@article{b0c0170c9ca34af2a134162c547446f8,
title = "Increased local failure for patients with intermediate-risk rhabdomyosarcoma on ARST0531: A report from the Children's Oncology Group",
abstract = "Background: The objective of this study was to evaluate local control for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531. Methods: This study analyzed 424 patients with intermediate-risk RMS. Patients were randomized to chemotherapy with either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC alternating with vincristine and irinotecan. With the goal of improving local control, radiation therapy (RT) was delivered early at week 4 and was concurrent with irinotecan in the experimental arm. Individualized local control plans for children 24 months old or younger were allowed. Local failure on ARST0531 was compared with local failure on the preceding COG intermediate-risk study, D9803. Results: For patients with group I/II alveolar RMS (n = 55), the 5-year cumulative incidence of local failure was 13.4%; for group III alveolar RMS (n = 141), it was 20.2%; and for group III embryonal RMS (n = 228), it was 27.9% (P =.03). Among patients with group III disease, local failure did not differ by histology, site, nodal status, RT modality, or treatment arm. Local failure was worse for a tumor size >5 cm (32.3% vs 16.7%; P =.001). Among patients with group III embryonal RMS, local failure was higher on ARST0531 than D9803 (27.9% vs 19.4%; P =.03). After the exclusion of patients 24 months old or younger or patients who did not receive radiation, local failure remained significantly increased on ARST0531 (P =.02). After adjustments for clinical prognostic factors, event-free survival and overall survival were worse on ARST0531 (P =.004 and P =.05, respectively). Conclusions: Despite interventions designed to enhance local control, local control was inferior on ARST0531 in comparison with D9803. The reason for this is unclear, but it could be the reduced cyclophosphamide dose on ARST0531.",
keywords = "clinical trial, cyclophosphamide, local control, radiation therapy, rhabdomyosarcoma",
author = "Casey, {Dana L.} and Chi, {Yueh Yun} and Donaldson, {Sarah S.} and Hawkins, {Douglas S.} and Jing Tian and Arndt, {Carola A.} and Rodeberg, {David A.} and Routh, {Jonathan C.} and Lautz, {Timothy B.} and Gupta, {Abha A.} and Yock, {Torunn I.} and Wolden, {Suzanne L.}",
note = "Funding Information: This research was supported by the Children's Oncology Group (grants U10CA180886, U10CA180899, U10CA098543, and U10CA098413), the St. Baldrick's Foundation, the Seattle Children's Foundation (from Kat's Crew Guild through the Sarcoma Research Fund), the Imaging and Radiation Oncology Core Group and Quality Assurance Review Center, and the National Institutes of Health (grant P30 CA 008748). Although two-thirds of children with intermediate-risk rhabdomyosarcoma (RMS) will become long-term survivors, local failure remains the dominant form of initial relapse and is a major obstacle to a cure. Prior strategies explored by the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group (COG), including radiation therapy (RT) dose escalation via a hyperfractionated approach and technical advances in imaging and RT, have not resulted in a difference in local control, although early data suggest that proton therapy may improve toxicity rates. Because of the young patient age and extensive morbidity associated with salvage options after local relapse, it is imperative to explore new strategies to improve local control. One goal of the most recent COG clinical trial for intermediate-risk RMS, ARST0531, was to maximize local control via the early introduction of RT at week 4 and concurrent delivery of RT with irinotecan, a potential radiosensitizer. The incorporation of vincristine and irinotecan (VI) into the systemic therapy backbone also allowed for reduced systemic doses of cyclophosphamide with the intent of minimizing both acute and late toxicities such as hemorrhagic cystitis and infertility. With such interventions designed to improve local control, we hypothesized that local control on ARST0531 would be improved in comparison with historical cohorts. Thus, the objective of the current analysis was to determine the local failure rate on COG ARST0531 and compare it with the rate in the immediately prior COG study for intermediate-risk RMS, D9803. The objective of this study was to evaluate local control for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531. Funding Information: This research was supported by the Children{\textquoteright}s Oncology Group (grants U10CA180886, U10CA180899, U10CA098543, and U10CA098413), the St. Baldrick{\textquoteright}s Foundation, the Seattle Children{\textquoteright}s Foundation (from Kat{\textquoteright}s Crew Guild through the Sarcoma Research Fund), the Imaging and Radiation Oncology Core Group and Quality Assurance Review Center, and the National Institutes of Health (grant P30 CA 008748). Funding Information: Douglas S. Hawkins reports grants and nonfinancial support from Loxo Oncology, Bayer, and Bristol-Myers Squibb; nonfinancial support from Celgene; and grants from Merck Sharpe Dohme, Lilly, Eisai, GlaxoSmithKline, Novartis, and Sanofi outside the submitted work. Carola A. Arndt reports stock ownership in Merck and Pfizer outside the submitted work. Torunn I. Yock reports grants from Protom, Elekta, IBA, and MIM outside the submitted work. Suzanne L. Wolden reports personal fees from Y-mAbs Therapeutics outside the submitted work. The other authors made no disclosures. Publisher Copyright: {\textcopyright} 2019 American Cancer Society",
year = "2019",
month = sep,
day = "15",
doi = "10.1002/cncr.32204",
language = "English (US)",
volume = "125",
pages = "3242--3248",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "18",
}