Long-Term Follow-up of High-Dose Chemotherapy with Autologous Stem Cell Transplantation in Children and Young Adults with Metastatic or Relapsed Ewing Sarcoma: A Single-Institution Experience.

Forty-seven patients with metastatic disease at diagnosis or recurrent Ewing sarcoma (EWS) received high-dose chemotherapy (HDC) followed by tandem (n = 20, from February 13, 1997, to October 24, 2002) or single (n = 27, from October 1, 2004, to September 5, 2018) autologous hematopoietic stem cell transplantation (ASCT). To our knowledge, this is the largest single-institution study with sustained long-term follow-up exceeding 10 years. All patients who underwent single ASCT received a novel conditioning regimen with busulfan, melphalan, and topotecan. The overall survival (OS) and disease-free survival (DFS) were 46% and 37% at 10 years and 42% and 37% at 15 years, respectively. Disease status at transplant and the time to disease relapse prior to ASCT were identified as important prognostic factors in OS, DFS, and risk of relapse. At 10 years, patients who underwent transplantation in first complete response (1CR) had an excellent outcome (OS 78%), patients in 1CR/second complete response (2CR)/first partial response (1PR) had an OS of 66%, and patients at third or more complete response, second or more partial response, or advanced disease had an OS of 26%. Ten-year OS for patients without a history of relapse, with late relapse (≥2 years from diagnosis), or with early relapse (<2 years from diagnosis) was 75%, 50%, and 18%, respectively. Selected patients in 1CR, 2CR, 1PR, and with late relapse had excellent, sustained 10- and 15-year OS and DFS.

Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group.

BACKGROUND: Although chemotherapy has improved outcome of osteosarcoma, 30-40% of patients succumb to this disease. Survivors experience substantial morbidity and mortality from anthracycline-induced cardiotoxicity. We hypothesized that the cardioprotectant dexrazoxane would (i) support escalation of the cumulative doxorubicin dose (600 mg/m(2)) and (ii) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data. PROCEDURE: Children and adolescents with nonmetastatic osteosarcoma were treated with MAP (methotrexate, doxorubicin, cisplatin) or MAPI (MAP/ifosfamide). Dexrazoxane was administered with all doxorubicin doses. Cardioprotection was assessed by measuring left ventricular fractional shortening. Interference with chemotherapy-induced cytotoxicity was determined by measuring tumor necrosis after induction chemotherapy. Feasibility of intensifying therapy with either high cumulative-dose doxorubicin or high-dose ifosfamide/etoposide was evaluated for "standard responders" (SR, <98% tumor necrosis at definitive surgery). RESULTS: Dexrazoxane did not compromise response to induction chemotherapy. With doxorubicin (450-600 mg/m(2)) and dexrazoxane, grade 1 or 2 left ventricular dysfunction occurred in five patients; 4/5 had transient effects. Left ventricular fractional shortening z-scores (FSZ) showed minimal reductions (0.0170 ± 0.009/week) over 78 weeks. Two patients (<1%) had secondary leukemia, one as a first event, a similar rate to what has been observed in prior trials. Intensification with high-dose ifosfamide/etoposide was also feasible. CONCLUSIONS: Dexrazoxane cardioprotection was safely administered. It did not impair tumor response or increase the risk of secondary malignancy. Dexrazoxane allowed for therapeutic intensification increasing the cumulative doxorubicin dose in SR to induction chemotherapy. These findings support the use of dexrazoxane in children and adolescents with osteosarcoma.

Feasibility Study of a Novel Experimental Induction Protocol Combining B43-PAP (Anti-CD19) Immunotoxin With Standard Induction Chemotherapy in Children and Adolescents With Relapsed B-Lineage ALL: A Report From the Children's Oncology Group.

BACKGROUND: B43-pokeweed antiviral protein (B43-PAP) is a high-affinity anti-CD19 immunotoxin that is capable of causing apoptotic death in B-lineage leukemic cells with a drug-resistant phenotype. B43-PAP exhibited in vivo antileukemic activity in preclinical studies as well as on a single-agent phase I clinical trial. This pediatric phase I/II study evaluated the toxicity profile and efficacy of B43-PAP immunotoxin in combination with standard induction chemotherapy in children and adolescents with relapsed CD19-positive B-lineage acute lymphoblastic leukemia (B-ALL). Pharmacokinetic profile and immunogenicity of B43-PAP were assessed. EXPERIMENTAL DESIGN: B43-PAP in combination with standard 3 and 4-drug induction chemotherapy was administered on days 9-13 and 21-25 of a 28-day treatment course with vincristine, prednisone, L-asparaginase, daunomycin, and intrathecal methotrexate. Thirty patients with relapsed B-ALL were enrolled on study CCG-0957. RESULTS: Grade III/IV nonhematologic dose-limiting toxicities were encountered in 4 patients evaluable for toxicity and included myalgias, motor dysfunction, pulmonary toxicity, and elevated liver transaminase. Dose-limiting toxicities occurred only with the 4-drug regimen. Fourteen patients achieved a complete remission at the end of induction among the 20 patients evaluable for response. CONCLUSIONS: B43-PAP in combination with standard induction chemotherapy can be safely administered and exhibits clinical antileukemic activity against relapsed B-ALL.

Distress screening, rater agreement, and services in pediatric oncology.

OBJECTIVE: Empirically based data support the validity of the distress thermometer recommended by the National Comprehensive Cancer Network as a standard screen for patient distress. However, the feasibility and utility of the distress thermometer has not been studied in the pediatric oncology setting. We conducted a study to: (1) investigate the validity of an adapted distress thermometer with pediatric oncology patients, (2) assess the degree of agreement among different respondents, including physician and psychosocial staff, with respect to (a) the pediatric cancer patient's distress and (b) the caregiver/parent's distress, and (3) to evaluate the relationship between distress levels and the psychosocial services provided to patients and families. METHODS: Ninety-one patients and their English and Spanish-speaking caregivers were prospectively assessed at 3-month intervals for 1 year. The quantity of psychosocial services provided to each family was logged for a 12-month period. RESULTS: Convergent validity was demonstrated by reasonable agreement between the pediatric distress rating tool and standardized measures. Additionally, the demographic and medical predictors of distress were consistent with previously reported findings using more extensive assessment. There was reasonable agreement among multiple raters of the child's distress; however, there was discrepancy between self-ratings of caregiver distress and psychosocial staff ratings of caregiver distress. This difference in perception impacted the quantity of psychosocial services provided following the baseline assessment. CONCLUSION: The single-item distress thermometer is a viable option as a rapid screening tool of patient and caregiver distress to help efficiently identify those who should be evaluated further.

Phase II clinical trial of imatinib mesylate in therapy of KIT and/or PDGFRalpha-expressing Ewing sarcoma family of tumors and desmoplastic small round cell tumors.

BACKGROUND: We have previously shown that the receptor tyrosine kinases, KIT and PDGFRalpha, are expressed on ESFT cell lines, and that imatinib induces dose-dependent apoptosis (1). We conducted a Phase II trial to evaluate the effectiveness of imatinib for patients with recurrent ESFT or DSRCT expressing KIT and/or PDGFRalpha. PATIENTS AND METHODS: Patients were selected for tumor immunohisto-chemical expression > or =2+/4+ for KIT or PDGFRalpha. Imatinib was administered orally 400 mg twice/day for 28 days/course. Primary endpoint was response. RESULTS: Seven patients were enrolled and evaluated. One patient with 3+/4+ PDGFRalpha and 3+/4+ KIT expression had a partial response through 8 courses. 4 patients had progression after 1 cycle. Two patients were not evaluable due to one early death and one refusing treatment. CONCLUSION: This study intended to enrich for molecular factors that potentially predict response. Given the poor prognosis with recurrent ESFT, further studies with other novel KIT and PDGFRalpha inhibitors are needed.

Phase 2 trial of recombinant tumor necrosis factor-alpha in combination with dactinomycin in children with recurrent Wilms tumor.

Tumor necrosis factor (TNF), a peptide produced by macrophages with cytostatic and cytolytic effects, demonstrated single agent antitumor activity and synergistic effect when administered with dactinomycin in in vitro tumor cell lines, in vivo xenograft models, and adult and pediatric phase 1 clinical trials. This phase 2 pediatric trial evaluated the efficacy and further defined the toxicity profile of recombinant TNF (rTNF) and dactinomycin in patients with recurrent or refractory Wilms tumor. On this 2 stage Children's Cancer Group trial, dactinomycin (15 microg/kg/d, IV) immediately followed by rTNF (200 microg/m/d, IV), once daily for 5 consecutive days, was administered to patients with recurrent or refractory Wilms tumor. Cycles repeated every 21 days to a maximum of 12 courses. Nineteen of 21 consecutive patients, ranging 0.9 to 16.5 years of age at the time of initial diagnosis, were evaluable for response and toxicity. Three patients (15.8%) had a complete response, 5 (26.3%) had stable disease, and 11 (57.9%) had progressive disease. Following 59 patient treatment cycles, the most commonly observed grade 3/4 toxicities were thrombocytopenia (40.7%), elevated liver transaminases (23.7%), neutropenia (20.3%), leucopenia (13.6%), anemia (11.9%), and myalgias (10.2%). Before completion of stage 2, the study closed due to unavailability of rTNF. The documented complete responses and disease stabilization suggest antitumor activity of rTNF with dactinomycin in patients with recurrent Wilms tumor. The combination was well tolerated. Although grade 3/4 adverse events were reported, dose adjustments were not required. Toxicities resolved without significant interventions.

Phase 2 study of temozolomide in children and adolescents with recurrent central nervous system tumors: a report from the Children's Oncology Group.

BACKGROUND: Effective chemotherapy is lacking for most types of central nervous system (CNS) tumors in children. Temozolomide, an agent with activity against adult brain tumors, was investigated in children and adolescents with recurrent CNS tumors. METHODS: Temozolomide was administered orally as monthly 5-day courses at doses of 200 mg/m(2)/d (patients with no prior craniospinal irradiation [CSI]) or 180 mg/m(2)/d (prior CSI). Patients with a complete (CR) or partial (PR) response or stable disease (SD) could continue temozolomide for up to 12 cycles. RESULTS: The cohort comprised 122 patients, including 113 with CNS tumors. Median age was 11 years (range, 1-23 years). Among 104 evaluable patients with CNS tumors, 5 PRs and 1 CR were observed. PRs occurred in 1 of 23 evaluable patients with high-grade astrocytoma, 1 of 21 with low-grade astrocytoma, and 3 of 25 with medulloblastoma/primitive neuroectodermal tumor (PNET). The CR occurred in an additional patient with medulloblastoma/PNET. No responses were observed in patients with ependymoma, brain-stem glioma, or other CNS tumors. Notably, 41% of patients with low-grade astrocytoma had SD through 12 courses. The most frequent toxicities were grade 3 or 4 neutropenia (19%) and thrombocytopenia (25%); nonhematologic toxicity was infrequent. CONCLUSIONS: Although overall objective responses were limited, further exploration of temozolomide may be warranted in children with medulloblastoma and other PNETs, or in patients with low-grade astrocytoma, perhaps in a setting of less pretreatment than the patients in the current study, or in the context of multiagent therapy.

Upfront window trial of topotecan in previously untreated children and adolescents with poor prognosis metastatic osteosarcoma: children's Cancer Group (CCG) 7943.

BACKGROUND: Patients with metastatic osteosarcoma have a poor prognosis. The objectives of the study were to determine the antitumor activity and toxicity of topotecan (daily x5) in newly diagnosed patients with metastatic osteosarcoma followed by chemotherapy (ifosfamide, carboplatin, etoposide [ICE], alternating with cisplatin and doxorubicin [CD]). METHODS: Newly diagnosed patients (< or =30 years of age) with extensive metastatic disease (primary and > or =5 pulmonary nodules and/or bone metastases) with normal hepatic, renal, and cardiac function were eligible. Patients were eligible to receive further topotecan after standard chemotherapy if they exhibited a response. Twenty-eight patients were enrolled. Seventeen had metastases to the lung only and 11 had metastases to the bone or multiple sites. Of 28 patients enrolled, 27 could be evaluated for response. A limited dose escalation was incorporated. RESULTS: No responses were seen in the 11 patients treated at 3 mg/m(2)/day. One partial response (PR) and 1 clinical response (CLR) were reported among 15 patients who received topotecan at 3.5 mg/m(2)/day. No dose-limiting toxicity was observed. Principal nondose-limiting toxicities were hematologic and gastrointestinal. The 2- and 5-year event-free survival rates were low, 7% and 4%, respectively, but the 2- and 5-year overall survival rates were 44% and 22%, respectively. CONCLUSIONS: Topotecan at dose of 3.5 mg/m(2)/day can be safely administered upfront to newly diagnosed patients without excessive toxicity. Insufficient activity was seen with topotecan in this schedule to warrant further studies in osteosarcoma. The combination of ICE and CD was tolerable when delivered after initial topotecan therapy.

A phase 2 trial of all-trans-retinoic acid in combination with interferon-alpha2a in children with recurrent neuroblastoma or Wilms tumor: A Pediatric Oncology Branch, NCI and Children's Oncology Group Study.

BACKGROUND: The combination of the antiproliferative and differentiation-inducing effects of retinoids together with the antiproliferative, immunostimulatory, and differentiation-potentiating effects of interferon-alpha (IFN-alpha) were the basis for the development of this combination in pediatric patients with refractory neuroblastoma or Wilms tumor. PROCEDURE: A phase 2 trial of all-trans-retinoic acid (ATRA), administered orally at a dose of 90 mg/m(2)/day in three divided doses for 3 consecutive days per week, and IFN-alpha2a, administered subcutaneously daily at a dose of 3 x 10(6) U/m(2)/day for 5 consecutive days per week, in 4 week cycles was performed. A two-stage design was used for each disease stratum. RESULTS: Seventeen patients (16 evaluable) with neuroblastoma, median age 9 years, and 15 patients (14 evaluable) with Wilms tumor, median age 6 years, were enrolled. Overall, the combination was well tolerated, with headache being the most common toxicity observed. There were no complete or partial responses. The median number of cycles administered was 1 (range 1-9). Four patients with neuroblastoma had stable disease for 12 or more weeks. CONCLUSIONS: The combination of ATRA and IFN-alpha2a was inactive in children with relapsed or refractory neuroblastoma and Wilms tumor. The lack of activity with this combination in children with refractory neuroblastoma is similar to the disappointing phase 2 results of single agent 13-cis-retinoic-acid (13cRA) and does not support further development of ATRA for children with relapsed neuroblastoma.

Phase II investigation of docetaxel in pediatric patients with recurrent solid tumors: a report from the Children's Oncology Group.

BACKGROUND: Docetaxel, which is an antitubulin agent, has demonstrable activity against murine and human tumors. The current study was designed to determine response rates to docetaxel in various strata of recurrent solid tumors of childhood and to assess toxicity in a group of patients who were assigned to receive it. METHODS: Docetaxel was given at a dose of 125 mg/m2 once every 21 days as a 1-hour intravenous infusion for a maximum of 12 courses. From January 1997 to November 2001, 109 male patients and 68 female patients (total, 177 patients) were enrolled, and 173 patients were eligible. The median patient age at entry was 13 years (range, 1-27 yrs). One hundred sixty patients were evaluable for response. RESULTS: There were no deaths attributable to study drug. Hematologic toxicity was common during therapy. Dermatologic, neurologic, pulmonary, and infectious side effects as well as edema were significant. One patient each had acute myeloid leukemia, acute lymphoid leukemia, and high-grade glioma reported as secondary malignancies. One patient with osteosarcoma and 1 patient with rhabdomyosarcoma achieved a complete response. Partial responses were observed in patients with Ewing sarcoma (3 patients), osteosarcoma (1 patient), squamous cell carcinoma (1 patient), and medulloblastoma (1 patient). Seventeen patients had stable disease. The 1-year and 5-year overall survival rates for the 160 evaluable patients were 24% (standard error = 4%) and 6% (standard error = 2%), respectively. CONCLUSIONS: Docetaxel demonstrated activity in patients with recurrent Ewing sarcoma but was found to be ineffective for treating the other types of recurrent solid tumors that were studied.

Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate.

PURPOSE: To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). PATIENTS AND METHODS: Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 double dagger 2 factorial design. The primary end point for analysis was EFS. RESULTS: Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. CONCLUSION: The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.