Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group.

BACKGROUND: The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated. PROCEDURE: Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). RESULTS: Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%). CONCLUSIONS: The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles.

Abnormal liver transaminases and conjugated hyperbilirubinemia at presentation of acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. While hepatitis is a well-known complication during the treatment phase of ALL, the association of abnormal liver biochemistries at initial presentation of leukemia is poorly described. The aim of this study is to examine the prevalence and assess the clinical impact of hepatitis at diagnosis in children with ALL. PROCEDURE: All children diagnosed with ALL at BC Children's Hospital between 2001 and 2006 were included. Charts were reviewed and data recorded to a computerized spreadsheet. Descriptive statistical analyses were performed. RESULTS: One hundred forty-seven ALL patients were identified. Over one third of patients had abnormal liver transaminase values (AST and/or ALT). Of the patients with abnormal transaminases, (52%) had ALT elevations twice the upper limit of normal. Risk factors for elevated transaminases included a high WBC count at diagnosis, older age, bulky disease, and T-cell leukemia. Conjugated hyperbilirubinemia was observed in 3.4% of subjects. Of these cases, 60% received steroids prior to induction chemotherapy and all had rapid resolution of their hyperbilirubinemia to normal levels. CONCLUSIONS: Elevated transaminases are common at initial presentation of ALL and are likely due to hepatic injury from leukemic infiltrates. Conjugated hyperbilirubinemia at presentation may require treatment modification and dose reduction. A short course of steroids prior to initiation of induction chemotherapy appears to result in rapid resolution of the hyperbilirubinemia with subsequent ability to provide full dosing of induction chemotherapy.

A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: a Children's Oncology Group study.

BACKGROUND: Imatinib mesylate is a small molecule inhibitor of certain tyrosine kinases, most notably the chimeric bcr-abl fusion protein found in CML. It also inhibits KIT and PDGF receptor tyrosine kinases in vitro. Ewing sarcoma, osteosarcoma, neuroblastoma, desmoplastic small round cell, and synovial sarcomas often overexpress KIT or the PDGF receptor. A phase II study of imatinib in children and young adults with select solid tumors was performed. PROCEDURE: Patients less than 30 years of age with refractory or recurrent Ewing sarcoma, osteosarcoma, neuroblastoma, desmoplastic small round cell, synovial sarcomas or GIST were eligible. Imatinib was administered daily for 28 day courses at a dose of 440 mg/m(2)/day. Responses were assessed according to Response Evaluation Criteria in Solid Tumor (RECIST). RESULTS: Seventy eligible patients, 48 male and 22 female, were enrolled and 59 were evaluable for response. Only one partial response was seen among 24 patients with Ewing sarcoma. There were no other objective responses. Hemorrhagic pleural effusions occurred in seven patients with pulmonary lesions, four of whom had progressive disease at the time of the hemorrhage. Intratumoral bleeding was reported in three additional patients. CONCLUSION: Imatinib as a single agent at a dose of 440 mg/m(2)/day demonstrated little or no activity as a single agent in children with relapsed or refractory Ewing sarcoma, osteosarcoma, neuroblastoma, or desmoplastic small round cell tumors.

Understanding clinical trials in childhood cancer.

Clinical trials in paediatric cancer continue to be a key factor in progress toward better treatment and prognosis. Paediatricians and family physicians may be asked by patients and families for their advice regarding participation in such trials. The significant advances in the success of treatment of paediatric cancer have come, in part, from the high participation rate of patients in such studies. The present article reviews the definitions and goals of phase 1, 2 and 3 trials. A known and trusted physician or paediatrician can be helpful in conjunction with the oncologist in guiding patients and their families and helping them understand the risks and benefits of participation in clinical trials.

Immune evasion strategies of pediatric precursor-B acute lymphoblastic leukemia after allogeneic bone marrow transplantation-a case study.

Bone marrow transplantation (BMT) is the primary curative option for refractory/relapsed pediatric acute lymphoblastic leukemia. Although post-transplantation relapse remains a frequent cause of transplantation failure, the mechanisms underlying this are poorly understood. In this study, we compared allogeneic T cell stimulation induced by sequentially obtained precursor-B acute lymphoblastic leukemia (ALL) samples from a single patient with overt graft versus leukemia (GVL) activity. We observed a loss of T cell stimulatory capacity by post-transplantation relapse samples and changes in expression of MHC and the costimulatory molecule CD137 ligand. This study suggests that escape from immune mechanisms after withdrawal of immune suppression is important to ALL progression.

TDP1 and PARP1 deficiency are cytotoxic to rhabdomyosarcoma cells.

UNLABELLED: Rhabdomyosarcoma is the most common soft tissue sarcoma in children. Metastatic rhabdomyosarcoma in children has a 5-year event-free survival rate of <30%, and a recent clinical trial with irinotecan, a topoisomerase I inhibitor, failed to improve outcome. Therefore, it was surmised that failure of irinotecan may be the result of overexpression of the DNA repair enzyme tyrosyl-DNA phosphodiesterase (TDP1), which processes topoisomerase I-DNA complexes resulting from topoisomerase I inhibitor treatment. Using human tissue microarrays and gene expression arrays, a marked overexpression of TDP1 protein and mRNA in RMS tumors was observed. Critically, knockdown of TDP1 or inhibition of poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme in the same complex as TDP1, sensitized rhabdomyosarcoma cell lines to analogues of irinotecan. Interestingly, BRCA1/2 mutations or altered expression was not detectable in rhabdomyosarcoma cells; however, TDP1 knockdown and PARP-1 inhibition alone were cytotoxic to a subset of rhabdomyosarcoma cells, suggesting that they harbor genetic lesions in DNA repair components that have synthetic lethal interactions with loss of TDP1 or PARP1 function. Furthermore, culturing embryonal rhabdomyosarcoma cells in serum/nutrient-restricted medium increased cellular cytotoxicity upon PARP-1 inhibition and was intrinsically cytotoxic to alveolar, though not embryonal rhabdomyosarcoma cells. The results of these studies suggest a compensatory role for TDP1 in rhabdomyosarcoma after topoisomerase-I based therapy and further demonstrate that TDP1 knockdown, PARP-1 inhibition, and dietary restriction have therapeutic validity. IMPLICATIONS: Selective targeting of TDP1 and/or PARP-1 in rhabdomyosarcoma induces cytotoxicity and sensitizes to DNA damaging agents.

Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults.

BACKGROUND: Imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor approved for use in the management of chronic myeloid leukemia in adults and children and in gastrointestinal stromal tumors in adults. Population pharmacokinetic (PPK) studies evaluating the effect of population covariates on the pharmacokinetics of imatinib and its active metabolite have been developed in adults with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, this still remains to be described in children. PURPOSE: The objectives of the analysis were to develop a PPK model of imatinib and its active metabolite, CGP74588, to describe exposure in children and young adults and to identify covariates that are predictors of variability in disposition. METHODS: Plasma concentrations from 26 subjects with Philadelphia (Ph+) leukemia (Phase I study) and 15 subjects with refractory solid tumors (Phase II study), who received oral imatinib at doses ranging from 260 to 570 mg/m(2), were available for the PPK analysis in NONMEM. Blood samples were drawn prior to dosing and over 24-48 h on days 1 and 8 of the studies. Covariates studied included weight, age, albumin, alanine aminotransferase and the study population. RESULTS: The pharmacokinetics of imatinib and CGP 74588 were well described by one and two compartment models, respectively. Total body weight was the only covariate found to significantly affect Cl/F and V/F. The final imatinib-CGP 74588 model is summarized as follows: CL/F (imatinib) (L/h) = 10.8 x (WT/70)(0.75), V/F (imatinib) (L) = 284 x (WT/70) and D1(duration of zero order absorption,imatinib) (h) = 1.67 and CL/F (CGP 74588) (L/h) = 9.65 x (WT/70)(0.75), V1/F (CGP 74588) (L) = 11.6 x (WT/70), Q (CGP 74588) (L/h) = 2.9 x (WT/70)(0.75) and V2/F (CGP 74588) (L) = 256*(WT/70). Model evaluation indicated that the final model was robust and satisfactory. CONCLUSIONS: Current imatinib dosing guidelines in pediatrics is based on the achievement of exposures consistent with doses known to be safe and efficacious in adults. Dose adjustments in children are guided empirically by the observance of drug-related toxicities. While, the pharmacokinetics of imatinib and its active metabolite, CGP 74588 in children are consistent with prior knowledge in adults, the model will form the basis to support the design of future trials, particularly with a view to managing toxicities and exploring dosing in this population.

Case selection in minimally invasive surgical treatment of neuroblastoma.

PURPOSE: The experience with minimally invasive surgery (MIS) in the treatment of neuroblastoma (NB) is anecdotal. The purpose of this study was to evaluate a retrospective cohort of NB patients who underwent MIS resection of their primary tumors. METHODS: A retrospective study of NB patients who underwent MIS resection of their primary tumors over a 3-year period was undertaken. Study outcomes included complications, completeness of resection, and event-free and overall short-term survival. RESULTS: Of a total of 21 children who underwent surgical resection for NB during the period of study, 8 (38%) underwent selected MIS resection. Six of the eight (75%) tumors were adrenal in origin and the remainder were located in the posterior mediastinum. Distribution by International Neuroblastoma Staging System (INSS) stage was: stage 1 (3), stage 2 (2), and stage 4 (3). One stage 4 tumor was N-myc amplified. All stage 4 patients experienced a >50% tumor volume cytoreduction in response to preoperative chemotherapy. All MIS resections were performed without need for blood transfusion, or conversion to open procedure, and there were no perioperative complications. All eight patients were alive and disease-free at a median 18-month follow-up. CONCLUSIONS: With appropriate preoperative case selection based on anatomic features, MIS tumor resection in patients with NB can be performed safely and effectively.

Successful treatment of a child with a primary intracranial rhabdomyosarcoma with chemotherapy and radiation therapy.

Primary rhabdomyosarcoma of the central nervous system (CNS) is rare in both adults and children (Taratuto et al. (1985) Acta Neuropathol (Berl) 66(2):98-104). The outcome in the majority of cases is poor, and many cases are associated with early mortality (Celli et al. (1998) J Neurooncol 36(3):259-267). There are very few cases reported in the literature of survival beyond 2 years after diagnosis. We report a case of primary intracranial embryonal rhabdomyosarcoma in a 5-year-old girl who was treated successfully with local radiation therapy (RT) and a combination of two different chemotherapeutic regimens. The patient is clinically well 26 months after diagnosis, with no definitive evidence of residual disease.