bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma heparanase as a significant marker of treatment response in pediatric malignancies: Pilot study
Authors: Ben Arush M. W. , Shafat I. , Ben Barak A. , Postovsky S. , Elhasid R. , Vlodavsky I. , Ilan N. 
Published: March 2020

9540 Introduction: The aim of this pilot study was to determine heparanase plasma levels (HP) at diagnosis and at restaging in children diagnosed with cancer, and to investigate whether this parameter provides prognostic information for remission after induction therapy and response to treatment. Patients and Methods: Heparanase plasma levels of 45 consecutive pediatric patients (pts) with various types of cancer were assayed at diagnosis and at restaging. Mean age: 10.3 years (y) (0.5y-21y), 20 females, 25 males. Levels of heparanase were determined using a commercially available ELISA anti-human heparanase immunoassay kit. According to diagnosis, bone marrow aspiration, CAT scan, MRI, technetium bone scan, PET-CT fusion were performed to assess response to treatment after the first month of induction for leukemia patients, 2 to 3 courses of chemotherapy for other malignancies. Results: Changes in HP levels were found to correlate with response to treatment for most of the children. At diagnosis, average HP level was 1,539 pg/mL (range, 55 pg/mL-6,567 pg/mL) and decreased at restaging to 943 pg/mL (range, 0 pg/mL -3,682 pg/mL) (p=0.0133). At diagnosis, the average HP of the 37 patients in CR or VGPR was 1,692 pg/mL and at restaging decreased to 928 pg/mL (p=0.0071). At diagnosis, the average HP level for the 5 pts with TP or PR was 1,873 pg/mL and increased to 2,633 pg/mL at restaging (p=0.4223). Due to the small number of patients we did not observe any correlation with diagnosis or any other clinical prognostic factor. Conclusions: Changes in plasma heparanase levels correlated with response to treatment for all of the children diagnosed with cancer. This provides a rationale for exploring clinical interest in plasma heparanase measurements of a larger group of children with malignancies, and using the test for clinical trials of antiangiogenic therapies. No significant financial relationships to disclose.
Phase II study of the combination of cisplatin + temozolomide in malignant glial tumours in children and adolescents at diagnosis or in relapse (cistem2/nct00147160)
Authors: Grill J. , Lowis S. , Frappaz D. , Michalski A. , Picton S. , Jouvet A. , Robson K. , Jaspan T. , Couanet D. , Le Deley M. 
Published: March 2020

9543 Background: Temozolomide has been shown moderately effective in pediatric high-grade glioma (HGG). By decreasing the activity of MGMT, principal mechanism of resistance to temozolomide, cisplatin may increase the activity of this alkylating agent. Methods: Patients aged 4 to 21y with HGG outside the brainstem were treated at diagnosis or at relapse every 28 days with a combination of cisplatin 80 mg/m2 intravenously on day-1 and temozolomide 200 mg/m2 orally on days 2–6, according to the pediatric phase I recommendations. Patients treated at diagnosis had to proceed to involved field radiotherapy after the chemotherapy window. According to initial response, patients were offered additional courses, up to seven. We considered that this combination would be of interest if the response rate was superior or equal to 20%, using a two-stage Simon design in 3 cohorts: evaluable non measurable (infiltrative) at diagnosis (cohort A1); measurable disease (nodular) at diagnosis (A2); recurrent disease (B). The primary endpoint was complete or partial response after two courses, confirmed by central review. Up to 29 evaluable pts were to be entered in each cohort. If fewer than 4/29 responses were observed, it would be concluded that the combination is ineffective. Results: 56 pts were entered from 10/2003 through 07/2006 in 25 centers. One was excluded after central pathology review and 3 due to insufficient radiology work-out. 42 had grade III and 13 grade IV gliomas, including 21 tumors with oligodendroglial features. No response was observed in the first 11 pts in cohort A1 and in the first 12 pts in cohort B. Two partial and 4 minor responses were confirmed in 29 pts of cohort A2 leading to a 7% response rate (95% CI, 1–23%). Median time to progression was 1.7, 7.1 and 6.9 months in cohorts A1, A2 and B, respectively. Toxicity was manageable except in pts with large infiltrative lesions who did not tolerate hydration. Conclusion: CISTEM combination has insufficient efficacy in pediatric compared to adult HGG despite efficient down-regulation of MGMT activity. To overcome resistance to temozolomide in children and adolescents, one may need to target other known resistance mechanisms such as mismatch-repair deficiency. [Table: see text]
A phase I study of cetuximab and irinotecan in pediatric patients (pts) with refractory solid tumors
Authors: Trippett T. M. , Kuttesch J. , Herzog C. , Boklan J. , Bagatell R. , Hunger S. , Arceci R. , Lu H. , Langer C. , Gore L. 
Published: March 2020

9547 Background: Irinotecan has shown antitumor activity in a number of pediatric tumors. In adults with colorectal cancer, combining irinotecan with cetuximab enhances clinical activity as compared to treatment with irinotecan alone. We implemented this first-in- pediatrics phase I study to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of cetuximab and irinotecan in pediatric patients. Methods: 35 heavily pre-treated pts with refractory solid tumors were enrolled: brainstem glioma/astrocytoma (16), hepatoblastoma (4), neuroblastoma (2), other (13). Weekly cetuximab was escalated in 3 sequential dose levels: 75, 150 or 250mg/m2; Irinotecan was given at 16 or 20 mg/m2/day over 1 hour [daily × 5] for two weeks, every 21 days. Correlative EGFR expression (immunohistochemistry and FISH) and/or mutations, pharmacokinetics (PK) of and immune response to cetuximab were performed. Results: Pts were treated in two age cohorts (ages 1–12 yrs = Group A, and 13–18 yrs = Group B). PK analyses show linearity, with similar t1/2, clearance, and volume of distribution between groups. Irinotecan-related DLT in 2/6 pts in Group A/dose 2 necessitated dose de-escalation. Three pts experienced Grade 3 hypersensitivity infusion reaction and were discontinued. A pt with an EGFR-negative high-grade glioma (dose level 1) achieved a >70% reduction in tumor size and remains on study for 16+ months (24 cycles). A pt with ependymoma experienced a partial response (PR) and continues on cycle 12+. 9 pts received ≥4 cycles of therapy. 16 pts had a best response of stable disease or PR (mean 17 wks, range 5–66+ wks) for a clinical benefit rate of 45%. Conclusions: The combination of cetuximab and irinotecan is well-tolerated over multiple repeat cycles without cumulative toxicity in children with refractory CNS and non-CNS solid tumors. Promising preliminary anti-cancer activity was observed in a variety of pediatric solid tumors. Detailed biologic correlative and PK data will be presented. [Table: see text] No significant financial relationships to disclose.
Osteosarcoma in children aged less than five years at diagnosis: Experience of the Cooperative Osteosarcoma Study Group
Authors: Kager L. , Zoubek A. , Kevric M. , Dominkus M. , Lang S. , Exner U. G. , Mass R. , Jürgens H. , Bielack S. 
Published: March 2020

9554 Background: The incidence of osteosarcoma considerably varies with age and preschool children are reported to be extremely rarely affected. This study was conducted to investigate presentation, treatment, and outcome in very young children with osteosarcoma. Patients and Methods: The authors retrospectively analyzed the collected data of 2,706 consecutive patients with newly diagnosed high-grade osteosacroma of bone registered in the COSS studies between 1976 and 2005; and identified 28 patients (1%) aged less than five years at diagnosis. Demographic, diagnostic, tumor, and treatment related variables; response and survival data of these 28 patients were analyzed. Results: Of the 28 (male, N = 16; female, N = 12) identified toddlers (two years, N = 4; three years, N = 10; four years, N = 14), 27 presented with a high-grade central osteosarcoma of an extremity (femur, N = 12; humerus, N = 10; tibia, N = 5) and one with a secondary osteosarcoma of the orbit. The size of the primary extremity tumor was large in 74% of patients. Primary metastases were detected in 4/28 children. All 28 patients received multiagent chemotherapy, and 13 of the 21 analyzed tumors responded well to neoadjuvant chemotherapy (>90% necrosis). Limb sparing surgery was feasible in 11 children, whereas ablative procedures were performed in 14 patients. A macroscopically complete surgical remission of all clinically detectable tumors was achieved in 24/28 patients during front line therapy. With a median follow-up of 1.7 years (4.2 years for survivors), 15/28 patients were alive. Outcome was poorer for the 28 toddlers compared to the 2,678 older patients (5-year event free survival 43% ± 10% vs. 56% ± 1%)(P = 0.02). Conclusion: Osteosarcoma is extremely rare in preschool children. These young patients often have large tumors which may require mutilating resections. Despite the high rate of ablative surgery, the prognosis, however, may be poorer compared to older patients. No significant financial relationships to disclose.
ITCC phase I study of erlotinib as single agent in children with refractory and relapsed malignant brain tumors and in combination with irradiation in newly diagnosed brain stem glioma
Authors: Geoerger B. , Hargrave D. , Ndiaye A. , Frappaz D. , Doz F. , Leblond P. , Gentet J. , Riccardi R. , Paoletti X. , Le Deley M. , Vassal G. 
Published: March 2020

9556 Background: Erlotinib hydrochloride (OSI-774), a selective inhibitor of the EGFR tyrosine kinase, may be active in childhood brain tumors, particularly in combination with irradiation. Methods: Multicenter, non-randomized phase I study with separate dose findings for erlotinib as single agent in children with refractory or relapsing brain tumors (group 1), and combined to irradiation in newly diagnosed brain stem glioma (group 2). Erlotinib was administered orally daily at 75, 100, 125 or 150 mg/m2. Dose escalation was performed in a classical 3+3 methodology for group 1 and according to the continuous reassessment method for group 2; dose-limiting toxicity (DLT) was evaluated at 3 and 6 weeks, respectively. Results: In total, 31 patients have been entered to date, 30 received treatment, 17 in group 1 (3 relapsing brain stem glioma, 4 ependymoma, 4 oligodendroglioma, 6 other) and 13 in group 2 with a median age of 9 and 6 years (range 4–16 and 2–12), respectively. Median treatment duration was 1.5 and >5 months, respectively. In group 1, 3 patients each were treated at 75 mg/m2 and 100 mg/m2, 7 at 125 mg/m2, 4 at 150 mg/m2. One patient with a glioneuronal tumor treated at 125 mg/m2 experienced G5 intra-tumoral hemorrhage at day 4 which was considered as DLT; at 150 mg/m2, 1 patient with an oligodendroglioma experienced G3 asthenia at day 18 and G3 intratumoral hemorrhage at day 29, and 1 patient with an ependymoma experienced G5 intra-tumoral hemorrhage at day 49. In group 2, 1/6 patients treated with erlotinib 75 mg/m2 and irradiation experienced seizures and died, no DLT occurred in 6 patients at 100 mg/m2. Non-hematological toxicities included G1-G2 erythema, folliculitis, dry skin, trichomegaly, G1 transaminitis, bilirubinemia, G1–3 asthenia, G1–5 intra-tumoral hemorrhage. Minor tumor response was observed in an oligodendroglioma. Pharmacokinetic and biological evaluations are ongoing. Conclusions: Erlotinib was well tolerated in children with cutaneous symptoms being the most frequent treatment toxicity. However, neurological toxicity and intra-tumoral hemorrhage was notable in these children with brain tumors. Inclusion at 125 mg/m2 is ongoing to confirm the MTD. No significant financial relationships to disclose.
Phase III study on larynx preservation comparing induction chemotherapy and radiotherapy versus alternating chemoradiotherapy in resectable hypopharynx and larynx cancers. EORTC protocol 24954–22950
Authors: Lefebvre J. , Horiot J. , Rolland F. , Tesselaar M. , Leemans C. R. , Geoffrois L. , Hupperets P. , Lacombe D. , Bogaerts J. , Bernier J. 
Published: March 2020

LBA6016 Background: Final analysis of a larynx preservation study comparing sequential induction chemotherapy and radiotherapy (XRT) versus alternating chemoradiotherapy in treating resectable hypopharynx and larynx cancers. Methods: Patients (pts) with untreated, resectable T3-T4 larynx or T2-T3-T4 hypopharynx, N0-N2, M0 squamous cell carcinoma (SCC) were randomized in this prospective Phase III trial. Pts received in the control arm (SEQ) 2 cycles of cisplatin/5-FU (CF), followed in case of response by 2 additional cycles of CF, followed on day 80 by XRT (70 Gy / 35 fractions / 7 weeks), or in the experimental arm a CF cycle in weeks 1, 4, 7 and 10, alternated with XRT (20 Gy / 10 fractions) during the three 2-week intervals (ALT). Pts had surgery and postoperative XRT in case of non- response. The primary endpoint was survival with a functional larynx (FLS), with events including local relapse, laryngectomy, tracheotomy, gastrostomy, feeding tube, and death. With 450 patients and 3 yrs minimum followup per pt, this trial was planned to provide 80% power to detect a difference of 11% (from 28% to 39%) in this endpoint at 3 years by 2-sided Logrank test (Type I error 5%). Results: The trial enrolled 450 pts (224 to SEQ, 226 to ALT) from July 1996 to May 2004. Median followup is 6.5 years (yrs). 76 pts discontinued treatment for toxicity (34 on SEQ, 42 on ALT). Hazard ratio (HR) for FLS was 0.84 (95% CI 0.67–1.05, p=0.12) with medians 1.6 yrs on SEQ and 2.3 yrs on ALT. OS (medians of 4.4 and 5.2 yrs) and PFS (medians of 3.0 and 3.1 yrs) were similar for SEQ and ALT, respectively. At 3 yrs, cumulative incidence of larynx events was 46% on SEQ and 38% on ALT (HR 0.79, p=0.09). Grade 3/4 mucositis was seen in 32% of pts who received RTX on SEQ, and 21% on ALT. Late severe edema and/or fibrosis was observed in 16% of pts in SEQ and 11% in ALT. Conclusion: A 8% difference in larynx function preservation rate at 3 yrs favoring ALT did not translate into statistically significant differences. ALT, as a form of chemoradiation, did not lead to increased incidence and severity of mucositis. There were no relevant long-term sequelae in either arm. No significant financial relationships to disclose.
Does tetracycline prevent/palliate epidermal growth factor receptor (EGFR) inhibitor-induced rash? A phase III trial from the North Central Cancer Treatment Group (N03CB)
Authors: Jatoi A. , Rowland K. , Sloan J. A. , Gross H. M. , Fishkin P. A. , Kahanic S. P. , Novotny P. J. , Schaefer P. L. , Dakhil S. R. , Loprinzi C. L. 
Published: March 2020

LBA9006 Purpose: Many patients who receive EGFR inhibitors develop an acneiform rash, and anecdotal reports suggest tetracycline is effective in treating it. To our knowledge, however, no rigorous trials have ever been published to substantiate this approach. This double- blinded, placebo-controlled trial was conducted to assess the role of tetracycline in preventing EGFR inhibitor-induced rash and/or reducing its severity. Methods: 61 patients were randomly assigned to tetracycline 500 mg orally twice a day×4 weeks versus an identical, similarly prescribed placebo. Eligibility criteria required all patients to have begun an EGFR inhibitor </= 7 days prior with no rash at study entry. Patients were to be followed for 8 weeks. Physician assessments of rash incidence, severity, and adverse events, occurred at 4 and 8 weeks. Patients completed a weekly rash diary, quality of life questionnaire (SKINDEX-16), and EGFR inhibitor compliance questionnaire. Thirty patients per group provides 90% power to detect a difference in rash incidence (the primary endpoint) of 40% between groups and of rejecting the null hypothesis of equal proportions with a type I error of 5% (2-sided). Results: Treatment arms were balanced on baseline characteristics, drop out rates, and rates of discontinuation of the EGFR inhibitor. Rash incidence was comparable across arms. Physicians reported that 16 tetracycline-treated patients (70%) and 22 placebo-exposed patients (76%) developed a rash (p=0.61). However, tetracycline appears to have lessened rash severity. By week 4, physician-reported grade 2 rash occurred in 17% of tetracycline-treated patients (n=4) and 55% of placebo- exposed patients (n=16); (p=0.04). Tetracycline-treated patients reported better scores on certain quality of life parameters (SKINDEX-16), such as skin burning or stinging, skin irritation, and being bothered by a persistence/recurrence of a skin condition. Adverse events were comparable across arms. Conclusion: Tetracycline did not prevent EGFR inhibitor-induced rashes. However, diminished rash severity and improved quality of life suggest this antibiotic merits further study. No significant financial relationships to disclose.
Freedom from progression (FFP) by adding paclitaxel (T) to doxorubicin (A) followed by CMF as adjuvant or primary systemic therapy: 10-yr results of a randomized phase III European Cooperative Trial in Operable Breast Cancer (ECTO).
Authors: Zambetti Milvia , Baselga José , Eiermann Wolfgang , Guillem Vicente , Semiglazov Vladimir , Lluch Ana , Sabadell Dolores , Bozhok Alla , Byakhov Mikhail J. , Ojeda Belen , Mansutti Mauro , Mariani Gabriella , Moliterni Angela , Cortes-Funes Hernan , Colozza Marian , Pienkowski Tadeusz , Magazzu Domenico , Valagussa Pinuccia , Bonadonna Gianni , Gianni Luca 
Published: March 2020

537 Background: At the time the ECTO was designed in 1996, taxanes were only indicated for patients with metastatic breast cancer. However, paclitaxel and docetaxel were still to be tested in the adjuvant setting. In addition there was relatively scarce information on the comparative efficacy of neoadjuvant and adjuvant regimens. The ECTO trial was designed to evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic (neoadjuvant) therapy. Methods: A total of 1,355 women with operable breast cancer were randomized to one of three treatments: 1) surgery followed by adjuvant single agent doxorubicin (A) followed by CMF (arm A); 2) surgery followed by adjuvant paclitaxel plus doxorubicin (AT) followed by CMF (arm B); 3) AT followed by CMF followed by surgery (arm C). The two co-primary objectives were to assess the effects on freedom from progression (FFP) of: 1) the addition of paclitaxel to post-operative chemotherapy (arm B versus arm A); and 2) primary versus adjuvant chemotherapy (arm B versus arm C). Results: At 10 years, in the adjuvant setting FFP remained statistically significant in favor of AT followed by CMF (arm B, HR 0.77, P=0.045). Distant FFP was similarly improved but overall survival was not (HR 0.82, P=0.24). There was no significant difference in FFP when chemotherapy was given after surgery compared with the same regimen given before surgery (arm B vs arm C, HR 0.79, P=0.07). In the primary chemotherapy arm, patients who achieved a pathological complete remission (pCR) had improved distant FFP (P < 0.001) compared to patients who did not achieve pCR. When given as primary systemic therapy, the paclitaxel-containing regimen allowed breast-sparing surgery in a significant percentage of patients, which did not translate in an increased risk of ipsilateral breast recurrence compared to the risk observed in patients in the adjuvant arms. Conclusions: Incorporating paclitaxel into anthracycline-based adjuvant therapy resulted in a significantly improved FFP and DFFP.
Phase 2 study of the CDK4 inhibitor abemaciclib in dedifferentiated liposarcoma.
Authors: Dickson Mark Andrew , Koff Andrew , D'Angelo Sandra P. , Gounder Mrinal M. , Keohan Mary Louise , Kelly Ciara Marie , Chi Ping , Antonescu Cristina R. , Landa Jonathan , Qin Li-Xuan , Crago Aimee Marie , Singer Samuel , Tap William D. 
Published: March 2020

11004 Background: The oncogene cyclin-dependent kinase 4 (CDK4) is amplified in > 90% of de-differentiated liposarcomas (DDLS). We previously demonstrated that treatment with the CDK4 inhibitor palbociclib results in favorable progression-free survival (PFS) in DDLS. Abemaciclib is a newer and more potent CDK4 inhibitor. This single-arm phase 2 study was designed to test the activity of abemaciclib in DDLS. Methods: Participants were adults with advanced DDLS, measurable disease by RECIST 1.1, any (or no) priory therapy, and progression by RECIST in the 6 months prior to study entry. The primary endpoint was PFS at 12 weeks. Based on historical data, promising drugs have 12-week PFS of ≥ 40% and not promising ≤ 20%. This study would be positive if 12-week PFS was ≥ 60%. The study was approved by the Institutional Review Board of Memorial Sloan-Kettering Cancer Center and all patients provided written informed consent. The study was registered at Clinicaltrials.gov (NCT02846987) and study drug was provided by Eli-Lilly. Results: Treatment was abemaciclib 200 mg by mouth twice daily continuously. 30 patients were treated and 29 were evaluable for the primary endpoint. Patient characteristics: Median age 62 (range 39-88), 60% male. Lines of prior therapy: 0 (50%); 1 (33%); ≥ 2 (17%). The observed PFS at 12 weeks was 76% (95% CI 57-90%). Median PFS was 30.4 weeks (95% CI 28.9-NE). There was one partial response. A further 3 patients had > 10% decrease in tumor size by RECIST but did not meet the criterion for partial response. Grade 3-4 toxicity included anemia (37%), neutropenia (20%), thrombocytopenia (17%) and diarrhea (7%). Conclusions: This study met its primary endpoint. In patients with advanced progressive DDLS, abemaciclib treatment results in favorable PFS and objective tumor response with manageable toxicity. Updated response data and results of paired tumor biopsies will be presented. Clinical trial information: NCT02846987.