the centers vs 85 before 2003. Neoadjuvant chemotherapy included Ewing’s-like chemotherapy with MSKCC’s P6 regimen (<18 yrs of age) and VAI in adults. We further analyzed the MDACC cohort. In univariate analysis radiotherapy, surgery, CHPP, removal of primary mass + metastases, age < 30 and patients treated after 2003 were associated with significantly improved overall survival. Multi-variate analysis showed that patients treated after 2003 had 59% lesser hazard (HR=0.41) than those treated earlier (p=0.04). Comparing 1990-2003 vs. 2004-2010 survival >3 yr with DSRCT was <25 % and is now >50 %, a significant improvement. Conclusions: We present long-term outcomes for the largest series of patients diagnosed with DSRCT. A multidisciplinary approach to DSRCT treatment is required to prolong 3- and 5-yr overall survival. Our recent improved outcomes required not only aggressive chemotherapy but also regional local control measures. Best adjuvant therapy remains to be determined. A treatment algorithm will be proposed.
Immunohistochemical identification of SDHA-mutant gastrointestinal stromal tumors (GISTs).
Authors: Wagner Andrew J. , Remillard Stephen P. , Zhang Yixiang , Hornick Jason L.
Published: March 2020

10029

Background: GISTs are most commonly driven by activating mutations in KIT or PDGFRA. However, 15% of GISTs in adults and >90% in children lack such mutations. A subset of KIT/PDGFRA wild-type GISTs shows distinctive morphologic and clinical features and loss of expression of succinate dehydrogenase (SDH) B. Only a fraction of SDHB-deficient GISTs carry loss-of-function mutations in SDHB or SDHC. Due to the complexity of its locus and the presence of several pseudogenes, SDHA is rarely analyzed. Recently, mutations in SDHA were shown to lead to loss of expression of SDHA and SDHB in paraganglionomas. We sought to determine whether SDHA IHC could identify GISTs with SDHA mutations. Methods: Tumors (n=11) with features of SDH-deficient GIST (gastric origin, epithelioid morphology, multinodular/plexiform architecture) were selected from pathology archives under an IRB-approved protocol. Expression of SDHA and SDHB was determined on tumor sections by IHC. Genomic DNA was isolated from SDHA-negative tumors and amplified using primers specific to introns flanking each of the 15 SDHA exons. Amplicons were bidirectionally sequenced and compared to genomic repository data. Exons with somatic mutations were also examined in DNA from corresponding normal tissue to determine germline status. Results: All tumors (100%) were deficient for SDHB expression by IHC. Four of 11 (36%) SDHB-deficient GISTs also lacked expression of SDHA. SDHA expression was intact in the 7 remaining tumors, including 3 with known SDHB (n=2) or SDHC (n=1) mutations. Nonsense mutations in SDHA were identified in all 4 SDHA-deficient tumors, caused by a single base pair (bp) substitution (n=3) or a single bp deletion (n=1), and heterozygous mutations were also found in DNA from normal tissue of all 4 patients. Somatic loss of the 2nd allele has thus far been found in 3 of 4 tumors; 2 by loss of heterozygosity and 1 by a 13-bp deletion. Further analysis of the 4th specimen is ongoing. Conclusions: SDHA mutations are a common cause of SDH-deficient GISTs and result in combined loss of expression of both SDHA and SDHB. Loss of SDHA expression by IHC reliably predicts SDHA mutations and can be used to select cases for SDHA genetic testing.
Dasatinib first-line treatment in gastrointestinal stromal tumors: A multicenter phase II trial of the SAKK (SAKK 56/07).
Authors: Montemurro Michael , Domont Julien , Blesius Aurore , Rutkowski Piotr , Roth Arnaud , Von Moos Roger , Inauen Roman Ignaz , Bui Nguyen Binh , Burkhard Roger , Knusli Claudio , Bauer Sebastian , Cassier Philippe A , Schwarb Heike , Le Cesne Axel , Koeberle Dieter , Dunet Vincent , Dietrich Daniel , Biaggi Christine , Prior John , Leyvraz Serge
Published: March 2020

10033

Background: First line imatinib has improved the outcome of patients (pts) with gastrointestinal stromal tumor (GIST), but primary and secondary resistance remain a problem. Dasatinib is a second generation tyrosine kinase inhibitor (TKI) and inhibits the activity of bcr-abl, src-family kinases along with a number of other oncogenic kinases including kit. In vitro, dasatinib has shown activity against imatinib-resistant cell lines. Routinely, pts diagnosed with GIST and treated with TKIs are monitored by computed tomography (CT). 18F-fluorodeoxyglucose positron-emission-tomography (FDG-PET) measures tumor metabolic activity for early response assessment, which might be of particular use in the clinical trial setting. Methods: This two-stage phase II trial investigated dasatinib in pts with TKI-naïve GIST. Dasatinib starting dose was 2x70mg/day in pts with histologically proven, FDG-PET positive GIST. Response evaluation was done by serial CT and FDG-PET using EORTC PET response criteria (Young et al. 1999). Elective surgery was allowed after 6 months of trial treatment. Primary endpoint was response (CR+PR) by FDG-PET after one month of dasatinib. Results: 47 of planned 52 pts have been enrolled from December 2007 to November 2011, when the trial was terminated due to slow accrual. 43 pts were eligible. Median age was 61 years, 24 pts were male, 19 female and 41 had a performance status of 0 or 1. At a median follow-up of 11.9 months, 20 pts were still on treatment. Pts went off trial for elective surgery (n=6), progression (n=11), toxicity (n=3), and three patients died (one on-drug). 5% of pts experienced G4, and 38% of pts G3 toxicity, which were most often gastrointestinal or pulmonary. 28% had their dose reduced or interrupted. The primary endpoint, FDG-PET response rate (CR+PR) at 4 weeks was 67% (13 CR, 16 PR, 7 SD, 3 PD, 4 not evaluable). Median progression-free survival is 11.1 months and median overall survival not yet reached. Conclusions: Dasatinib shows promising efficacy in TKI-naïve pts with FDG-PET positive GIST. Mutational data will be presented at the meeting.
A retrospective study from the Royal Marsden Hospital (RMH) of patients with malignant perivascular epithelioid cell tumors (PEComa) receiving treatment with sirolimus (SI) or temsirolimus (TSI).
Authors: Pedersen Joanna Vitfell , Benson Charlotte , Tunariu Nina , Mitchell Scott , Fisher Cyril , Thway Khin , Larkin James M. G. , Scurr Michelle , Judson Ian Robert
Published: March 2020

10038

Background: Perivascular epithelioid cell tumors (PEComas) are rare tumors driven by tuberous sclerosis complex gene mutations causing upregulation of mTOR. Two studies reporting a total of five patients (pts) have described the treatment of PEComa by mTOR inhibition. We report the outcome of 7 pts with PEComa treated with SI or TSI at RMH. Methods: A retrospective analysis was performed on all pts with PEComa referred to the Sarcoma unit at RMH between 2000 and 2011. Data collected included gender, performance status, site of primary tumour, tumour size, surgery, SI/TSI and SI/TSI dose, toxicity according to common toxicity criteria (CTC) version 2.0 and response by RECIST. Results: Five (71%) pts were female, median age was 46 years. Two (29%) had metastatic disease at baseline. Most common primary site was the gastrointestinal tract (29%). Six pts received SI, one TSI. Median treatment duration was 131 days (7-1135). TSI was given at 25 mg IV weekly. Median starting dose of SI was 3 mg daily (1-4), median highest dose was 4 mg daily (1-5). Best responses by computed tomography (CT) scan by RECIST criteria were partial response: 3 (43%), stable disease: 2 (29%) and progressive disease (PD): 1 (14%). One pt only received 7 days of SI and was therefore not evaluable. Two pts continue on treatment, 3 stopped due to PD, one stopped due to grade (gr) 3 thrombocytopenia and one due to gr 3 cough, but two weeks later had confirmed PD on CT. Other toxicities reported were generally mild (gr 1/2) and included mucositis (n:3), rash (n:2), fatigue (n:1), anaemia (n:1), tooth pain (n:1) and oedema (n:1). One pt experienced a grade 3 trigeminal nerve pain leading to dose reduction in SI. Therapeutic drug monitoring was not performed. Conclusions: Our study confirms that SI and TSI are well tolerated with good clinical response and supports the continuous administration of SI or TSI for PEComas. A median treatment time of only 131 days indicates that most pts have a good response to treatment, but responses are sometimes short-lived and further treatment options are needed, justifying further research into inhibitors of this signalling pathway.
Sarcoligo: Impact of local ablative treatment of oligometastatic sarcomas on overall survival.
Authors: Thariat Juliette , Moureau-Zabotto Laurence , Penel Nicolas , Italiano Antoine , Bay Jacques-Olivier , Sunyach Marie-Pierre , Boudou-Rouquette Pascaline , Salas Sébastien , Le Maignan Christine , Ducassou Marie , Aldabbagh Kais , Isambert Nicolas , Kalbacher Elsa , Pan Qiong , Pautier Patricia , Hijazi Hussam , Bertucci François , Thyss Antoine ,   Groupe Sarcome Francais-Groupe d'Etude des Tumeurs Osseuses
Published: March 2020

10042

Background: 40-50% of sarcomas become metastatic. Median survival of metastatic patients has improved over time. The probably multifactorial reasons for such improvement are not fully clear. Noteworthy, for patients with a controlled primary and a limited number of lung metastases, complete resection of their metastases yields survival rates of up to 40% at three years. Advances in surgery, radiotherapy and radiofrequency have fostered the use of local treatments for various metastatic sites (lung, liver, spine...). Methods: A multicentric retrospective study of the Groupe Sarcome Francais (GSF-GETO); approved by the nationally-review board and ethical committee, was conducted to assess the impact of local ablative treatment on overall survival. Patients who had had oligometastases (any site, 1-5 synchronous metastases) at diagnostic or during the course of disease between 2000 and 2010 were included. Results: Median age of the 243 oligometastatic sarcoma patients was 53 years-old (11-86). Patients had grade I, II and III in 7.5%, 29.6% and 63.3% of cases, respectively with various histologies. 69% of patients underwent local ablative treatment of metastases. Median follow-up was 59 months (4-212) for living patients. Median overall survival was 51 months (1-348). On univariate analysis, grade, histology, absence of chemotherapy, local ablative treatment (surgery, irradiation, radiofrequency or chemoembolisation) correlated with survival but not age or site of oligometastasis. On multivariate analyses, grade (hazard ratio HR 0.12 [CI95 0.3-0.6]) and local ablative treatment (HR 3.8 [CI95 2.1-7.1]) remained significant. Conclusions: Local ablative treatment of metastases is associated with better survival in sarcoma patients with oligometastatic disease. The role of the locoregional treatment of metastases and its impact on quality of life should be assessed prospectively.
Association between body weight and efficacy outcomes during trabectedin therapy for recurrent advanced soft tissue sarcoma (STS).
Authors: D'Incalci Maurizio , Galmarini Carlos , de la Riba Alvarez Ines , Badri Nadia , Schöffski Patrick
Published: March 2020

10047

Background: Trabectedin is the first marine-derived antineoplastic drug approved in Europe for the treatment of patients with recurrent advanced STS. Different studies have implicated tumor-derived cytokines as mediators of cachexia in cancer patients. Preclinical studies have demonstrated that trabectedin acts on tumor microenvironment particularly reducing IL-6, which is involved in cancer-induced cachexia (Germano et al. 2011, Ligouri et al. 2011). Methods: This exploratory retrospective analysis evaluated the association between body weight increase during treatment with respect to baseline and efficacy outcomes in 319 adult patients with recurrent STS. Patients were treated in four phase II trials with trabectedin at the approved dose of 1.5 mg/m2, given as a 24-hour infusion every 3 weeks. An analysis of the concordance between weight increase and objective response (OR) rate, tumor control (TC) rate (OR+stable disease lasting ≥3 months), progression-free survival (PFS) and overall survival (OS) was performed. Results: Correlation between weight increase and responses was observed: 68% of patients who achieved OR and 70% of patients with TC increased their weight for a median of 1.2 kg. Remarkably, PFS (5.1 vs. 1.9 months; p<0.0001, log rank) and OS (21.0 vs. 8.2 months; p<0.0001, log rank) were significantly prolonged in patients who gained weight during treatment. Six and 12-months Kaplan-Meier PFS estimates and survival rates at 12, 24 and 36 months were also better in those patients. Additionally, in Cycle 1-2, a significant relationship between weight increase and improved median PFS (4.2 vs. 2.2 months; p<0.0001) and OS (19.4 vs. 9.3 months; p=0.0002) was observed. This is in concordance with the tendency to gain weight starting from the first cycle of treatment. Conclusions: This analysis suggests that weight gain is associated with favorable efficacy outcomes when patients are treated with trabectedin. Further research is needed to assess the prognostic value of weight changes as a complementary source of evaluation on the long-term clinical outcomes and impact of trabectedin on tumor microenvironment.
Interest of tumor to liver ratio 18F-FDG uptake in positron emission tomography for detection of neurofibrosarcoma in neurofibromatosis 1 patients.
Authors: Combemale Patrick , Mognetti Thomas , Allanore Laurence , Bensaid Benoit , Giammarile Fransesco , Pinson Stephane , Drouet Alain , Wolkeinstein Pierre , Blay Jean-Yves ,   French Network on Neurofibromatosis
Published: March 2020

10049

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are difficult to detect in neurofibromatosis 1 (NF1) individuals. The 18F FDG positron emission tomoscintigraphy (FDG PET) is a useful tool. The Standard Uptake Value (SUV) is the gold standard but it is subject to individual variation among patients and medical centers. So we assessed the interest of FDG PET based on a specific tumor to liver uptake ratio (T/L) instead of SUV to find a reproducible and constant cut-off for detecting malignant tumors. Methods: From 2000 to 2010, we conduct a multi centric study: all patients with NF1 and presenting clinical signs of MPNST suspicion (increased tumor size, induration or pain) underwent a FDG PET. Preliminary study estimated a T/L ratio of 1.5 as cut-off for malignity. Based on semi-quantitative analysis of FDG PET images, patients were compared with this cut-off value. Results: 98 patients with 125 tumors were included. FDG PET evaluation identified 42/125 suspected lesions with T/L > 1.5; among these 30 MPNST and 12 benign lesions were found. 83/125 tumors were classified as non-suspicious and 82 were actually benign according to histology or long term follow up. The 1.5 T/L cut off corresponds to 99 % Negative Predictive Value (NPV) and 71% Positive (PPV). The positive likelihood ratio (LR) was thus equal to 7, 69 and the Negative LR to 0, with 97% sensitivity and 87% specificity. When T/L ratio is < 1.5, MPNST is eliminated with 99% NPV, thus avoiding useless surgery. When T/L ratio is above 1.5, there is a strong suspicion of malignancy. But there is a risk of false positivity, which requires discussion before any therapeutic decision. On the over hand we found no significant correlation between SUVmax and malignancy. Conclusions: This study confirms the FDG PET in the detection of NF1-associated MPNST. The tumor/liver ratio with a cut off 1.5 has a very sensitive and specific value to sort out malignant from benign tumors and thus provides adequate surgery. More this semi-quantitative analysis method is just as easy as SUV, more sensitive and more reproducible.
Head and neck sarcomas: A comprehensive cancer center experience.
Authors: Tejani Mohamedtaki Abdulaziz , Ridge John A. , Galloway Thomas J , von Mehren Margaret
Published: March 2020

10064

Background: Head/neck sarcomas are rare, accounting for 1% of head/neck malignancies and 5% of sarcomas. There are about 1000 cases/year in the U.S. comprising of many histologic subtypes making rigorous study of these tumors difficult. Outcomes have historically been worse in this anatomic group due to unique obstacles encountered during their treatment. Methods: We retrospectively analyzed cases of head/neck soft tissue sarcomas treated at Fox Chase Cancer Center (1999–2009). Study objectives were to describe clinicopathologic characteristics, treatment and outcomes of adult head/neck sarcoma patients and identify prognostic factors for disease control and survival. Cox proportional hazards regression analysis was performed to identify predictors of DFS and OS. The HR and 95% CI for Cox model and median DFS/OS from Kaplan-Meier curves were calculated. Results: 31 patients were identified. Median age was 50 (range 15–91). 23 patients were male. Most tumors were high grade (25) and almost all were localized at presentation (29). Common histologies were synovial cell (6), rhabdomyosarcoma (5), angiosarcoma (4), lipsarcoma (4) and leiomyosarcoma (3). 25 patients with localized stage underwent excision: 9 had surgical resection only, 10 had surgical resection with neo/adjuvant radiation and 6 had surgical resection as well as neo/adjuvant chemotherapy and radiation. 7 patients required re-excision to achieve negative margins. Median DFS was 1.1 years (95% CI: 0.7–12.1) and median OS was 3.3 years (95% CI: 2.1-5.4). Of 16 patients with recurrent disease, 12 were local. Patients with positive margins had worse DFS (p=0.04) and OS (p=0.03). Tumors greater than 5cm were associated with worse DFS (p=0.07). Age and grade did not correlate with outcome. Conclusions: Head/neck sarcomas are difficult to completely excise due to anatomic constraints and local recurrence rates are high. Achieving a negative margin is critical in improving outcome. Median DFS and OS are worse than those achieved with other subsites. Head/neck sarcomas are best managed in a multi-disciplinary setting. [Table: see text]
Efficacy of newly developed platinum complexes against osteosarcoma, bone-targeting platinum, and proteasome inhibitory platinum.
Authors: Igarashi Kentaro , Yamamoto Norio , Shirai Toshiharu , Hayashi Katsuhiro , Nishida Hideji , Takeuchi Akihiko , Tanzawa Yoshikazu , Kimura Hiroaki , Miwa Shinji , Inatani Hiroyuki , Shimozaki Shingo , Odani Akira , Tsuchiya Hiroyuki
Published: March 2020

10075

Background: Cisplatin is one of the most effective anti-cancer drugs available for the treatment of human solid tumors including osteosarcoma. As we had already reported, we have utilized caffeine in our chemotherapy protocol. And we achieved excellent clinical results. But effectiveness of cisplatin has been limited by side effects, and resistance. Here we developed two novel platinum compounds. 3Pt is trinuclear platinum complex bearing geminal bisphosphonate moieties, 1Pt is mononuclear platinum complex which has proteasome inhibitory activity. We performed comparative studies of our novel platinum compounds with osteosarcoma. Methods: Two novel platinum complexes were synthesized by Prof. Odani at school of pharmaceutical sciences of our university and cisplatin and caffeine were obtained from constructor. Three cell lines (MG63, 143B, and LM8) were used. Cell survival after a 72 hrs exposure to these compounds was assessed by WST-8 assay, and IC50 value was calculated for each compound. Apoptosis was assessed by DNA fragmentation and Annexin V-FITC/propidium iodine assay. Results: Each compound strongly caused concentration-dependent cytocidal effect. IC50 value of trinuclear compound is superior to cisplatin, and both complexes showed caffeine potentiation. Apoptosis induction and acetylation of histon H2AX were observed. In vivo, 1Pt showed almost same, 3Pt showed strong antitumor effect compared to cisplatin. Conclusions: Two novel platinum compounds that we developed showed strong ant-tumor effect in osteosarcoma in vitro and in vivo. As bisphosphonate has high affinity to calcium ions, 3Pt targets bone tissue and expected to reduce side effects at extraskeletal sites and to overcome the drug resistance. Proteasome inhibitory platinum compound has never been reported before, we will investigate its anti-tumor mechanism precisely.
EURAMOS-1 study: Recruitment, characteristics, and initial treatment of more than 2,000 patients (pts) with high-grade osteosarcoma.
Authors: Whelan Jeremy , Hook Jane , Bielack Stefan S. , Marina Neyssa , Smeland Sigbjorn , Jovic Gordana , Krailo Mark D. , Kühne Thomas , Eriksson Mikael , Butterfass-Bahloul Trude , Teot Lisa A. , Kager Leo , Gelderblom Hans , Sundby Hall Kirsten , Hogendoorn Pancras C. W. , Sydes Matthew Robert , Bernstein Mark L. ,   EURAMOS
Published: March 2020

10081

Background: EURAMOS is a transAtlantic collaboration formed to improve survival in osteosarcoma by conducting RCTs in a clinically relevant timeframe. EURAMOS-1, the largest study conducted in this rare cancer, has completed accrual. It includes two randomized comparisons investigating treatment optimization on the basis of histological response to neoadjuvant chemotherapy. Methods: Pts ≤40yrs with resectable, high grade extremity or axial osteosarcoma were eligible for registration. All were planned for 2 cycles of neoadjuvant methotrexate, doxorubicin, cisplatin (MAP) then surgical resection of the primary tumour. Pts with complete macroscopic resection and no disease progression were eligible for randomization: [i] “good responders”, <10% viable tumor, MAP +/- 18m maintenance pegylated interferon; [ii] “poor responders”, ≥10% viable tumor, MAP vs MAPIE (MAP + ifosfamide, etoposide). Target sample size was ~1,260 pts randomized requiring ~2000 pts registered estimating a non-randomization rate of 30-35%. Results: From Apr 2005 to Dec 2011, 2,260 pts were registered and 1,332 randomized from 17 countries, 320 sites: median age 14yrs (IQR 11-17); 59% male; 50% femoral site; 23% definite/possible metastases; 92% conventional osteosarcoma (diagnostic biopsy). At Sep 2011 planned IDMC review, neoadjuvant treatment data were known for 2024 pts; 1926 (95%) completed 2 cycles pre-operative MAP with 3 treatment related deaths. 59% pts were randomized; non-consent was the most frequent reason for non-randomization. Relative to expected age-specific incidence (UK NCIN 1979-2007) there was apparent under recruiting of older pts: females ≥15yrs and all pts >19yrs, with greater under recruitment of females than males <35yrs. Pts 20-29yrs were less likely to be randomized than those aged 5-19 and ≥30 yrs, 52% vs 57-62%. Conclusions: EURAMOS-1 demonstrates that large RCTs are feasible in rare cancers with inter-continental collaboration and is a model for future trials. Neoadjuvant MAP was safe in a geographically diverse cohort. Improving clinical trial access and randomization rates for young people is still required. Multiple funders detailed at bit.ly/ymUR9w.
A retrospective safety analysis of adult patients treated with high-dose methotrexate for osteosarcoma in Stockholm, Sweden.
Authors: Alm Daniel , Linder Stragliotto Christina , Folin Annika , Bergh Jonas , Foukakis Theodoros
Published: March 2020

10083

Background: Patients with osteosarcoma are routinely treated with pre- and post-operative chemotherapy that includes high-dose methotrexate. The treatment is associated with a risk of severe renal and hepatic toxicity. Methods: All patients with osteosarcoma that had received at least one cycle of high-dose methotrexate at the adult oncology department, Karolinska University Hospital were retrospectively identified. Treatment toxicity, including hematologic, renal, hepatic toxicity, infections and oral mucositis were registered and graded according to CTCAE v 4.0. A possible relationship between methotrexate blood concentration and toxicity was investigated. Results: Sixteen eligible patients that had received a total of 103 cycles of high-dose methotrexate were identified. Ten patients experienced a severe hepatic toxicity, (Grade 3, n=5 and Grade 4, n=5). Grade 3 renal toxicity was seen in one patient and although reversible, it led to treatment interruption. Reversible, grade 2 elavation of serum creatinine occured in 5 cases. Four grade 3 infections were seen in 2 patients and 8 patients had at least one occurrence of Grade 3 oral mucositis. Thrombocytopenia was a common event (Grade 3, n=5 and Grade 4, n=2) but no severe bleeding complications were observed. One patient died as a result of multi-organ failure two days after methotrexate administration. Methotrexate blood concentration at 24 hours from administration could predict for renal toxicity (p<0.005, by chi-square test), but not for other toxicity. Conclusions: High-dose methotrexate in adult patients with osteosarcoma was frequently associated with severe, however reversible toxicity.
Early assessment of MCV to predict clinical outcome in patients with advanced gastrointestinal stromal tumors (GIST) receiving imatinib.
Authors: Constantinidou Anastasia , Krikelis Dimitrios , Olmos David , Scurr Michelle R. , Jones Robin Lewis , Ashley Sue , Judson Ian Robert
Published: March 2020

10086

Background: In patients with advanced GIST, imatinib trough levels have been associated with a lower rate of clinical benefit. Anecdotal observations have suggested that commencing treatment with imatinib may be associated with an increase in red blood cell size as measured by MCV and MCH, indicating the effect of imatinib on KIT signalling in the bone marrow. Methods: In this retrospective review we examined a possible connection between changes in MCV and MCH after the first 3 months (mo) of treatment with imatinib and progression-free survival (PFS). Data for patients with inoperable advanced or metastatic GIST treated between 2000 and 2011 were available for analysis. Patients were categorised in quartiles according to the distribution of the percentage of change of MCV and MCH between start of imatinib (baseline) and 3 (+/- 0.5) mo (ratio %=MCV change at 3 mo/MCV at baseline). PFS curves were plotted using the Kaplan-Meier method and compared using the log rank test. Results: One hundred and thirty patients were eligible for analysis and the demographics were: male:female 84:46, median age at presentation: 60.5 (23.5-86.5) years, commonest primary tumour sites: stomach (72/130) and small bowel (44/130), commonest metastatic site: liver (76/130). In the patients with a 10% or over increase in MCV (p75-p100) at the 3 mo (+/-0.5) time point a significantly longer PFS was observed compared to those with a smaller magnitude of change (PFS of 37.1 mo vs 24.3 mo, p=0.032). A similar trend although not statistically significant was observed in patients with MCH of 15% or over (p75-p100) with PFS of 34.0 mo vs 25.8 (p=0.125). The two parameters (MCV and MCH) showed a high correlation of percentage change (r2=0.85). The patients with a 10% MCV increase and /or 15% MCH increase (total=40) showed a significantly longer PFS (34.0 mo) compared to those with lower percentage change (PFS= 24.3) p=0.035. Conclusions: Simple laboratory parameters may be indicators of imatinib pharmacokinetics and may therefore be used as surrogate markers of clinical outcome. Larger prospective studies are required to confirm the results of this study.
Final analysis of phase II study of EZN-2208 (PEG-SN38) in metastatic breast cancer (MBC).
Authors: Osborne Cynthia R. C. , O'Shaughnessy Joyce , Holmes Frankie Ann , Kim Hyun Sue , Kocs Darren M. , Steinberg Michael S. , Richards Paul D. , Vukelja Svetislava J. , Berkowitz Noah C. , Buchbinder Aby
Published: March 2020

1017

Background: EZN-2208 is a water-soluble PEGylated conjugate of SN38. EZN-2208 results in prolonged exposure of tumors to SN38 via preferential accumulation of EZN-2208 in the tumor and prolonged release of SN38. These data represent the final analysis of our study evaluating EZN-2208 in MBC. Methods: EZN-2208 9 mg/m2 (SN38 equivalents) was delivered as a 60-minute IV infusion, weekly for 3 wks in 4‑wk cycles. The primary objective was to determine the overall response rate (RR) in female patients with metastatic breast cancer (MBC) who had received prior adjuvant or metastatic therapy with either 1) anthracycline and taxane (AT) or 2) anthracycline, taxane, and capecitabine (ATX). Secondary objectives included evaluation of RR based on tumor receptor status, duration of response, progression-free survival (PFS), overall survival (OS), and safety. Results: Patients with MBC (n=164) were treated with a median (range) of 3.3 (0.3-22) cycles of EZN-2208. The objective response rate (RR) was 20% for AT and 9% for ATX. The clinical benefit rate (CBR=%CR + %PR + %SD ≥6 months) was 41% and 27% in patients in the AT and ATX cohorts, respectively. The RR and CBR among ER+ patients were 11% (10/91 pts) and 41.8% (38/91 pts). In patients who progressed during or within 30 days of prior platinum-containing regimens (Platinum Progressors), the CBR was 20% (8/40 pts). Among triple negative breast cancer (TNBC) patients, the RR and CBR were 22.5% (11/49 pts) and 36.7% (18/49 pts). For TNBC, Platinum Progressors, the CBR was 26.1% (6/23 pts). Overall, most common reported drug-related adverse events were diarrhea, nausea and neutropenia. Conclusions: EZN-2208 has notable activity in patients with previously treated MBC and appears to be an active agent for treatment of TNBC. Patients with TNBC, who had been previously treated with a platinum-based regimen, also derive clinical benefit from EZN-2208. The safety profile of EZN-2208 is acceptable with good tolerability in most patients. Further evaluation of EZN-2208 in MBC in general and TNBC in particular is warranted.
10-year update of E2197: Phase III doxorubicin/docetaxel (AT) versus doxorubicin/cyclophosphamide (AC) adjuvant treatment of LN+ and high-risk LN- breast cancer and the comparison of the prognostic utility of the 21-gene recurrence score (RS) with clinicopathologic features.
Authors: Sparano Joseph A. , O'Neill Anne , Gray Robert James , Perez Edith A. , Shulman Lawrence N. , Martino Silvana , Badve Sunil S. , Baehner Frederick L. , Childs Barrett H , Yoshizawa Carl N. , Rowley Steve , Davidson Nancy E. , Shak Steven , Goldstein Lori J.
Published: March 2020

1021

Background: At 5 years, AT did not improve disease free survival or overall survival and RS was a more accurate predictor of relapse than standard clinicopathologic characteristics for patients with hormone receptor (HR) positive tumors. Methods: A Phase III Intergroup trial tested adjuvant AT vs. AC. Women with 1-3 N + or N - and T-size > 1cm were randomized to 4 cycles of AT (60 mg/m2/60 mg/ m2) or AC (60 mg/m2/600 mg/m2) q 3 wk x 4. Patients(pts) with ER + and/ or PR + tumors received tam for 5 yrs. Pts were stratified by nodal, HR (ER+ PR+, ER+PR-, ER-PR+, ER-PR-, ER/PR unk) and menopausal status. The primary endpoint was DFS. A sample of 465 pts with HR + breast cancer with 0 to 3 positive axillary nodes who did (N =116) or did not have a recurrence had tumor tissue evaluated using the 21- gene assay. Grade and HR expression were evaluated locally and centrally. Results: 2952 pts were randomized between 7/30/98 and 1/21/00. 2883 were eligible and analyzable. Arms were balanced for age, HR, menopause, nodes, surgery, grade and T-size: median age 51; 64% ER +; 65% LN-; grade: 10% low, 38% int., 46% high; and median T-size - 2.0 cm. At a median follow-up of 11.5 years the DFS/OS results are shown in the table below. RS was a highly significant predictor of recurrence including node negative and node positive disease (P < .0001) and predicted recurrence more accurately than clinical variables. Conclusions: At 11.5 yrs. median follow-up, there remains no difference in DFS or OS, although there continue to be fewer events in the AT arm in the prespecified ER/PR negative subgroup. At 10 years, the RS continues to be a more accurate predictor of relapse than standard clinical features. [Table: see text]
Breast cancer multifocality-multicentricity and locoregional recurrance.
Authors: Lei Xiudong , Lynch Siobhan P. , Hsu Limin , Meric-Bernstam Funda , Buchholz Thomas A. , Zhang Hong , Hortobagyi Gabriel N. , Valero Vicente , Gonzalez-Angulo Ana M.
Published: March 2020

1029

Background: The impact of multifocality (MF) and multicentricity (MC) on locoregional (LR) control for invasive breast cancer, and the optimal local treatment strategy for these tumors, is unknown. In particular, there is disagreement in the literature regarding the use of Breast Conservation Therapy (BCT). We evaluated a large single institution cohort of MF and MC breast cancers to determine if they had inferior LR control rate when compared to their unifocal counterparts. Methods: MF and MC were defined pathologically as more than one lesion in the same quadrant and more than one lesion in separate quadrants, respectively. Patients were categorized by presence or absence of MF or MC disease and by the LR treatment modality received – BCT (n=256), mastectomy alone (n=466), or mastectomy plus post-mastectomy radiation therapy (n=184). 10 patients who underwent BCT for MC disease against physician advice were excluded. MF and MC tumors were analyzed both as a group and as separate entities. Kaplan-Meier product limit method was used to calculate 5-year LR control rate. Cox proportional hazards models were fit to determine independent associations of MF/MC disease with LR control. Results: Median follow up was 52 months. Out of 3722 patients with stage I-III disease who did not receive neoadjuvant chemotherapy, 906 (24%) had MF (n=673) or MC (n=233) disease. 5-year rate of LR control rate was 99% in the MF group, 96% in the MC group, and 98% in the unifocal group, (P = 0.44). Subset analysis revealed no statistical difference in LR control regardless of the type of LR treatment, (P = 0.67 in the BCT group, P = 0.37 in the mastectomy alone group, and P = 0.29 in the mastectomy plus post-mastectomy radiation therapy group). There were 21 in-breast recurrences after BCT (8.2%). After controlling for other risk factors, MF and MC did not have an independent impact on LR control rate. Conclusions: MF and MC disease are not independent risk factors for LR recurrence. Patients with MF and MC breast cancer had similar rates of LR control to their unifocal counterparts, regardless of LR treatment modality. Our data suggest that BCT is a safe option for patients with MF tumors and that MF or MC disease alone is not an indication for post-mastectomy radiation therapy.
Pathologic complete response rates observed in women with locally advanced and inflammatory breast cancer receiving neoadjuvant carboplatin and paclitaxel.
Authors: Shinde Arvind Manohar , Yim John H , Kruper Laura , Vito Courtney , Chen Steven L. , Paz Isaac Benjamin , Luu Thehang H. , Tagawa Tomoko , Yu Kim Wai , Wilczynski Sharon , Shaw Sally , Vora Lalit , Park Jinha Mark , Somlo George
Published: March 2020

1035

Background: Pathologic complete response (pCR) following neoadjuvant chemotherapy (NCT) is predictive of outcome in patients with locally advanced breast cancer (LABC). A non-anthracycline containing NCT regimen (Sikov et al. JCO 10/09) may reduce the risk of associated secondary hematologic malignancies and cardiac toxicity while yielding comparable pCR rates. Methods: A retrospective review of all LABC and inflammatory breast cancer (IBC) cases treated from 4/09 to 12/11 with a NCT regimen of carboplatin (AUC of 6, administered on day 1) and paclitaxel 80 mg/m2 (given weekly on a 21-28 day cycle) was conducted at the City of Hope Cancer Center (COHCC). Pts with HER2+ (HER+) tumors received trastuzumab during the NCT treatment. All pCRs (pCR of primary only – "pCR1°"; pCR of primary and lymph nodes – "pCR-All") were determined by a COHCC pathologist based on final surgical specimens. Results: 38 pts were identified, with 39 breast primaries; 18% had IBC, 62% of LABCs/IBCs were hormone receptor positive (HR+), 46% of tumors were HER2+, and 26% were triple negative. Median age was 51 [27-63]. All pts completed the planned number of cycles. Four pts required carboplatin dose reductions, 4 pts required dose reductions in paclitaxel, 3 pts had paclitaxel changed to nab-paclitaxel, and 17 pts required G-CSF to complete their planned treatment. One pt receiving trastuzumab experienced asymptomatic LVEF decline below normal limits. Conclusions: A non-anthracycline-containing NCT regimen of carboplatin/paclitaxel was well tolerated and resulted in high pCRs when given to triple negative (HER2-/HR-) pts, and HER2+ pts, especially with HER2+HR- subtypes. The findings warrant further studies of this regimen in a prospective randomized setting. [Table: see text]