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Addition of Pazopanib to Preoperative Chemoradiotherapy in Children and Adults With Soft-Tissue Sarcoma


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In an interim analysis of a joint Children’s Oncology Group and NRG Oncology phase II trial (ARST1321) reported in The Lancet Oncology, Aaron R. Weiss, DO, and colleagues found that the addition of pazopanib to preoperative chemoradiotherapy significantly increased the rate of pathologic near-complete response in children and adults with large intermediate- or high-grade soft-tissue sarcoma.

Aaron R. Weiss, DO

Aaron R. Weiss, DO

Study Details

The multicenter open-label trial included 81 adults (aged ≥ 18 years) or children (aged between 2 and < 18 years) from sites in the United States and Canada with newly diagnosed trunk or extremity chemotherapy-sensitive soft-tissue sarcoma > 5 cm in diameter. Patients were randomly assigned between July 2014 and October 2018 to receive preoperative chemoradiotherapy with (n = 42) or without (n = 39) pazopanib given at 350 mg/m2 once daily in children and at 600 mg once daily in adults. Pazopanib was started concurrently with the first cycle of chemotherapy and continued throughout pre- and postoperative treatment, excluding the 7-day period before surgery and for at least 14 days after surgery. Patients received ifosfamide (2.5 g/m2 per dose on days 1–3 with mesna) and doxorubicin (37.5 mg/m2 per dose on days 1 to 2) at 3-week intervals, with 45-Gy radiotherapy beginning with the start of the second cycle of chemotherapy, followed by surgical resection at week 13. The primary outcome measure was ≥ 90% pathologic response at week 13 in the per-protocol population.

Responses

A total of 42 patients were evaluable for response. Reasons for exclusion from analysis included discontinuation from protocol therapy prior to surgery and missing pathology review. At the planned second interim analysis, median follow-up among evaluable patients was 0.8 years in the pazopanib group and 1.0 years in the control group. 

A 90% pathologic response or higher was observed in 14 (58%) of 24 patients in the pazopanib group vs 4 (22%) of 18 patients in the control group (P = .020), with a between-group difference of 36.1% (83.8% confidence interval [CI] =16.5%–55.8%). The 83.8% confidence interval excluded 0, with the improvement due to the addition of pazopanib thus crossing the predetermined efficacy boundary and trial enrollment being halted.

Radiographic evaluation at week 13 prior to surgery showed that 14 (52%) of 27 patients in the pazopanib group and 14 (58%) of 24 patients in the control group had a partial response or better.

Adverse Events

The most common grade 3 or 4 adverse events were leukopenia (43%), neutropenia (41%), and febrile neutropenia (41%) in 37 patients in the pazopanib group and neutropenia (9%) and febrile neutropenia (9%) in 35 patients in the control group. Pediatric and adult patients had similar rates of grade 3 and 4 toxicity. Pazopanib-related serious adverse events occurred in 59% of patients, with the most common being febrile neutropenia (10 patients; 27%). No treatment-related deaths were reported.

The investigators concluded, “In this presumed first prospective trial of soft-tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of [pathologic] near-complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft-tissue sarcoma. The comparison of survival outcomes requires longer follow-up.”

Dr. Weiss, of the Department of Pediatrics, Maine Medical Center, Portland, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the National Institutes of Health, St. Baldrick’s Foundation, and Seattle Children’s Foundation. For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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