Lauren Long

Molecular confirmation of Ewing sarcoma.

Objective To analyze retrospectively results of reverse transcription polymerase chain reaction (RT-PCR) testing and demographic information in ?patients with known or suspected Ewing sarcoma/primitive neuroectodermal tumor family of tumors referred to the National Cancer Institute and to describe factors influencing the determination of molecular marker status. Patients and Methods Tumor samples from 76 patients from February 1997 to December 1999 were analyzed. In all cases, the diagnosis of this family of tumors was confirmed by histopathologic review. Results In 58 patients, the presence of a translocation associated with this family of tumors was confirmed using RT-PCR. Specifically, there were 45 Ewing sarcoma (EWS)-FLI type 1 translocations, four EWS–FLI type 2 translocations, five EWS–ERG translocations, and four less common EWS–FLI variants. Of patients with a confirmed translocation, four were confirmed only after nested RT-PCR techniques were used. In five patients who initially underwent needle biopsy, the diagnosis was confirmed only after open biopsy or repeat needle biopsy was undertaken.Samples from 18 patients were translocation-negative. Of these, seven samples were deemed inadequate for RT-PCR testing as a result of inappropriate tissue handling or the presence of necrotic material. Five patients were found to have a different diagnosis after complete histopathologic and molecular characterization. Six samples remained, in which adequate tissue was obtained with no evidence of a characteristic translocation. Conclusions In apparently translocation-negative samples, close attention should be given to the possibility of an alternative diagnosis, the potential need for nested RT-PCR, and the possibility of an inadequate sample. Strong consideration should be given to the use of open biopsy as opposed to needle biopsy to avoid the need for repeat biopsies and the potential for inaccurate assessment of molecular marker status.

Treatment late effects in long-term survivors of pediatric sarcoma

To assess health and musculoskeletal function in survivors of pediatric sarcomas.

Treatment of metastatic osteosarcoma with the somatostatin analog OncoLar: Significant reduction of insulin-like growth factor-1 serum levels

Background Insulin-like growth factor-1 (IGF-1) has been implicated in the growth and/or metastasis of osteosarcoma (OS) and chondrosarcoma based on in vitro and experimental animal studies. Study Purpose To determine the degree of growth hormone (GH), IGF-1 axis blockade, toxicities, and antitumor effect of OncoLar (ONC) (Novartis, East Hanover, NJ, U.S.A.) in OS. Design/Methods A phase 1 study with ONC enrolled 21 OS patients (median age 19 y) in four cohorts: ONC 60 mg or 90 mg intramuscularly every 4 weeks with/without tamoxifen (TAM) 20 mg oral daily. Results There were no dose-limiting toxicities. Nineteen percent of patients had grade III drug-related toxicities including: 62% of patients showed progressive disease after two courses (8 wk). Nineteen percent received four courses. No clinical responses were observed. At weeks two and eight of therapy, IGF-1 serum levels dropped 46% (P < 0.0001, n = 21) and 53% (P = 0.003, n = 10). The difference of the area under the curve (AUC) minus baseline AUC (&Dgr;AUC) for arginine-stimulated GH serum levels at week two was lower than baseline (P < 0.01). At weeks two and eight, GH peak values were lower than baseline (P < 0.0001 and P = 0.002, respectively). Conclusions A long-acting somatostatin analog was able to lower IGF-1 levels of OS patients. IGF-BP-3 and GH were only transiently reduced. Although ONC was well tolerated, no sustained clinical responses were observed. The pathophysiology of serum versus tissue concentrations of IGF-1 as well as the interplay of IGFs, IGF-binding proteins, and other growth factors and cytokines in osteosarcoma warrants further investigation. A better understanding of these processes should lead to a more effective exploitation of these pathways for the targeted therapy of OS.

Thromboembolic Events in Children and Young Adults With Pediatric Sarcoma

PURPOSE Adults with malignancy are at increased risk for venous thromboembolic events (TEs). However, data in children and young adults with cancer are limited. PATIENTS AND METHODS To determine the risk and clinical features of TEs in children and young adults with sarcoma, we reviewed records on 122 consecutive patients with sarcoma treated from October 1980 to July 2002. RESULTS Twenty-three TEs were diagnosed in 19 of 122 (16%; 95% CI, 10% to 23%) patients. Prevalence by diagnosis was Ewing sarcoma, eight of 61 (13%); osteosarcoma, two of 20 (10%); rhabdomyosarcoma, four of 26 (15%); and other sarcomas, five of 15 (33%). TEs developed in 23% of patients with metastases at presentation versus 10% with localized disease (odds ratio, 2.59; 95% CI, 0.9 to 7.1; P < .06). Fifty-three percent of patients with thrombosis had a clot at presentation. A lupus anticoagulant was detected in four of five evaluated patients. There was a single fatality due to pulmonary embolism. Patients who were diagnosed with cancer after 1993 had a higher rate of TE (7% v 23%; P < .015). Of the 23 events, 43% were asymptomatic. Main sites of thromboses were deep veins of the extremities (10 of 23; 43%), pulmonary embolism (five of 23; 22%), and the inferior vena cava (four of 23; 17%). TEs were associated with tumor compression in eight of 23 (35%) and with venous catheters in three of 23 (13%). CONCLUSION Thromboembolism is common in pediatric patients with sarcomas. Thromboses are detected frequently around the time of oncologic presentation, may be asymptomatic, and seem to be associated with a higher disease burden. Children and young adults with sarcoma should be monitored closely for thrombosis.

Randomized Trial and Pharmacokinetic Study of Pegfilgrastim versus Filgrastim after Dose-Intensive Chemotherapy in Young Adults and Children with Sarcomas

Purpose: To compare the effectiveness, tolerance, and pharmacokinetics of a single dose of pegfilgrastim to daily filgrastim in children and young adults with sarcomas treated with dose-intensive combination chemotherapy. Experimental Design: Patients were randomized to receive a single dose of 100 mcg/kg of pegfilgrastim s.c. or 5 mcg/kg/day of filgrastim s.c., daily until neutrophil recovery after two treatment cycles with vincristine, doxorubicin, and cyclophosphamide (VDC) and two cycles of etoposide and ifosfamide (IE). The duration of severe neutropenia (absolute neutrophil count, ≤500/mcL) during cycles 1 to 4 and cycle duration for all cycles were compared. Pharmacokinetics of pegfilgrastim and filgrastim and CD34+ stem cell mobilization were studied on cycle 1. Growth factor–related toxicity, transfusions, and episodes of fever and neutropenia and infections were collected for cycles 1 to 4. Results: Thirty-four patients (median age, 20 years; range 3.8-25.8) were enrolled, and 32 completed cycles 1 to 4. The median (range) duration of absolute neutrophil count of <500/mcL was 5.5 (3-8) days for pegfilgrastim and 6 (0-9) days for filgrastim (P = 0.76) after VDC, and 1.5 (0-4) days for pegfilgrastim and 3.75 (0-6.5) days for filgrastim (P = 0.11) after IE. More episodes of febrile neutropenia and documented infections occurred on the filgrastim arm. Serum pegfilgrastim concentrations were highly variable. Pegfilgrastim apparent clearance (11 mL/h/kg) was similar to that reported in adults. Conclusion: A single dose per cycle of pegfilgrastim was well tolerated and may be as effective as daily filgrastim based on the duration of severe neutropenia and number of episodes of febrile neutropenia and documented infections after dose-intensive treatment with VDC and IE. (Clin Cancer Res 2009;15(23):7361–7)

Adjuvant chemotherapy for the treatment of advanced pediatric nonrhabdomyosarcoma soft tissue sarcoma: The national cancer institute experience†‡

The survival of children and adolescents with advanced (unresectable or metastatic) nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) is poor. In order to clarify the role of combining chemotherapy with aggressive local control using surgery and/or radiation, we reviewed our institutional experience with the treatment of advanced pediatric NRSTS.

SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors

Background Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported. Methods We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two-stage design was used (target response rate 40%). Results 34 NF1 (median age 33 years) and 14 sporadic (median age 40 years) MPNST patients enrolled. Five of 28 (17.9%) evaluable NF1 MPNST patients had a partial response (PR), as did 4 of 9 (44.4%) patients with sporadic MPNST. Stable disease (SD) was achieved in 22 NF1 and 4 sporadic MPNST patients. In both strata, results in the initial stages met criteria for expansion of enrollment. Only 1 additional PR was observed in the expanded NF1 stratum. Enrollment was slower than expected and the trial closed before full accrual. Conclusions This trial was not powered to detect differences in response rates between NF1 and sporadic MPNST. While the OR rate was lower in NF1 compared to sporadic MPNST, qualitative responses were similar, and disease stabilization was achieved in most patients.

Thromboembolic events (TEE) in children and young adults with sarcoma.

8524 Background: Adults with malignancy are at increased risk for thromboembolic events (TEE). However, data on TEE in pediatric patients with cancer are limited. METHODS To ascertain the risk and clinical features of TEE in pediatric sarcoma patients, we reviewed records on 119 consecutive patients with sarcoma treated from 10/80 to 07/02. RESULTS Median patient age was 18 years (range 4-32). Twenty-two TEE were diagnosed in 18/119 (15.1%) patients. Incidence by diagnosis was Ewings sarcoma 7/61 (11.5%), osteogenic sarcoma 2/20 (10%), rhabdomyosarcoma 4/24 (16.7%) and other sarcomas 5/14 (35.7%). TEE developed in 12/51 (23.5%) patients with metastases at presentation vs. 6/68 (8.8%) with local disease (p=0.028). Thromboses were detected at presentation in 13/22 (59.1%), during the initial treatment cycle in 4/22 (18.2%), and at recurrence in 5/22 (22.7%). Ten (45.5%) events were asymptomatic (detected on routine imaging or autopsy). Sites of thromboses were deep veins of the extremities 10/22 (45.5%), pulmonary embolism 4/22 (18.2%), inferior vena cava (IVC) 4/22 (18.2%), superior vena cava 1/22 (4.5%), right atrium 2/22 (9.1%), and superior sagittal sinus 1/22 (4.5%). TEE were associated with tumor compression in 8/22 (36.4%) and with indwelling venous catheters in 3/22 (13.6%). A lupus anticoagulant was detected in 2 of 4 patients evaluated. Initial treatment included standard heparin in 9/22 (40.9%), low molecular weight heparin in 4/22 (18.2%), thrombolysis in 3/22 (13.6%), and IVC filter placement in 4/22 (18.2%). CONCLUSIONS Thromboembolism is common in children and young adults with sarcomas. Thromboses are frequently detected around the time of oncologic presentation, may be asymptomatic, and appear to be associated with a higher disease burden including metastasis and local tumor compression. Pediatric patients with sarcoma should be monitored closely for TEE. No significant financial relationships to disclose.