Suman Malempati1, Brenda J Weigel2, Yueh-Yun Chi3, Jing Tian3, James R Anderson4, David M Parham5, Lisa A Teot6, David A Rodeberg7, Torunn I Yock8, Barry L Shulkin9, Sheri L Spunt10, William H Meyer11, Douglas S Hawkins12. 1. Department of Pediatrics, Oregon Health & Science University, Portland, Oregon. 2. Division of Pediatric Hematology/Oncology and Blood and Marrow Transplant, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota. 3. Department of Biostatistics, University of Florida, Gainesville, Florida. 4. Merck and Co, North Wales, Pennsylvania. 5. Department of Pediatrics, Children's Hospital of Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California. 6. Department of Pathology, Boston Children's Hospital, Boston, Massachusetts. 7. Department of Surgery, East Carolina University, Greenville, North Carolina. 8. Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. 9. Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee. 10. Stanford University School of Medicine, Stanford, California. 11. Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. 12. Pediatric Hematology/Oncology, Seattle Children's Hospital, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Abstract
BACKGROUND: The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children's Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose-intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin-like growth factor-1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone. METHODS: Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m2 ) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites. RESULTS: One hundred sixty-eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow-up of 2.9 years, the 3-year event-free survival rate was 16% (95% confidence interval, 7%-25%) with cixutumumab and 18% (95% confidence interval, 2%-35%) with temozolomide. CONCLUSIONS: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.
BACKGROUND: The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children's Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose-intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin-like growth factor-1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone. METHODS: Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m2 ) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites. RESULTS: One hundred sixty-eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow-up of 2.9 years, the 3-year event-free survival rate was 16% (95% confidence interval, 7%-25%) with cixutumumab and 18% (95% confidence interval, 2%-35%) with temozolomide. CONCLUSIONS: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.
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