Investigating Risk-Based Treatment Strategies for Pediatric Non-Rhabdomyosarcoma Soft-Tissue Sarcoma


Key Takeaways

  • The trial stratified patients into low, intermediate, and high-risk groups based on tumor size, grade, and metastatic status.
  • Four treatment arms included surgery alone, surgery with radiotherapy, surgery with chemotherapy and radiotherapy, and a modified chemotherapy and radiotherapy regimen.
Robert Lawrence Randall, MD, FACS

Robert Lawrence Randall, MD, FACS

A phase 3 trial (NCT00346164; ARST 0332) is investigating risk-based treatment strategies for patients under the age of 30 with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS). This trial seeks to address the unique challenges posed by NRSTS in the pediatric and young adult population, according to Robert Lawrence Randall, MD, FACS.

“Because NRSTS is relatively uncommon in children compared with adults, there have been fewer studies focused on this group within the Children’s Oncology Group,” Randall explained.

The trial enrolled patients with histologically confirmed NRSTS and stratified them into three risk groups based on tumor size, grade, and metastatic status. The primary objectives were to assess event-free survival, overall survival, and patterns of treatment failure using a risk-based strategy.

Patients were assigned to one of four treatment arms: surgery alone, surgery with radiotherapy, surgery with chemotherapy and radiotherapy, or a modified chemotherapy and radiotherapy regimen. The study aimed to tailor treatments to the risk level of each patient, minimizing exposure to aggressive therapies when possible while maintaining effective disease control.

In an interview with OncLive®, Randall elaborated on the importance of this risk-based approach, emphasizing the need to avoid overtreatment, particularly in young patients, to reduce long-term adverse effects while ensuring optimal outcomes. Randall, a leading expert in sarcoma treatment, provided insights into the potential clinical implications of this research and the importance of multidisciplinary collaboration in managing NRSTS.

Randall is The David Linn Endowed Chair for Orthopedic Surgery, chair of the Department of Orthopedic Surgery, and professor in the Department of Orthopedic Surgery at The University of California, Davis in Sacramento.

OncLive: What is the rationale for conducting this phase 3 study?

Randall: ARST 0332 was a study that looked at risk-based treatment strategies for NRSTS in patients less than 30 years of age. The most common soft tissue sarcoma in the pediatric population is rhabdomyosarcoma. In the adult population, it’s NRSTS. But in the paradigm of the Children’s Oncology Group, because so many of the soft tissue sarcomas are rhabdomyosarcoma, we use the nomenclature of NRSTS, to be specific, because the biology and the treatment of rhabdomyosarcoma is relatively distinct.

With that as a backdrop, there have not been a lot of studies in the Children’s Oncology Group looking at NRSTS, because they are just not that common relative to adults. They’re [also] a very heterogeneous group of [diseases]; there are many histologic subtypes and grades. It’s been a challenge to put together a study, but thanks to Sheri L. Spunt, MD, and our colleagues at the Children’s Oncology Group we were successful in opening this study after years of design and enrollment.

What was the primary goal of this study?

We wanted to assess event-free survival and overall survival and the pattern of treatment failure in patients with NRSTS treated with this risk-based strategy. So again, these were patients less than 30 years of age with a good performance status, and they were all newly diagnosed [according to the] World Health Organization criteria for soft tissue sarcomas. These included a variety of different histologic subtypes. Patients were assigned to three risk groups: a low-risk group, which included patients with nonmetastatic disease who had an R0 or R1 resection in addition to low-grade disease or disease that was less than 5 cm in diameter; an intermediate group, which comprised patients with nonmetastatic disease who also underwent an R0 or R1 resection but had high-grade disease or disease that was greater than 5 cm; and a high-risk group, which included patients with metastatic disease.

What was the design of this study?

We had about 529 evaluable patients enrolled from February 2007 to February 2012. There were four treatment arms. Group A was surgery only. Group B [in addition to surgery] also received 55.8 Gy of radiotherapy. Group C was treated with chemotherapy with an additional 55.8 Gy of radiotherapy. Group D received chemotherapy with a dose reduction of 45 Gy to see if decreased radiotherapy provided adequate local control.

What were some of the findings observed?

The 5-year EFS and OS rates for the low-risk group were quite good at 89% and 96%, respectively. For the intermediate-risk group, those respective rates were 65% and 79%. For the high-risk group, the rates were 21% and 35%. There were some AEs, but the safety profile was pretty well tolerated.

This does highlight that risk stratification is appropriate for patients with NRSTS less than 30 years of age. Most patients with low risk can be cured without any adjuvant therapy, meaning with surgery alone. Radiotherapy may also be adequate in controlling the disease and neoadjuvant chemoradiation and delayed surgery permits less radiotherapy exposure for optimizing local control, decreasing complications, and hopefully improving survival.

What is the significance of risk-based therapy for this population?

We try to avoid radiation therapy in children as much as we can because of the morbidities associated with radiation. Having those small, lower grade tumors be able to be excised and treated just with surgery and having an excellent outcome is a finding in and of itself. But then the idea of being able to tailor back radiotherapy and showing that we still get adequate local control as well as systemic management [is even better]. We [also] like to avoid cytotoxic chemotherapy in kids. For groups A and group B, avoiding chemotherapy and still having reasonable local control is [an important] finding.

When you’re deciding whether a patient may just need surgery alone, or if they need an additional therapy beyond that, [it is important to have a] multidisciplinary approach mapped out from the get go.

It is very important that these patients, [upon diagnosis, get reviewed by all of the tumor board panel which includes surgeons, radiation therapists, pediatric and/or medical oncologists, and then allied support staff, which are really critical as well. With this data we can say that smaller low-grade tumors do not need these other modalities, but for these larger higher grade lesions that are more at risk, getting everyone aligned upfront for neoadjuvant therapy, and hopefully dose reduction of radiation can really improve the delayed cytotoxic effects of some of the adjuvant therapies.

What advice would you give providers based on the results of this trial?

Although this study was [conducted with] patients less than 30 years of age, I do think it is generalizable to older patients as well. However, we have no data to support that statement. [The main message for] medical oncologists is that patients with relatively low risk can potentially avoid cytotoxic therapy and even potentially radiotherapy.


  1. Observation, radiation therapy, combination chemotherapy, and/or surgery in treating young patients with soft tissue sarcoma. April 28, 2022. Accessed July 1, 2024.
  2. Spunt SL, Million L, Chi YY, et al. A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children’s Oncology Group prospective study. Lancet Oncol. 2020;21(1):145-161. doi:10.1016/S1470-2045(19)30672-2

Related Videos
Hannah Walker-Mimms, MS
Christina L. Roland, MD, MS, FACS
Christina L. Roland, MD, MS, FACS
Misako Nagasaka, MD
Meredith McKean, MD, MPH
Damon R. Reed, MD
Brian A. Van Tine, MD, PhD
Breelyn A. Wilky, MD
Damon R. Reed, MD