bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Comparison of Pazopanib and Doxorubicin as First-Line Treatment in Patients With Metastatic Soft Tissue Sarcoma Age 60 Years or Older: Results of a German Intergroup Study
Authors: Grünwald Viktor , Karch Annika , Schuler Markus , Schöffski Patrick , Kopp Hans-Georg , Bauer Sebastian , Kasper Bernd , Lindner Lars H. , Chemnitz Jens-Marcus , Crysandt Martina , Stein Alexander , Steffen Björn , Richter Stephan , Egerer Gerlinde , Ivanyi Philipp , Zimmermann Silke , Liu Xiaofei , Kunitz Annegret 
Published: August 2020

PURPOSE Doxorubicin is a standard of care in patients with advanced, inoperable soft tissue sarcoma (STS). We tested whether pazopanib has efficacy comparable to that of doxorubicin in elderly patients with STS and offers superior tolerability for hematologic toxicity. PATIENTS AND METHODS Patients age 60 years or older without previous systemic treatment for progressive advanced or metastatic STS who had Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were included. Treatment consisted of pazopanib 800 mg once per day or doxorubicin 75 mg/m2 once every 3 weeks (≤ 6 cycles) after being randomly assigned in a 2:1 ratio. Noninferiority was assumed for progression-free survival (PFS), if the upper limit of the 95% CI for the hazard ratio (HR) was less than 1.8. Neutropenia and febrile neutropenia were key secondary end points. The European Organisation for Research and Treatment of Cancer (30-item) Quality of Life Questionnaire and geriatric assessment were used to measure patient-reported outcomes. Cox regression analysis and Kaplan-Meier curves were used for analysis. RESULTS Pazopanib and doxorubicin were given to 81 and 39 patients, respectively. The median age was 71 years (range, 60-88 years). PFS was noninferior (HR, 1.00; 95% CI, 0.65 to 1.53) and the incidence of grade 4 neutropenia and febrile neutropenia favored pazopanib. Objective response rates for pazopanib and doxorubicin were 12.3% and 15.4%, respectively. Overall survival did not differ significantly between arms (HR, 1.08; 95% CI, 0.68 to 1.72; P = .735). Geriatric assessment revealed 2 or more comorbidities in 15.8% of the patients and impairment of activities of daily living in 28.3% of patients. CONCLUSION Pazopanib was noninferior to doxorubicin, rendering pazopanib a putative therapeutic option in the first-line treatment of STS in patients age 60 years or older. The distinct adverse event profile may be used to counsel patients and tailor therapy to individual needs.
Phase III trial of gemcitabine plus docetaxel (GD) compared to capecitabine plus docetaxel (CD) with planned crossover to the alternate single agent in metastatic breast cancer (MBC)
Authors: Seidman A. D. , Brufsky A. , Ansari R. H. , Rubinsak J. R. , Stein R. S. , Schwartzberg L. S. , Stewart J. F. , Zhao L. , Gill J. , Tai D. 
Published: August 2020

1000 Background: GD and CD are efficacious in patients (pts) with MBC. This study compared safety and efficacy of GD and CD induction regimens, where the alternate, single-agent, crossover therapy (GD to C or CD to G) was predetermined. Primary endpoint was time to progressive disease (TTP). Secondary endpoints included toxicities, overall response (ORR), and overall survival (OS). Methods: This multicenter, open-label, phase III study enrolled MBC pts with possible prior anthracycline therapy, adjuvant or neoadjuvant taxane therapy, but no taxane therapy for MBC ≤6 months prior to entry. Enrollment of 442 pts (221 per arm) was planned with 385 progressions required to achieve 80% power for a 2-month observed difference in median TTP between arms. Pts were randomized to: GD: G 1,000mg/m2 Days 1, 8 plus D 75 mg/m2 Day 1, q21 days; or CD: C 1,000 mg/m2 BID, Days 1–14 plus D 75 mg/m2 Day 1, q 21 days. Upon disease progression, pts were given crossover C or G at doses and schedules identical to induction. ORR was assessed by RECIST. Results: Demographics of 472 enrolled pts were balanced between arms; 57% had prior anthracycline. GD caused greater myelosuppression than CD, but without greater febrile neutropenia. Gastrointestinal toxicities, mucositis, and hand-foot syndrome were greater with CD. More pts in the CD arm (n=61, 26.2%) versus the GD arm (n=41, 17.2%) discontinued due to toxicity (p=0.023). ORR, TTP, and OS were not significantly different comparing GD and CD. However, ORR and TTP were significantly greater for the GD to C crossover monotherapy compared to CD to G. Post-hoc analysis of crossover pts showed that the TTP sum from induction through crossover was 6.1 months greater for GD to C. Conclusions: GD and CD had similar efficacy with toxicity profiles consistent with prior clinical experience. Results suggest that the GD to C crossover sequence may provide a clinical benefit over CD to G. [Table: see text] [Table: see text]
Association of primary mediastinal B-cell lymphoma (PMBL) in children (C) and adolescents (A) with a significantly inferior prognosis: Final results of the FAB/LMB 96 trial
Authors: Gerrard M. , Waxman I. , Sposto R. , Auperin A. , Harrison L. , Pinkerton R. , Perkins S. L. , McCarthy K. , Raphael M. , Patte C. , Cairo M. S. 
Published: August 2020

10001 Background: Single pediatric cooperative group studies have demonstrated an EFS ranging from 65 - 75% in C & A with large cell lymphomas arising in the mediastinum (Lones/Cairo et al, J Clin Oncol, 2000; Burkhardt/Reiter et al, Br J Haematol, 2005; Seidman/Reiter et al, J Clin Oncol, 2003). Recently, Staudt and Shipp have independently demonstrated that following gene expression profiling by oligonucleotide microarray that PMBL resembles more like classical Hodgkin lymphoma than diffuse large B-cell lymphoma with enhanced NF-κB pathway gene expression (Rosenwald et al, J Exp Med, 2003; Abramson et al, Blood, 2005). It remains to be determined what the optimal therapy for C & A with PMBL is and if poor outcome subgroups can be identified. Methods: We analyzed the results of C & A with PMBL treated with group B therapy on FAB/LMB 96 (Patte/Cairo et al, Blood, 2007). Results: There were 528 patients with stage III/IV disease treated on group B therapy on FAB/LMB 96 resulting in a 2 yr EFS of 84% (CI95: 82–86%). Forty-two of these patients had PMBL; M/F: 26/16; 10 - 14 vs 15 -19 yrs: 28/14; and LDH < 2 vs ≥ 2 upper normal: 20/22. Response to COP reduction: 1 CR (100%), 33 IR (20–99%) and 7 NR (< 20%). There was no significant difference in EFS with respect to age, gender, COP response and initial LDH. 5 yr EFS and OS were 54% (CI95: 38–68%) and 73% (CI95: 56–84%), respectively. 5 yr EFS was significantly inferior compared to the remainder of the other patients with stage III disease treated on group B therapy (54%: CI95 38–68% vs 85%: CI95 81–88%) (p < 0.001). Conclusions: PMBL in C & A is associated with a significantly inferior EFS compared to other histological forms of stage III/IV mature B-NHL. Alternate treatment strategies including consideration of underlying biological differences need to be developed to improve EFS in C & A with this poor-risk sub-group of mature B-NHL. No significant financial relationships to disclose.
Identification of SGK1 as a novel predictive marker for treatment response in medulloblastoma
Authors: Sturm D. , Remke M. , Pleier S. , Witt H. , Reifenberger G. , Felsberg J. , Kulozik A. , Korshunov A. , Lichter P. , Pfister S. 
Published: August 2020

10006 Background: We have recently demonstrated that both gains (5-year OS 16%) and losses (5-year OS 100%) of chromosome 6q define distinct clinical and biological subgroups of medulloblastoma. However, the underlying molecular mechanisms accounting for the prognostic impact of these aberrations so far remained unclear. Methods: To identify potential candidate genes on chromosome 6q targeted by these genomic aberrations, a genome wide mRNA expression profiling study was performed for 47 well-characterized medulloblastoma samples and correlated to chromosome 6q DNA copy-number status. Results were validated by real-time quantitative PCR (RTQ-PCR). SGK1 protein expression was examined by immunohistochemistry on a tissue-microarray which represents a large independent cohort of uniformly treated medulloblastoma patients (n = 260). Results of both studies were correlated with survival data available for all investigated samples. Results: Expression profiling revealed the AKT homologue SGK1 as an interesting candidate gene on chromosome 6q showing very close correlation to 6q copy-number status. Direct correlation could be confirmed by RTQ-PCR showing that SGK1 mRNA levels were significantly upregulated in tumors with gain of chromosome 6q (median log2-ratio when normalized against normal cerebellum = 3.88) and, in contrast, downregulated in cases carrying deletions of this region (median log2-ratio = -1.97). On protein level, we found high SGK1 protein levels to be highly associated with poor overall survival as assessed by immunohistochemistry (Kaplan-Meier method; p < 0.00001). Conclusions: We identified SGK1 as an interesting novel candidate gene on chromosome 6q contributing to the striking differences in overall survival of cases with chromosome 6q gain or loss, who are known to have a very poor or especially good prognosis, respectively. The fact that SGK1 encodes for a serum- and glucocorticoid inducible kinase which is both structurally and functionally homologous to the antiapoptotic kinase AKT further underlines the potential role of this gene. Based on the reported results, we propose SGK1 protein expression as a novel prognostic marker in medulloblastoma. No significant financial relationships to disclose.
Phase I study of fenretinide (4-HPR) oral powder in patients with recurrent or resistant neuroblastoma: New Approaches to Neuroblastoma Therapy (NANT) Consortium trial
Authors: Marachelian A. , Kang M. H. , Hwang K. , Villablanca J. G. , Groshen S. , Matthay K. K. , Maris J. , DeSantes K. B. , Reynolds C. P. , Maurer B. J. 
Published: August 2020

10009 Background: Fenretinide (4-HPR), a cytotoxic retinoid, achieved limited and variable plasma levels when tested in a corn oil-based capsule. 4HPR/Lym-X-Sorb (LXS) oral powder is a new formulation intended to increase bioavailability, especially in children. Methods: This trial sought to define the toxicities, dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics of 4-HPR/LXS oral powder when given mixed in Slim-Fast nutritional shakes, twice a day for 7 days, every 21 days. Eligible patients had high-risk neuroblastoma with recurrent/progressive disease, or disease refractory or persistent after frontline therapy. Dose escalation was in 30% increments using the traditional 3 + 3 design. Plasma levels were measured by HPLC. Results: Thirty-two patients accrued to 8 Dose Levels (DL) (352 –2210 mg/m2/day); 30 patients were evaluable. No MTD was identified. There was a DLT elevation of alkaline phosphatase on DL1. No other DLT's were observed. Other toxicities included dry skin, elevated triglycerides, reversible nyctalopia, and transient transaminase elevation. Course 1 day 7 peak 4HPR plasma levels (Dose (mg/m2/day) - mean, (range)) were: 352 –6 μM (3.8–9.6); 458–11.5 μM (9.7–14.9); 595–17.6 μM (6–24.3); 774–15 μM (9.1–25.3); 1006–6.7 μM (5.2–9.2); 1308–13.9 μM (2.9–23.8); 1700–19.7 μM (17.3–24.3); and 2210–10.8 μM (4–16.5). Course 2 day 7 peak plasma levels trended higher than course 1 at DL5–8. Three patients with isolated bone marrow disease and one with MIBG avid bone lesions, had complete responses (DL4, DL4, DL7, DL8) receiving 10, 17, 18 and 10 courses of therapy, respectively. Six patients had stable disease for 4–27 courses (median 5.5) (DL3, DL4, DL4, DL5, DL6, DL8). Twenty patients had progressive disease. Central review of responses is pending. Conclusions: 4-HPR/LXS oral powder was well tolerated, obtained 2 - 5 fold higher 4HPR plasma levels than fenretinide capsules on the same dose and schedule (P < 0.01), and showed anti-tumor activity (complete responses in 4/15 patients at DL4–8). Based on pharmacokinetic data, a recommended Phase II dose and schedule is 1700 mg/m2/day × 7days every 3 weeks. No significant financial relationships to disclose.
Significance of tumor biology compared to metastatic pattern (INSS 4 versus 4s) and age for prognosis of neuroblastoma less than 18 months of age
Authors: Taggart D. R. , London W. B. , Schmidt M. L. , Zhang Y. , Dubois S. G. , Monclair T. , Pearson A. D. , Cohn S. L. , Matthay K. K. 
Published: August 2020

10010 Background: Neuroblastoma is a heterogeneous disease with variability in outcome among different risk groups. Historically, INSS stage 4s neuroblastoma (age less than 12 months, stage 1 or 2 primary tumor with metastases limited to liver, skin and bone marrow) has a more favorable outcome than infant stage 4 disease. The aim was to determine if metastatic pattern (4 vs 4s) predicted favorable prognosis in infants < 12 months or in toddlers aged 12–18 months when stratifying by biology. Methods: Outcome was analyzed by log rank tests and Cox models for 656 infants with stage 4s neuroblastoma and 1,019 stage 4 patients < 18 months of age in the International Neuroblastoma Risk Group database (n=8,800). Prognostic factors (tumor ploidy, histology, grade, MKI, LDH, MYCN, 11q, 1p, primary site) were tested for association with age/stage subgroups (Fisher's exact test) and in Cox models. Results: MYCNamplification, 1p aberration, diploidy, and high MKI and LDH were more frequent in infant stage 4 than infant 4s tumors. The incidence of unfavorable biology was higher in toddlers aged 12–18 months, but did not differ with stage 4 vs. 4s pattern. EFS was significantly better for infants <12 months with stage 4s than stage 4 (p=0.0004). EFS was similar for toddlers 12–18 months for stage 4 vs. 4s pattern (p=0.3893). Within the 717 patients with 4s pattern of metastases, age 12–18 months had worse EFS than <12 months (p<0.0001). After adjustment for age in 6 separate models, MYCN, 11q, 1p, MKI, and LDH were statistically significant prognostic factors. Although treatment regimens differed, EFS was similar for <12 months vs. 12–18 months for MYCN not amplified patients in both 4S pattern (p=0.8469) and stage 4 (p=0.3783). Conclusions: For patients with MYCN not amplified tumors, outcome for patients 12–18 months is similar to those <12 months regardless of the pattern of metastases. Tumor biology is more critical than metastatic pattern for prognosis of patients aged 12–18 months with stage 4 neuroblastoma. [Table: see text] No significant financial relationships to disclose.
A phase I trial and pharmacokinetic study of IMC-A12 in pediatric patients with relapsed/refractory solid tumors: A Children's Oncology Group Phase I Consortium study
Authors: Malempati S. , Weigel B. , Ingle A. M. , Ahern C. H. , Carroll J. M. , Roberts C. T. , Fox F. E. , Voss S. , Adamson P. C. , Blaney S. M. 
Published: August 2020

10013 Background: IMC-A12, a fully human IgG1 monoclonal antibody to the Insulin-Like Growth Factor-I Receptor (IGF-IR), is active preclinically in a variety of pediatric solid tumors. We performed a phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of IMC-A12 in children with refractory solid tumors. Methods: IMC-A12 was administered as a weekly 1 hr IV infusion, without interruption. Two dose levels, 6 and 9 mg/kg, were evaluated using a standard 3+3 cohort design. After defining initial safety, patients (pts) with refractory Ewing sarcoma (ES) were treated in an expanded cohort at each dose level. Results: 24 eligible patients (11 male), median 15.3 yrs (range, 7.0 to 21.5), were enrolled. Among the 12 pts enrolled on the dose-escalation component, DLT (grade 4 thrombocytopenia) occurred in 1/6 pts at 6 mg/kg. No DLTs occurred in 6 pts at 9 mg/kg or in the ES cohort. 1/10 evaluable pts with ES at the 6 mg/kg dose had a partial response; no CRs were observed. Grade 2 or higher non-DLTs possibly attributable to IMC-A12 observed in the first course include anemia (n=4), leukopenia (n=1), lymphopenia (n=2), neutropenia (n=2), opportunistic infection (n=1), ↑liver transaminases (n=2), and hyperglycemia (n=1). No ≥ grade 3 hyperglycemia occurred. Mean (± SD) trough IMC-A12 concentrations were 59.8 ± 31.1 and 117 ± 70.8 μg/ml at the 6 and 9 mg/kg dose levels, respectively. A majority of pts at both dose levels exhibited > 50% reduction in PBMC IGF-IR protein levels. Conclusions: In order to exceed target trough concentrations associated with optimal anti-tumor activity in pre-clinical models, 9 mg/kg IV weekly is the recommended Phase II IMC-A12 dose in children. A phase II protocol for children with refractory solid tumors will be performed. [Table: see text]
Frontline treatment of localized osteosarcoma without methotrexate: Results of the St. Jude Children's Research Hospital OS99 trial
Authors: Daw N. C. , Neel M. D. , Rao B. N. , Billups C. A. , Wu J. , Jenkins J. J. , Villarroel M. , Luchtman-Jones L. , Quintana J. , Santana V. M. 
Published: August 2020

10036 Background: Standard treatment of osteosarcoma includes cisplatin and high-dose methotrexate (HD-MTX), but both agents are associated with significant toxicity and MTX administration requires complex pharmacokinetic monitoring. In our previous OS91 trial, the combination of carboplatin and ifosfamide with doxorubicin and HD-MTX yielded outcomes comparable to those of cisplatin-based regimens with less long-term toxicity in localized osteosarcoma. Methods: Between 1999 and 2006, we conducted a multi-institutional trial (OS99) to evaluate the activity of carboplatin, ifosfamide, and doxorubicin without HD-MTX in newly-diagnosed patients with localized osteosarcoma. Treatment comprised 12 cycles of chemotherapy given every 3 weeks: 3 consecutive cycles of carboplatin (dose targeted to AUC 8 mg/ml×min on day 1) and ifosfamide (2.65 g/m2 daily for 3 days) and one cycle of doxorubicin (25 mg/m2 daily for 3 days) followed by definitive surgery (week 12) and 2 additional cycles of carboplatin/ifosfamide and 3 cycles each of ifosfamide/doxorubicin and carboplatin/doxorubicin for a total of 35 weeks. The log rank test was used to compare survival and event-free survival (EFS) distributions. Results: A total of 72 eligible patients were enrolled. The median age was 13.4 years and 41 (57%) were male. The most common tumor site was the femur (n = 46; 64%). The median follow-up for survivors was 4.4 years. Forty of the 66 (60.6%) evaluable patients had good histologic response (tumor necrosis > 90%) to preoperative chemotherapy. There was no difference in EFS or survival distributions between OS99 and OS91. Four-year estimates of EFS were 68.1 ± 6.7% for OS99 compared to 70.2 ± 6.6% for OS91 (p = 0.89). The 4-year OS was 82.4% ± 5.7% for OS99 compared to 74.5% ± 6.3 for OS91 (p = 0.25). Conclusions: OS99 produced outcomes similar to cisplatin or HD-MTX containing regimens and offers an alternative treatment regimen especially for patients with renal compromise and institutions where pharmacokinetic monitoring of MTX is not available. No significant financial relationships to disclose.
Fifteen years experience of the Brazilian Osteosarcoma Treatment Group (BOTG)
Authors: Petrilli A. S. , de Camargo B. , Odone Filho V. , Lustosa D. , Borsato M. L. , Calheiros L. M. , Brunetto A. L. , Barreto J. H. , Ferraro A. A. 
Published: August 2020

10039 Background: This is a 15-year analysis of disease characteristics and treatment outcome from three consecutive studies of BOTG. Results from protocols III and IV were previously published (J Clin Oncol. 24:1161–8, 2006). Methods: 604 histologically confirmed high-grade osteosarcoma patients were enrolled into these multicentric studies (with 4, 5, and 20 institutions in studies III, IV, and 2000, respectively). Results: Of the 604 patients, 578 were evaluable with osteosarcoma of extremities, mean age at enrollment of 14, mean time to diagnosis of 4.4 months, advanced disease (tumors diameter > 12cm) in 45% and metastatic disease in 30% of the patients. Statistically significant prognostic factors were: tumor size, histological response (Huvos grade), presence of metastasis at diagnosis and type of surgery. Time to diagnosis was not predictable of survival. Advanced disease was associated to presence of metastasis and to a poorer histological response. During the first 5 years, 53% of the patients had conservative surgery with 19.6% of local recurrence and these numbers were 65.5% and 14% in the next 5 years and 62.3% and 11% during the last 5 years. The overall survival (OS) at 5 years was 44%, 45% and 46% respectively. In the whole cohort of patients, overall survival (OS) was 45.7% at 5 years and 43% at 10 years and event free survival (EFS) was 43% and 34%. For non-metastatic patients, OS was 56.5% and 54% and EFS was 53% and 44%, respectively. Conclusions: Over these 15 years, we were able to increase limb salvage procedures with a significant drop in local recurrence, reaching survival rates similar to some international studies. This cumulative experience enabled the expansion of the collaborative group, the identification of prognostic factors, dissemination of knowledge, and the development of the current protocol for osteosarcoma treatment, which is a multicentric, randomized study with good quality data collection over 26 sites in Latin America. No significant financial relationships to disclose.
Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: A phase I/II study
Authors: Swaby R. , Blackwell K. , Jiang Z. , Sun Y. , Dieras V. , Zaman K. , Zacharchuk C. , Powell C. , Abbas R. , Thakuria M. 
Published: August 2020

1004 Background: Neratinib (HKI-272) is an orally administered irreversible pan-ErbB receptor tyrosine kinase inhibitor. In an ongoing phase II study, the preliminary objective response rate was 26% in patients with ErbB2+ advanced breast cancer with prior trastuzumab therapy. This study assessed the safety and preliminary efficacy of the combination of neratinib plus trastuzumab. Methods: Patients with advanced ErbB2+ breast cancer that progressed following trastuzumab therapy were enrolled. The primary endpoint was 16-week progression free survival rate (PFS). In part 1 (dose escalation), patients received neratinib 160 mg or 240 mg daily plus trastuzumab 4 mg/kg IV loading dose then 2 mg/kg weekly. In part 2, patients received weekly trastuzumab with neratinib 240 mg daily. Timed blood samples were collected for PK analyses. PK analysis is ongoing. Results: 45 patients (part 1 n = 8; part 2 n = 37) were enrolled (mean age 52 yr); 9 are active. In part 1, cohorts 1 and 2 were fully enrolled with 4 patients each. No dose limiting toxicities were observed. Most common AEs, any grade, were diarrhea (91%), nausea (51%), anorexia (40%), vomiting (38%), and asthenia (27%). Grade 3/4 AEs were diarrhea (13%), nausea (4%), vomiting (4%). Two patients receiving neratinib 240 mg reported AEs leading to withdrawal. No AEs of congestive heart failure and no significant drops of left ventricular ejection fraction were reported. Among 33 patients evaluable for efficacy, objective response rate was 27% (95% CI, 13% - 46%); 16-week PFS rate (for part 2) 47% (95% CI, 29% - 63%); median PFS was 19 weeks (95% CI 15 - 32 weeks). Conclusions: Neratinib plus trastuzumab was well tolerated with no significant or unexpected toxicities, and demonstrated clinical activity. [Table: see text]