bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overall and cause specific long term mortality following childhood cancer: The role of cancer treatment
Authors: de Vathaire F. , Tukenova M. , Oberlin O. , Doyon F. , Guibout C. 
Published: March 2020

9520 Background: A multi-centre French cohort study was performed to evaluate the role of treatment in the long-term overall and cause-specific mortality among childhood cancer survivors. Methods: This study cohort included 3,057 patients treated for a solid tumours before the age of 17 between 1942–1986, in 5 French centres and who survived at least 5 years from diagnosis. Detailed clinical and therapeutic data were extracted for each patients from medical records. For 2,081of the 2,178 patients who received radiotherapy, radiation doses were estimated at 188 anatomical sites, including heart (7 sites) and lungs (10 sites). 98% of patients were identified in French National Registry of Physical Persons (RNIPP) and we obtained the death causes of 95% of dead patients. Overall and cause-specific mortality standardized ratios (SMR), absolute excess risk (AER) of death were studied using Poisson regression. Results: 50% of patients were treated by chemotherapy (CT) plus radiotherapy (RT), 22% by CT alone and 21% by RT alone. During an average follow-up of 25 years, 465 patients dead. The overall SMR was 7.3 (95% CI: 6.7–8.0) and AER was 6 deaths per 1,000 person-years. SMR for death due to cancer other than the 1st cancer (SC) was 16.1 (95%, CI 13.5–18.9). SMRs were significantly elevated for non-cancer overall mortality, infectious and parasitic diseases, diseases of the circulatory, nervous and respiratory system, congenital anomalies, symptoms, signs and ill- defined conditions’ (SMRs of 2.6, 15.7, 6.4, 8.5, 4.6, 3.2, respectively). RT was associated an increase in the risk for overall and SC related deaths (RR = 2.0; 95% CI: 1.5–2.7; RR = 1.8; 95% CI: 1.1–2.9; respectively). CT was associated with an increased risk for overall, SC and non- cancer related deaths (RR = 1.6; 95% CI: 1.3–2.0; RR = 1.9; 95% CI: 1.2–3.0; RR = 1.8; 95% CI: 1.1–2.9 respectively). We were not able to find any evidence for an interaction between CT and RT, whatever the end point considered. Among the 26 circulatory deaths, 24 received RT, the mean radiation dose of the heart (P=0.0006) and treatment with spindle inhibitors (P=0.009) were significantly associated to death by cardiac disease. Conclusions: In the future, death due to cardiac pathologies could be an important issue for long term survivors of childhood cancer. No significant financial relationships to disclose.
Conduct of an international collaborative osteosarcoma trial at centers located in a developed and developing country
Authors: Rivera G. K. 
Published: March 2020

9527 Background: We conducted a collaborative protocol (twinning program) for newly diagnosed patients with localized osteosarcoma (OS 99) at SJCRH (sponsor) and CMH (partner site), a public tertiary-care pediatric hospital and bone tumor center in Santiago, Chile. Methods: CMH was selected as the partner site because Chile has a well developed public health system including free treatment for children with cancer. SJCRH trained and financially supported specialized personnel and provided oversight of study conduct and monitoring. The study was approved by the respective Human Subjects Protection Committees and a Data Safety Monitoring Board. Treatment comprised 12 cycles of chemotherapy (with growth factor support) given every 3 weeks for a total of 35 weeks and definitive surgery after 4 cycles of chemotherapy. Pathology studies and selected imaging studies were centrally reviewed at SJCRH. Patient costs were covered by the Chilean Ministry of Health and SJCRH except for sargramostim which was donated by Berlex Oncology. Patient care and study conduct were discussed in a multidisciplinary forum on a monthly basis. The two study teams maintained close communication through videoconferencing, and site visits. Results: Of the 72 eligible patients enrolled on study, 22 were treated in Santiago (2003–2006). Rare discrepancies in interpretation of diagnostic imaging and pathology studies were addressed in a timely manner. Preliminary results demonstrated similar patient outcomes and treatment tolerance at the two sites. Limb-salvage surgery was performed in 12 Chilean patients. Median per-patient costs were lower in Chile (US $80,000) than at SJCRH ($400,000). Conclusions: It is feasible, safe, and cost-effective to simultaneously treat pediatric patients with osteosarcoma on modern protocols, through well designed and rigorously monitored twinning programs that include countries with different level of resources. No significant financial relationships to disclose.
Cancer in adolescents and young adults (AYA) in North Netherlands (1989–2003): Increased incidence, stable survival and high incidence of secondary tumors
Authors: van Gaal J. C. , de Bont E. S. , Bastiaannet E. , Schaapveld M. , Kluin-Nelemans J. C. , van der Graaf W. T. 
Published: March 2020

9538 Background: Lack of improvement in survival in AYA cancer patients as compared to children has led to increased awareness of this young population. We performed a population-based study of the incidence and survival of primary tumors and incidence of second tumors in patients 12–24 years, diagnosed in North Netherlands. Methods: Patients, diagnosed 1989–2003, classified according to Birch, were retrieved from the regional cancer registry and were divided into age groups (12–15, 16–19, 20–24). Age-specific incidence rates per 100,000 were calculated using population data from Statistics Netherlands. Three-year moving means of incidence were calculated for the three age groups. 5-years survival over time for males (M) and females (F) was calculated; difference in survival was assessed with log-rank test. Results: From 1989–2003 1,118 patients were diagnosed: lymphoma 22.9%, germ-cell malignancies 14.5%, melanoma 13.7%, carcinoma 12.7%, sarcoma 11.7%, CNS tumors 11.5%, leukaemia 10%. The total age-specific incidence rates per 100,000 were: M:13.4 (12–15 yrs), 26.9 (16–19 yrs), and 27.5 (20–24 yrs) and F:13.9, 20.7, 20.7. M/F ratio was 1.32. Between 1999–2003 a remarkable high incidence of Hodgkin's lymphoma in 16–19 yrs (M 9.4, F 7.6), germ cell malignancies 14.1 (M, 20–24), and melanoma 7.0 (F, 20–24) was found. The estimated annual percent change in incidence was 2.15% (p=0.001) overall. Multivariate analysis of the incidence showed a significant increase by age and year of diagnosis. The 5 years-survival was 0.80, 0.80 and 0.82 for the three age groups. Survival did not change significantly during the study period, except for a better survival for leukemias (p=0.04). With a follow-up of 8.7 years the relative risk of secondary tumors was 34.98 (23.06- 50.89; p<0.05). Conclusions: Between 1989 and 2003 the total incidence of cancer in AYA increased. Except for leukaemia survival was stable over time. No difference in survival between the age groups (12–15;16–19; 20–24) was found. From 1999–2003 a remarkable high incidence of Hodgkin's lymphomas (M, 16–19), germ cell malignancies (M, 20–24) and melanomas (F, 20–24) was observed. The relative risk of a secondary tumor in this young cohort was 35-fold increased. No significant financial relationships to disclose.
Research, policy and practice related to survivors of childhood, adolescent and young adult cancers in British Columbia (BC), Canada: A population-based approach
Authors: Rogers P. C. , Broemeling A. , Pritchard S. L. , Goddard K. , Xie L. , Poole B. , Sheps S. , McBride M. L. 
Published: March 2020

9539 Background and Purpose: Prevalence of long term survivors of pediatric, adolescent and young adult cancers is increasing. In BC we are using a multidimensional population approach to address research and care for these survivors. Information on trends in prevalence of survivors and use of physician services are presented. Methods: We have identified a cohort of patients under 25, diagnosed from population registries since 1970, and linked their records with person-based longitudinal records of health utilization. Results: Prevalence rate of cancer survivors aged 0–59 years, originally diagnosed under age 25, increased 5 fold between 1975 and 2005, from 26 per 100,000 to 147 per 100,000; 78% were aged 20 or older. A total subgroup of 3,787 individuals surviving five years or more, diagnosed between 1970 and 1995, were identified; 2,590 (68%) of these were linked to physician visit records (excluding visits within BC's Children's Hospital) from 1986 to 2000. In year 2000, 77% of survivors had at least one physician visit; 75% of survivors saw a family physician (FP), and 44% of survivors visited a specialist physician with a specialty that could be related to a late effect. Between 1986 and 2000 survivor prevalence increased 3.3% per year; total visits by survivors to FPs increased by 11.6% per year and by 10.6% per year to specialists. In 1986, 66% of physician visits were for patients older than 20 which increased to 79% by 2000. A provincial pediatric oncology network consisting of oncologists and community care representatives has been established to implement changes to long-term follow up policy. Conclusion: The prevalence rate and utilization of health services among survivors of childhood, adolescent and young adult cancers continues to escalate. Research results, along with other published literature, will inform the development of policy and practice within the BC Network. No significant financial relationships to disclose.
Prognostic factors in metastatic rhabdomyosarcoma (RMS): The results of a pooled analyze from U.S. and European cooperative groups
Authors: Oberlin O. , Rey A. , Lyden E. , Bisogno G. , Stevens M. C. , Meyer W. H. , Bergeron C. , Ellershaw C. , McDowell H. , Carli M. 
Published: March 2020

9542 Background: Prognosis factors on outcome for metastatic RMS are still matter of discussion. The analysis of a large cohort of patients can give arguments for development of risk-based therapy. Methods: We studied data from SIOP 84, SIOP 98, European Intergroup MMT89–91, Italian RMS4.99, IRS-III, -IV Pilot, -IV, -V, -D9501 to look at the influence of age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease at the 3 year event-free survival. Results: 788 patients were included in the analyze and 776 in the multivariate analyse. The 3 year overall survival and EFS were 34% (se 1.7) and 27 % (se 1.6) respectively. By univariate analysis, 3-year EFS was significantly influenced by age 10 years or more (15% vs 36%), alveolar histology (28% vs 40%), location of primary tumor in unfavorable site -parameningeal, extremity and “other” sites- (31% vs 48%) the presence of three or more metastatic (17% vs 38%), the presence of bone or bone marrow involvement (24% vs 45%). By multivariate analysis, histology had no more impact on EFS. The EFS was strongly correlated to the number of the 4 other unfavorable prognostic factors: age, site of the primary, number of metastis sites, bone/bone marrow involvement relative risks were 1.6 for age (p<0.0001), 1.4 for site of primary tumor (p=0.002), 1.3 for bone/bone marrow involvement (p=0.005), 1.4 for number of metastatic sites (p=0.002). EFS was 58% for the 46 patients without any factors and was respectively 40%, 22%, 14% and 4% in patients with 1 factor (250 patients), 2 factors (233 patients), 3 factors (177 patients) or 4 factors (70 patients) (p<0.01). Conclusions: This analysis identified subsets of patients with very different outcomes. Patients with EFS less than 50% might be appropriate candidates for experimental approaches. No significant financial relationships to disclose.
A phase Ib study of oxaliplatin in combination with fluorouracil (5FU) and leucovorin (LV) in pediatric patients (pts) with advanced solid tumors
Authors: Gore L. , Kuttesch J. , Hunger S. P. , Herzog C. , Narendaren A. , Boklan J. , Foreman N. K. , Ivy S. P. , Boucher N. , Trippett T. M. 
Published: March 2020

9548 Background: Platinums have significant activity in a wide variety of pediatric tumors, and oxaliplatin exhibits synergy with 5FU and LV in adults with colorectal cancer in FOLFOX regimens. The primary objectives of this study are to determine the maximum tolerated dose (MTD) of the modified FOLFOX6 regimen in pediatric tumors. Secondary objectives include safety, PK pharmacokinetic (PK) and PET scan efficacy analyses. Methods: Pts age <21 years with advanced cancers and adequate organ function are eligible. Patients are stratified by tumor type (CNS or non-CNS) to better delineate the potential neurotoxicity in patients with altered neurologic function. Pts received oxaliplatin starting at 85 mg/m2 and LV 400 mg/m2 over 2 hours on day 1 followed by a 5FU bolus of 400 mg/m2 then 2,400 mg/m2 continuous infusion over 46 hours, every 2 weeks (3 courses = 1 cycle), with integrated PK sampling in a limited dose escalation design. Standard 3+3 dose escalation, definitions of dose limiting toxicity (DLT), and dose modification for toxicity are implemented. The MTD is expanded to 15 patients to confirm and further characterize tolerability and toxicity. Results: To date, 15 very heavily pre-treated patients (7 M, 8 F) have received 25 cycles (range 1–4, median 2) of treatment at 2 dose levels. One of 8 pts at dose level 2 (oxaliplatin 100 mg/m2) developed DLT (delay in repeat treatment > 14 days due to grade 3 platelets). Treatment has been well tolerated. The most frequently reported related grade 3–4 adverse events (AEs) are reversible leukocytes (29%), neutropenia (43%), platelets (35%) and lymphopenia (21%). 31 of 90 courses (34%) have been delayed for neutropenia and thrombocytopenia. Anti-tumor activity to date includes a confirmed partial response lasting 15 weeks in a patient with osteosarcoma, and prolonged stable disease in 5 other pts with brain tumors (2), hepatoblastoma (2) and sarcoma (1). Conclusions: The modified FOLFOX6 regimen has significant but reversible myelosuppression in heavily pre-treated pediatric patients, but is tolerable and has promising activity in several tumor types. Cohort expansion continues at 100 mg/m2 of oxaliplatin. PET scan and pharmacokinetic analyses will be presented. No significant financial relationships to disclose.
Pre-clinical studies and phase I clinical trial of the anti-CD22 immunotoxin CAT-3888 (BL22) for pediatric acute lymphoblastic leukemia (ALL)
Authors: Wayne A. , Findley H. W. , Lew G. , Ahuja Y. , Gu L. , Stetler-Stevenson M. , Kreitman R. J. , Pastan I. 
Published: March 2020

9560 Background: ALL is the most common childhood malignancy. Although highly curable, therapy is associated with multiple toxicities and ALL remains the most frequent cause of pediatric cancer mortality. Most ALL is CD22+ and we evaluated the anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22 or CAT-3888) in the treatment of pediatric ALL. Methods: In vitro cytotoxicity was assessed on blasts from 42 children with CD22+ ALL. In vivo studies were performed using a xenograft model (SCID mouse - EU1 human ALL cell line). A pediatric phase I trial of CAT-3888 was initiated. Results: CAT-3888 induced in vitro cytotoxicity against most ALL samples (median IC50 9.8 ng/ml). A dose response was observed in murine xenografts with significant prolongation of leukemia free survival (p<0.05). 18 subjects (15 ALL, 3 lymphoma; 3 - 22 years of age) were treated on a Phase I trial at doses of 10 - 40 mcg/kg QOD for 3 - 6 doses with cycles repeated every 21 - 28 days. Treatment was well tolerated and no dose limiting toxicity was seen. Pharmacokinetics were influenced by disease burden and T1/2 showed an inverse relationship to marrow blasts (r2=0.5) consistent with rapid drug binding by CD22+ cells. All subjects were heavily pre-treated and had progressive high burden disease at the time of treatment. Transient clinical activity was observed in 16 of 18 subjects as evidenced by decreased peripheral blast count (8), decreased marrow infiltration (3), decreased extramedullary disease (2), increased platelet count (2), increased neutrophil count (1), increased reticulocyte count (1), improved PET scan (1), decreased tumor-associated pain (2), and/or peripheral blast count stabilization (3). A dose response was apparent with 4 of 9 (44%) achieving stable disease at or above doses of 30 mcg/kg. Conclusions: The majority of pediatric ALL blasts are highly sensitive in vitro to CAT-3888 at concentrations far below clinically achievable levels. CAT-3888 is well tolerated in pediatric patients and activity has been seen in most subjects treated on the phase I trial. CD22 represents a relevant target for pediatric ALL. A new higher affinity anti-CD22 immunotoxin (HA22 or CAT-8015) is in development. No significant financial relationships to disclose.
Phase I study of oral irinotecan, temozolomide, and vincristine for children with refractory solid tumors: A Children's Oncology Group study
Authors: Perentesis J. P. , Wagner L. M. , Ames M. M. , Reid J. M. , Stewart C. F. , Ingle A. M. , Blaney S. M. , Adamson P. C. 
Published: March 2020

9563 Background: Both temozolomide (TEM) and vincristine (VCR) can increase the preclinical activity of low-dose protracted irinotecan (IRN) against pediatric solid tumors. Because these drugs have different dose-limiting toxicities (DLTs) and mechanisms of action, we combined these three agents and sought to determine the maximum tolerated dose (MTD) of orally administered IRN when given with fixed- dose TEM and VCR in children with relapsed or refractory solid tumors, using the antibiotic cefixime to reduce IRN-associated diarrhea. Methods: We studied two dose levels of oral IRN (35 or 50 mg/m2) administered on days 1–5 and 8–12, combined with oral TEM 100 mg/m2 on days 1–5 and intravenous VCR 1.5 mg/m2 on days 1 and 8. Courses were repeated every 21 days. Oral cefixime was started 5 days before chemotherapy and continued daily. Results: Of 21 patients enrolled, 17 (ages 3–21, median 14 yrs) were evaluable for toxicity and have to date received 46 courses (range 1–8, median 2). At the IRN dose of 50 mg/m2/d, 4 of 12 patients had DLT, including elevated ALT/AST (1), abdominal pain (1), hypokalemia (1), anorexia (1), thrombocytopenia (1), and fatal liver failure in a patient with metastatic disease in the liver and porta hepatis (1). In contrast, none of 5 patients treated at the dose of 35 mg/m2/d experienced first-course DLT, defining this dose as the MTD. UGT1A1 genotype did not correlate with DLT in this small trial. The median SN-38 lactone area under the curve (0–6h) at the IRN dose of 50 mg/m2/day was 13.5 ng/ml*h (range 3.8 to 30.9); pharmacokinetic analysis of patients treated at 35 mg/m2/day is ongoing. Six patients with the following tumors received more than 2 courses: neuroblastoma, ependymoma, hepatoblastoma, fibrillary astrocytoma, osteosarcoma, and Ewing sarcoma. Central review of response data is underway. Three patients continue on therapy at the MTD. Conclusions: Oral administration of IRN together with TEM and VCR was feasible and well tolerated at the MTD of 35 mg/m2 given dx5x2. Further study using a shorter 5-day course of oral IRN is planned. No significant financial relationships to disclose.
A phase I study of zoledronic acid and low dose cyclophosphamide in children with recurrent/refractory neuroblastoma: A New Approaches to Neuroblastoma Therapy (NANT) study
Authors: Russell H. V. , Groshen S. , Ara T. , DeClerck Y. , Malkovsky M. , Reynolds C. P. , Matthay K. , Blaney S. M. 
Published: March 2020

9572 Background: Zoledronic acid (ZA), is a new generation, highly potent bisphosphonate that delays progression of bone metastases in adult malignancies. Bone metastases occur in 60% of children with advanced neuroblastoma. Pre-clinical studies demonstrated ZA with low dose chemotherapy delayed progression of osteolytic neuroblastoma lesions in a xenograft mouse model, prompting a phase I trial of ZA in neuroblastoma. Methods: Three dose levels of intravenous ZA (2, 3 or 4 mg/m2) administered every 28 days were evaluated in combination with continuous daily oral cyclophosphamide (CTX) (25 mg/m2/day) in patients with recurrent/refractory neuroblastoma and cortical bone lesions. The primary objective was to determine a recommended dose of ZA for future trials. Serial blood and urine samples were collected for pharmacokinetics, markers of osteoclast activity, and immunologic assays. Results: 14 patients (9 male), median age 7.9 years (0.8 - 26.6 years), were enrolled at ZA dose levels 2 mg/m2 (n=4), 3 mg/m2 (n=3), and 4 mg/m2 (n=7). To date, 13 patients are evaluable for toxicity. Thirty-nine cycles were administered with a median of 1 cycle per patient (range 1 - 12). Treatment was well tolerated; one DLT (Grade 3 hypophosphatemia) occurred at 4 mg/m2 ZA. Other grade 3 or 4 toxicities attributable to the combination included hypocalcemia (n=2), elevated transaminases (n=2), neutropenia (n=2), anemia (n=1), lymphopenia (n=1), and hypokalemia (n=1). Hypocalcemia occurred in 69% of first cycles and 8% of subsequent cycles. There were no renal toxicities or dental complications. There have been 2 partial responses by MIBG (central review pending), 4 stable disease, and 7 progressive disease; one patient is too early for response. Pharmacokinetic and correlative biology study results are pending. Conclusions: ZA is well tolerated and had evidence of responses when given with low dose CTX to children with recurrent/refractory neuroblastoma. The recommended dose of ZA for subsequent study is 4 mg/m2. Future studies incorporating ZA into the regimen for children with NB and cortical bone lesions are planned. No significant financial relationships to disclose.