bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outpatient administration of high-dose methotrexate for osteosarcoma treatment in Brazil
Authors: Macedo C. R. , Cappellano A. M. , Noguchi D. T. , Martinho A. P. , Dias C. G. , Dias C. G. , Malheiros R. C. , Dutra A. H. , Grings M. , Pires A. L. , Petrilli A. S. 
Published: August 2020

10038 Background: We describe the experience with outpatient administration of high dose methotrexate (HDMTX) and leucovorin rescue for osteosarcoma treatment at Instituto de Oncologia Pediátrica. Methods: HDMTX (12g/m2) is administered as part of the Brazilian Osteosarcoma Treatment Group Protocol in an ambulatory basis. Daily MTX serum levels and fluid controls follows until the serum level is <0,2 μ/L. Families were oriented to measure urinary pH and volume, PO intake and to adjust leucovorin dose as needed. To achieve treatment adherence, a family education program was developed. Concomitantly to HD chemotherapy, low dose oral cyclophosphamide and MTX (metronomic treatment) were provided to metastatic (M) patients. This is a retrospective analysis of the HDMTX courses administered between 2006 and 2008. Results: Out of 341 HDMTX infusions, administered to 42 patients, 42.5% had abnormal serum levels at hour 24, 8.8% at hour 48 and 33.2% at hour 72. After required interventions, 2.9% (n = 8) had serum levels >0.2 μ/L at hour 72 leading to delayed excretion. Of these, 7 had also creatinine elevation and main adverse events were mucositis, reversible transaminasis elevation and one sepsis. In the overall analysis, other toxicities included mucositis grade II (20%), nefrotoxicity (5.6%) and neutropenia grades III and IV (25.4%). Serious adverse events of seizure, allergic reaction, and Steven Johnson's Syndrome lead to suspension of future HDMTX administration in 4 patients (01 metastatic). The main differences found between M and non-M patients were 16.8% versus 8.7% of leucopenia grade IV and 12.1% versus 6.6% of anemia grades III and IV. Conclusions: Similar to other authors’ experience, outpatient administration of HDMTX lead to elevated serum levels in 42.5% of the infusions, demonstrating the importance of a well trained staff and early introduction of supportive therapies to avoid associated toxicities. To a developing country, this approach helps lowering treatment costs and infection risks and increases patient adherence to treatment, with acceptable toxicities, even with the introduction of metronomic treatment. No significant financial relationships to disclose.
Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): Phase I study CA180004
Authors: Somlo G. , Atzori F. , Strauss L. , Rybicki A. , Wu X. , Gradishar W. , Specht J. 
Published: August 2020

1012 Background: SRC family kinases (SFK) mediate numerous signal-transduction pathways relevant to breast cancer as well as osteoclast function. Dasatinib, a potent oral inhibitor of SFK and other kinases has preclinical activity in breast models and in vitro synergy with Cap in some breast cancer cell lines (KPL-4 and HCC-70). A phase I trial of dasatinib plus Cap was conducted to define dose-limiting toxicities (DLT), maximum tolerated (MTD), and recommended phase II (RP2D) doses. Methods: Sequential cohorts of pts with ABC were treated with Cap twice daily (BID) on days 1–14 and dasatinib daily in 21-day cycles using dose levels (DL) for Cap (mg/m2) and dasatinib (mg): DL1: Cap 825 + dasatinib 50 BID; DL2: Cap 825 + dasatinib 70 BID; DL3: Cap 1000 + dasatinib 70 BID; DL3a: Cap 1000 + dasatinib 100 once daily (QD). All pts had ECOG performance status 0–1, had prior anthracycline and/or taxane, and received ≤2 regimens in advanced setting. MTD was based on DLT in first cycle and RP2D also based on tolerability of additional cycles. Results: 31 pts with ABC, median age 53 years (range 36–78) were treated. Number of pts treated/evaluable for DLT/reported DLT (event) were DL1: 7/6/1 (headache, grade 3); DL2: 9/7/0; DL3: 6/6/1 (diarrhea, grade 3), and DL3a: 9/9/1 (pneumonia, grade 3). Most frequent AEs related to either drug and occurring at any time on study (n pts) were nausea (12), vomiting (7), diarrhea (6), abdominal pain (2), fatigue (8), headache (7), musculoskeletal pain (1), and pleural effusion (4); hand-foot syndrome (5) was as expected for Cap alone. 11 patients experienced a Grade 3–4 non-hematologic AE at some point during the study. Laboratory abnormalities were uncommon. To date, 20 pts have continued treatment for ≥6 weeks and 9 pts for ≥12 weeks. Number of pts who (at any time) reduced dasatinib/reduced Cap/discontinued for toxicity were DL1: 2/2/1; DL2 2/2/3; DL3: 2/1/2; DL3a: 0/1/1. Updated safety and efficacy data will be presented. Conclusions: Dasatinib + Cap was tolerated without unexpected combined-treatment toxicity; few pts required dose reduction in later cycles. The recommended phase II dose, Cap 1000 plus dasatinib 100 QD, is well tolerated and will be studied for efficacy in an expanded patient cohort. [Table: see text]
Randomized phase II trial of gefitinib plus anastrozole or fulvestrant in postmenopausal, metastatic breast cancer
Authors: Carlson R. W. , O'Neill A. , Vidaurre T. , Gomez H. L. , Badve S. , Sledge G. 
Published: August 2020

1013 Background: Preclinical data documents interactions between the signal transduction pathways for ER and for EGFR, and these interactions may relate to endocrine resistance in ER+ breast cancer. Limited clinical data is available. Methods: This multi-institutional, single-stage, non-comparative, randomized phase II study tested the EGFR tyrosine kinase inhibitor gefitinib 250 mg daily PO plus endocrine therapy with either anastrozole 1 mg/day PO (AG Arm) versus fulvestrant 250 mg IM every 4-weeks (FG Arm). Eligible pts were postmenopausal women with ER+ and/or PgR+ measurable metastatic breast cancer with no prior endocrine therapy for metastatic disease, no prior adjuvant AI or fulvestrant, no more than two chemotherapy regimens for metastatic disease, ECOG status 0–2, no CNS metastasis, and adequate bone marrow, liver, and renal function. Primary endpoint was RECIST determined clinical benefit (CR+PR+SD for ≥6 mos) and secondary endpoints were toxicity and interaction of biomarkers with clinical benefit. Results: 148 pts were registered, and 142 pts are eligible and analyzable, 73 to AG and 69 to FG. Treatment groups were balanced for race, age, ECOG status, and sites of disease. Median follow-up is 35 mos. Median N of 4-week cycles of treatment is 6 (range 1–42) in both groups. Treatment was terminated for disease progression in 74% v 75%, toxicity 7% v 10%, death 1% v 3%, withdrawal 8% v 1%, and other 3% v 7% in the AG v FG arms, respectively. Clinical benefit rate (95% CI) is 42% (30%-53%) v 38% (28%-52%) for AG v FG, respectively. Response rates are CR 3% v 4%, PR 21% v 17%, SD for ≥6 mos 18% v 17% for AG v FG. Median PFS is 5.7 mos v 5.2 mos and median OS is 30.2 mos v 23.8 mos for AG v FG, respectively. Overall worst toxicity grade experienced for AG is G1 and 2 = 62%; G3 = 28%; G4 = 4%, G5 = 3%; for FG was G1 and 2 = 58%; G3 = 27%; G4 = 7%; G5 = 4%. G3 + G4 + G5 toxicities occurring in ≥5% of either treatment are diarrhea (5% v 13%), SGOT elevation (7% v 8%), and infection without neutropenia (1% v 6%) for AG v FG. Conclusions: Both anastrozle and fulvestrant are active endocrine agents in combination with gefitinib and both are generally well tolerated. Anastrozole plus gefitinib appears to be the better combination to take forward for phase III comparisons. [Table: see text]
Relationship between survival and estrogen receptor (ER) status in pts with metastatic breast cancer (MBC) treated with capecitabine (C) and docetaxel (D): An exploratory data analysis
Authors: Gluck S. , Russell C. , O'Shaughnessy J. , Yuan G. , Odom D. , Sherrill B. , Blum J. 
Published: August 2020

1024 Background: Previous studies in pts with MBC have shown that women with ER+ tumors have a longer survival time compared to women with ER- tumors. An exploratory analysis was conducted to describe the relationship between survival and ER status among MBC pts treated with combination therapy consisting of C+D. Methods: This analysis used data from an open-label, randomized phase III trial of C+D vs D alone in pts with advanced and/or MBC. Survival analysis was used to investigate the effect of baseline ER status of the primary and metastatic tumors on overall survival (OS). ER status was defined as positive if positive for any tumor, negative if at least 1 negative test, otherwise unknown. Results: Among 506 intent-to-treat pts (randomized, received ≥1 dose), ER status was identified in 356. C+D: 90 ER+, 88 ER-; D alone: 95 ER+, 83 ER-. The unadjusted log-rank test showed a significant difference in OS between the C+D and D groups for ER+ but not ER- pts. In the ER+ group, median OS was longer in C+D vs D pts (538.5 vs 379.0 d) (hazard ratio [HR] 0.65; P=0.007). OS was significantly longer in ER+ vs ER- pts in the C+D group (538.5 vs 329.0 d) (HR 0.68; P=0.019) but not in the D group (379.0 vs 301.0 d) (HR 0.90; P=0.514). OS by time from diagnosis to recurrence and baseline tumor size showed no significant differences between ER+ and ER- pts. Conclusions: This exploratory analysis suggested a significant difference in OS between the C + D and D groups in ER+ (HR 0.65) but not ER- (HR 0.90) pts. Also, within the C+D group, the median OS was significantly longer in ER+ than ER- pts (HR 0.68). [Table: see text] [Table: see text]
A specific nomogram to predict subsequent brain metastasis in metastatic triple-negative breast cancer patients
Authors: Pusztai L. , Rouzier R. , Pusztai L. , Ibrahim N. 
Published: August 2020

1028 Background: The development of brain metastases is usually a fatal event in the history of breast cancer patients with metastatic disease other than brain (MDOB). We previously developed a global nomogram that includes immune-histochemical phenotype to predict the occurrence of brain metastasis (BM). We hypothesized that a nomogram specific to triple negative tumor (TN) could improve prediction BM occurrence in patients with MDOB, thus allowing allocation of preventive treatment more efficiently. Methods: Patients with metastatic BC presenting between 2000 and February 2007 treated at M. D. Anderson Cancer Center were included in this retrospective analysis. We tested 17 variables and developed a multivariate model to predict occurrence of subsequent BM in TN tumors and created a nomogram that could be used for individual prediction. The model was cross-validated by bootstrapping and compared to the global nomogram. Results: Among 2,136 patients with metastatic breast cancer including 641 patients with TN tumors, 362 developed BM during follow-up: young age, histological characteristics, short delay between initial diagnosis and MDOB, number of metastatic sites and initial number of metastatic nodes were significantly and independently associated with subsequent BM. The nomogram to predict BM developed on the TN population provided a better discrimination (area under the ROC curve [AUC] = 0.62) than the global nomogram (AUC = 0.58) for the TN tumors. Prediction with the specific nomogram and the global nomogram were highly correlated (correlation factor = 0.67, p < 0.0001). However, when a threshold at 15% was used, we observed 27% of discordant cases and the sensitivity of the specific nomogram was better. Conclusions: We developed a specific tool to predict subsequent BM in patients with metastatic TN breast cancer. This nomogram outperformed a global nomogram. No significant financial relationships to disclose.
Hepatobiliary abnormalities in patients with metastatic cancer treated with lapatinib
Authors: Moy B. , Rappold E. , Williams L. , Kelly T. , Nicolodi L. , Maltzman J. D. , Goss P. E. 
Published: August 2020

1043 Background: Lapatinib (LAP), a dual tyrosine kinase inhibitor (TKI), is effective in the treatment of HER-2-positive metastatic breast cancer. Liver toxicity has been reported as a side effect of several TKIs. We analyzed the liver safety of LAP using available data from 16 metastatic cancer trials. Methods: LAP (as monotherapy or in combination) was administered to 2,968 patients (pts) in metastatic cancer trials. Liver function tests were prospectively evaluated. We defined liver toxicity events as either NCI CTCAE grade (Gr) 3 or 4 alanine and aspartate aminotransaminases (ALT/AST) or meeting Hy's Law criteria (liver injury with jaundice). Results: Overall Gr 3 and 4 ALT/AST events were seen in 45/2,968 (1.5%) and 2/2,968 (0.07%) pts, respectively. Of LAP monotherapy pts, Gr 3 and 4 ALT/AST was seen in 13/1,470 (0.9%) and 1/1,470 (0.07%), respectively. Of LAP + monoclonal antibody (mAb) pts (trastuzumab or bevacizumab), Gr 3 and 4 ALT/AST was seen in 2/199 (1.0%) and 1/199 (0.5%), respectively. Ten of 645 pts (1.6%) treated with LAP + chemotherapy (capecitabine or paclitaxel) had Gr 3 ALT/AST. Twenty of 654 pts (3%) treated with LAP + letrozole had Gr 3 ALT/AST. Among 2,968 pts, Hy's law toxicity occurred in 8 (0.3%) pts: 2/1,470 (0.14%) pts treated with LAP alone, 1/199 (0.5%) pts treated with LAP + mAb, 4/645 (0.6%) pts treated with LAP + chemotherapy, and 1/654 (0.2%) pts treated with LAP + letrozole. Alternative causes of liver toxicity such as metastatic liver disease, infectious hepatitis, and heart failure will be reported at the meeting. Conclusions: Review of data from 16 clinical trials in metastatic cancer revealed low levels of liver toxicity for LAP. Oncologists should be vigilant for this rare side effect of LAP. A proposed monitoring algorithm of symptom assessment and frequency of hepatobiliary laboratory monitoring will be shown. [Table: see text]
Tolerability and efficacy of 500 mg fulvestrant in postmenopausal women with estrogen receptor (ER)+ advanced breast cancer
Authors: Come S. E. , Parker L. M. , Wulf G. , Kuter I. , Ryan P. D. , Tkaczuk K. , Borges V. , Kasper H. , Gelman R. , Winer E. P. 
Published: August 2020

1050 Background: At the approved dosage (AD) of 250 mg q 28d, fulvestrant has no dose-limiting toxicity and may not optimally inhibit/downregulate levels of ER. We evaluated the tolerability, efficacy, and pharmacokinetics of fulvestrant given at twice the AD. Methods: 35 postmenopausal patients with ER+ evaluable metastatic breast cancer who had not received endocrine therapy for advanced disease and were at least 12 months from the completion of any adjuvant endocrine therapy were enrolled in a single stage, phase II study. The median age was 64. 15 patients had received prior adjuvant endocrine treatment. 14 had visceral metastases. Treatment consisted of fulvestrant 500 mg (2 x 5 mL injections) on days 1, 15, 29, and q 28d thereafter. Toxicity and response were assessed q 28d by history, exam, and laboratory testing, and q 3 months by imaging. The primary endpoint was clinical benefit rate (CBR) defined as complete responses (CR) plus partial responses (PR) plus stable disease (SD) for > 6 months. This trial was powered to detect a 20% improvement in the 57% CBR reported for AD fulvestrant in the first-line metastatic setting (J Clin Oncol. 2004;22:1605–613). Results: Median time on study is 13 months (mo). 17 patients remain on treatment (8+ to 54+ mo). There has been no grade (gr) 3 or 4 treatment-related toxicity. Transient injection site discomfort or pruritis occurred in 13 patients (11 gr 1, 2 gr 2). A CBR of 86% was observed (95% CI 70%- 95%). The median time to progression is 22 mo. In the subset of 24 patients fulfilling RECIST criteria, 1 CR and 6 PR, and 15 SD were observed (overall response rate 29%, CBR 92%). Conclusions: Doubling the AD of fulvestrant does not increase toxicity. Monthly bilateral 5 mL injections are well tolerated. Importantly, the CBR is improved at this dose and schedule compared to the AD. [Table: see text]
Frequency of β-catenin heterozygous mutations in extra-abdominal fibromatosis as a surrogate marker for disease management
Authors: Dômont J. , Salas S. , Lacroix L. , Brouste V. , Dufresne A. , Terrier P. , Blay J. , Le Cesne A. , Coindre J. , Benard J. , Bonvalot S. 
Published: August 2020

10501 Background: Fibromatosis, a rare soft-tissue and locally invasive neoplasm, consist of distinct clinical entities including sporadic extra-abdominal fibromatosis (EAF). The potential morbidity of loco-regional treatments combined with the high local recurrence rate have led investigators to assess the possibility to design a “wait and see” policy in a subset of patients (pts). Up to date, molecular biomarkers of local recurrence of EAF remain unknown. As dysregulation of β-catenin (βC) expression hallmarks fibromatosis, herein we searched for βC mutations in a large retrospective European multi-centric tumors series to relate with clinicopathologic parameters. Methods: From 1987 to 2007, 155 pts with fibromatosis from all sites were gathered by the Conticanet Network were analysed. Direct sequencing of exon 3 βC gene was performed for 155 frozen tissues. All mutated cases were confirmed by an independent analysis. From this cohort, 101 pts with EAF surgically treated with curative intent and follow-up allowed us to relate βC mutational status to disease outcome. Results: Mutations of βC were detected in 84% of all cases. Among 101 pts with EAF surgically treated, similar mutations types and rates (87%) were observed, namely T41A (39.5%), S45P (9%), S45F (36.5%) and deletion (2%). There were 36 men and 65 women. Majority of pts were treated for primary EAF (57%). Most of surgical margin were RO (38%) or R1 (34%). Few pts were treated after surgery with radiation therapy (18%) and medical treatment (8%). With a median follow-up of 62 months, 51 pts (51%) relapsed. Neither clinicopathologic parameters were found to be significantly associated with βC mutational status. The five-year recurrence free-survival was significantly worse in βC mutated tumors regardless of a specific genotype, than in wild-type tumors (49 versus 93%, respectively, p=0.02). No significant difference was observed in considering either T41A, or S45F or S45P mutants, even if 45Fmutation appears to show a weak trend of significance for a dismal outcome. Conclusions: A high frequency (87%) of βC mutation hallmarks EAF from a large multicentric retrospective study. Moreover, wild type βC appears as a good prognosis marker that can be useful for therapeutic management of the EAF. [Table: see text]
Consolidation with high-dose chemotherapy for responding patients to standard chemotherapy in advanced, metastatic soft tissue sarcoma (STS): A randomized trial from FNCLCC-French Sarcoma Group
Authors: Binh N. N. , Chevreau C. , Penel N. , Bay J. , Coindre J. , Mathoulin-Pelissier S. , Ray-Coquard I. , Italiano A. , Genève J. , Blay J. 
Published: August 2020

10505 Background: Whether high dose (HD) chemotherapy improves disease-free (DFS) or overall (OS) survival has been suggested in phase II trial, but never explored in a randomized setting. This randomized, open, phase III study was designed to assess whether or not an HD chemotherapy with peripheral blood stem cells (PBSC) would improve OS in patients with advanced or metastatic STS responding to MAID chemotherapy. Methods: Pts aged 18 to 65 and with advanced STS were enrolled. After 4 courses of MAID, patients in PR or CR, or in whom complete surgical removal of all lesions was performed, were proposed for randomisation between 2 more cycles of MAID (control arm) vs 1 MAID followed by an intensification with MICE, ie: mesna (3.6g/m2, d1–5), ifosfamide (4g/m2, d1–4), carboplatin (UCA5, d2–4) and etoposide (300mg/m2, d1–4), followed by PBSC (HD arm). The primary endpoint was OS and the study was designed to detect by logrank test a 25% difference between the arms. Results: From 03/00 to 06/08, 266 patients were included and 87 were randomised (15 centres); low accrual and new treatment concepts lead to an IDMC in 11/08 who analysed 45 treated in the control arm (41 with full treatment) and 40 in the HD arm [only 21 received MICE, because consent withdrawal (6), insufficient PBSC harvest (5), tumor reprogression (4)]. Baseline characteristics (pts and tumors) were similar between treatment arms. With a 39 months follow-up, 25 pts were alive in the control arm, and 19 in the HD arm. The 3 years OS was 45.5% for control arm versus 35.8 for HD arm (HR = 1.12; 95% CI 0.58, 2.14; p = 0.72 Intention to treat analysis); PFS was 29.9% and 12.1 respectively (HR = 1.48; 95% CI 0.87, 2.53; p = 0.14). Higher rate of grade 3 - 4 hematologic (87% vs 46%), and digestive toxicity (33% vs 0%) were observed in the HD arm. Two treatment-related deaths occurred, both in the HD arm. Conclusions: In this study, HD chemotherapy for STS patients didn't improve OS and DFS. Consolidations with new concepts have to be explored. [Table: see text]
Updated outcome with long-term follow-up of imatinib for the treatment of progressive or recurrent aggressive fibromatosis (desmoid tumor): A FNCLCC/ French Sarcoma Group phase II trial
Authors: Dufresne A. , Penel N. , Salas S. , Le Cesne A. , Perol D. , Bui B. , Brain E. , Ray-Coquard I. , Jimenez M. , Blay J. 
Published: August 2020

10518 Background: We present updated results from a previously reported phase II trial assessing clinical efficacy of imatinib in progressive or recurrent aggressive fibromatosis (Fayette et al. ASCO 2007) Methods: Patients with aggressive fibromatosis not amenable to radiotherapy or non-mutilating surgery were eligible and received imatinib 400mg daily (increased to 800mg daily in case of progression) up to 1 year then stopped. The primary end point was non-progressive disease rate at 3 months. Independent radiological committee reviewed responses. The number of patients was calculated according to a optimal 2-stages design. Results: Forty patients were included between September 2004 and October 2005 in 15 centers. The median follow up is 33 months [95% CI: 32–35]. Toxicity of imatinib is similar to that previously reported. At 3 months, the nonprogression rate was 91% [95% CI: 77–96] with 1 (2%) complete and 3 (8%) partial confirmed responses observed. The non progression rates at 6, 9, and 12 months were 80%, 69% and 66% respectively. The median time to progression was 9.5 months. The 2-year progression-free survival (PFS) was 55%. No plateau was observed. The 2-year-overall survival was 95%. Two patients with mesenteric aggressive fibromatosis died from progressive disease. In multivariate analysis including clinical factors, only previous radiotherapy was associated with reduced progression free survival. None of the biological factors tested using IHC on TMA (PDGFR α, PDGFR β, β catenin, c-kit, E cadherine, MCSFR, cycline D1 and Erk) were found correlated to response, progression free or overall survival. Conclusions: With a 2.8 years median follow up, this is the largest study which confirms the high efficacy of imatinib (400 mg daily) in patients presenting with aggressive fibromatosis failing local treatment and with documented evidence of progressive disease before imatinib treatment. [Table: see text]