Risk-Based Therapy for Local Control in Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcoma Shows Promise

R. Lor Randall, MD, FACS

When downstaging soft tissue sarcomas with neoadjuvant chemotherapy was gaining traction in adult patients, members of the Children’s Oncology Group thought that a particular pediatric subgroup could potentially benefit from a similar approach: non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).

In came a phase 3 trial (NCT00346164) using a risk-based treatment strategy for pediatric patients with NRSTS, in which they are assigned to undergo resection with or without radiation and with or without chemotherapy, depending on their risk of recurrence. Observation was also an option depending on the tumor grade and margin status.

Investigators hoped to reduce the standard amount of radiation in this population and potentially utilize neoadjuvant or adjuvant therapy as a method to downstage disease; the primary end point was event-free survival.

“[We thought] ‘Hey, we have this patient population, too. Maybe we can learn something from the experience in the adult population and build this trial out for NSTRS in children to young adults’,” said senior study author R. Lor Randall, MD, the David Linn Endowed Chair for Orthopedic Surgery, as well as professor and chair of the Department of Orthopedic Surgery at University of California Davis Comprehensive Cancer Center.

Results showed that of 95 eligible patients for resection following neoadjuvant therapy, 89 (93.7%) achieved R0/R1 margins. The overall local control rates after radiation were: R0 (97%), R1 (85%), and R2/unresectable (33%).

In an interview with OncLive^®, Randall discussed the intriguing risk-stratification–based trial in NSTRS and how the findings can be used to guide treatment decisions in this pediatric population.

OncLive^®: What was the rationale to conduct this study in NRSTS?

Randall: This study specifically looked at multimodality therapy in the treatment of patients with NRSTS. This is a group of tumors that, while relatively common in adults, is less common in young adults and children. This was a sort of first of its kind [study] for the Children’s Oncology Group, to look at risk stratification of these patients with NRSTS and treat them with surgery alone or chemoradiation, based upon size and histologic subtype and grade of tumor.

This is a phase 3 trial for children and young adults with NRSTS with a risk-based treatment with primary resection and lower-dose radiation to optimize local control. We want to minimize long-term toxicity with radiation in these patients, because radiation in young adults can [cause] sequelae, growth arrests, and it can cause problems with secondary malignancies, etc. We really are radiation adverse as much as possible. We were hoping that with up-front resection, or potentially downstaging with chemotherapy, we could tailor back the radiation doses that these patients see.

The impetus, again, was that this is a poorly studied group of patients. While soft tissue sarcomas are uncommon, they tend to be more common in adults than kids. The NRSTS [population] is made up of 4% of pediatric patients, and only 1% is adults. The overall incidence and prevalence are much higher in adults because there is just so much more cancer. NRSTS is relatively poorly understood in contrast to rhabdomyosarcoma, which is very well studied and has a lot of information. Over 10 years ago, the Children’s Oncology Group leadership got together to try and build out a risk-stratification clinical trial to do this.

What is important to note about the trial’s design in comparison to other studies in sarcoma?

There is risk stratification for the low-risk, intermediate-risk, and high-risk patients. In the low-risk group, there are a couple of arms, which we call “arm A” and “arm B,” in the intermediate-risk group, there is “arm C” and “arm D,” and the high-risk group are the [metastatic patients, which aren’t the focus right now].

For nonmetastatic patients, they [are labeled for] upfront gross resection. If it's a low-grade tumor, and they have microscopic margins, negative or positive, they will potentially get observation, but they also may get resection at the discretion of the surgeon if it's a high-grade tumor. However, if it's small, less than 4 or 5 cm with negative margins, they get observation. If it's small, but they have positive margins, they get adjuvant radiotherapy. If it's, again, grossly resected, but it's high-grade and it's greater than 5 cm, they get adjuvant chemoradiation. If its unresectable, then they get neoadjuvant chemoradiation, and then resection.

This is the first time this has been done for this patient population—this age demographic— where they get stratified based upon tumor grade, tumor size, and microscopic margin status, if they've undergone some sort of intervention. What we are able to show was that the patients were able to tolerate the chemotherapy, and they actually had excellent local control rates when they had a complete resection plus the neoadjuvant radiotherapy, which hadn't been established before. For those who needed adjuvant radiotherapy for compromised margins, their local control outcomes weren't quite as good as the others, but they were still very good.

What other results are you able to share from this study?

With this up-front treatment, we were able to get a 90% local recurrence rate with lower radiation doses than had been used previously. The neoadjuvant chemotherapy in these intermedia-risk, large, high-grade tumors, were able to downstage [the disease] such that R0/R1 resection was able to be achieved.

What this also highlights is that all soft tissue sarcomas are not alike. There are certain histologic subtypes, like synovial sarcoma, that tend to be good partial responses [to systemic therapy] and can be downstaged. Therefore, these patients—whether they’re young adults, pediatric, or older adults—if they have a large synovial sarcoma, consideration for systemic therapy contemporaneously with neoadjuvant radiotherapy is definitely a way to downstage the tumor to optimize local control.

Reference

1. Million L, Hayes-Jordan A, Chi Y-Y, et al. Local control for high-grade non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) assigned to radiation therapy on ARST 0332: a report from the Children’s Oncology Group. Inter J Rad Onc Bio Phys. Published online February 3, 2021. doi:10.1016/j.ijrobp.2021.01.051