Risk-Stratification Can Be Used to Prevent Overtreatment in Children, AYA Patients With Synovial Sarcoma

The use of risk stratification in children and adolescent and young adult (AYA) patients with synovial sarcoma is an essential approach to appropriately tailoring local and systemic therapy and avoiding overtreatment, according to results of a subanalysis of the phase 3 ARST0332 trial (NCT00346164).¹

The phase 3 Children’s Oncology Group study, which used a risk-based treatment strategy for pediatric patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), assigned patients to undergo resection with or without radiation and with or without chemotherapy, depending on their risk of recurrence. Observation could also be chosen, depending on 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.

Most recently, data looking at the synovial sarcoma subset of the trial uncovered new findings about risk-stratified treatment choices in the population, which mainly comprises children and AYA patients. Risk stratification was based on metastasis, tumor grade, tumor size, and extent of surgical resection.

Based on their disease risk, patients with synovial sarcoma younger than 30 years received either surgery alone (arm A; low risk), radiation (B; low risk), chemoradiation (C), or neoadjuvant chemoradiation followed by surgery and adjuvant radiation (arm D). In arms C and D, patients were considered intermediate risk if they had no metastases and high risk if they had metastases.

At a median follow-up of 6.8 years, findings showed that of the 138 evaluable patients with synovial sarcoma, the estimated 5-year event-free survival (EFS) rates were 82%, 70%, and 8% for low-, intermediate-, and high-risk patients, respectively. The 5-year overall survival (OS) rates were 98%, 89%, and 13%, respectively.

The data suggest that patients with nonmetastatic synovial sarcoma have favorable outcomes even with less frequent use of radiation and at lower doses, explained study author R. Lor Randall, MD.

In an interview with OncLive, Randall, 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, discussed the recent findings within the synovial sarcoma subset of the phase 3 ARST0332 trial, and how these data will have a clinical impact on those treating this younger patient population.

OncLive: Please share some background to the ARST0332 trial and the subset analysis.

Randall: This is the Children's Oncology Group study that has looked at NRSTS soft tissue sarcoma. In the children's paradigm, we stratify soft tissue sarcoma into rhabdomyosarcoma and NRSTS. Then, within NRSTS, there are a plethora of different potential diagnoses. NRSTS, through the lens of pediatric oncology, is relatively less common than rhabdomyosarcoma.

In the adult world, NRSTS is the predominant force. Therefore, when you talk to medical oncologists, they tend to reference them just as soft tissue sarcomas, and they don't distinguish rhabdomyosarcoma versus NRSTS, because there is a very small percentage of rhabdomyosarcomas in adults.

This is a study spearheaded by Dr. Sheri L. Spunt, out of Stanford University School of Medicine. This really is her brain trust and I have been privileged to be part of the local control committee for this.

We looked at a subset analysis of synovial sarcomas in this study, and the crux of the paper is this risk stratification. Within these different breakdowns of nonmetastatic and metastatic disease, we basically [further divide patients as] low risk, intermediate risk, and high risk. Because this study was able to accrue many patients, we were able to get a large number of [patients with] synovial sarcomas. This study was designed to enroll patients up to age less than 30 years.

This was the most common soft tissue subtype. Synovial sarcoma tends to be considered the AYA soft tissue sarcoma; most soft tissue sarcomas are in patients over 40 years. They are not synovial sarcomas; they are pleomorphic sarcomas, myxoid liposarcomas, and a variety of other types of soft tissue sarcomas. However, synovial sarcoma tends to be the outlier in that it watersheds with children and young adults, so that's probably why we had a large number of patients.

Not surprisingly, the high-risk patients, which were the metastatic patients, had an overall 5-year EFS rate of 8%, which is obviously very, very low, vs those who had low-risk disease, which were the smaller, contained lesions that did not require systemic therapy and the overall EFS rate for those was 82%, which is pretty good.

However, the meat of the argument is the intermediate-risk group, which is a larger tumor, so they get radiation, chemotherapy, and local control with surgery. The [5-year EFS rate in the] intermediate-risk group was 70%, which is upwards of what historically has been the reported outcomes, which is around 60%.

The take-home message from this study is that we were able to avoid radiation in low-risk patients without adverse events, which is important finding. We were able to dose-modify the radiation to a slightly lower doses in a cohort of patients and still not affect EFS. Radiation in children and young adults is not tolerated as it is in older adults, because they have their whole life ahead of them. If they have open growth plates [for example], it will affect growth.

The radiation dose in younger patients, puts them at increased risk for secondary radiation and new soft tissue sarcomas later in life. Therefore, it's nice to be able to tailor back the radiation. The downside is that, not surprisingly, the outcome is very poor for patients with advanced metastatic disease, and we weren't able to move the needle on that.

When you have a patient with synovial sarcoma in front of you, how are you determining what risk they fall into to be able to treat them effectively? 

If they staged up, and if they're nonmetastatic, sometimes these tumors have been taken out by a surgeon, because they didn't suspect it was a soft tissue sarcoma. Therefore, if it's taken out and it's low grade, and the margins are OK, then they'll get observation. If the tumor is high grade, and the margin is compromised, then they go down and potentially go into this re-resection or not based upon the margin assessment. For tumors that are unresected that present and are also biopsy-proven to be high grade, and are greater than 5 cm, then they're going to get radiation as well as surgery.

What you can do is plug in the parameters of the patient, size of the tumor, grade of the tumor, and whether or not it's been grossly resected up front, and that stratifies them into low risk vs high risk. Then for high risk, it's obviously the patients with metastatic disease.

What is it about synovial sarcoma that makes it particularly more challenging to treat compared with some of the other sarcoma types?

The nice thing about this paper is that, for the intermediate-risk group, we have been able to demonstrate that they do a little bit better than the big grouping of soft tissue sarcomas overall. Now, some of that may be biologic-specific, but some of that may also be host-specific; perhaps the biology and the host age are intertwined there. However, the point is that because these patients tend to be younger than the rest of the cohort, in NRSTS, they are more resilient in terms of the systemic therapy. You probably don't get censoring and you'll get toxicity associated with chemotherapy.

You mentioned not being able to move the needle for high-risk patients. What are the next steps of this study or other areas of research looking to improve outcomes for those specific patients?

It does beg the question of potentially more aggressive local control, if you will, of the metastatic foci. We have talked previously about these patients with osteosarcoma with oligometastatic disease, where we know that those patients do poorly as well, with ways by which we can better manage pulmonary metastases with a variety of techniques.

The same can be applied to the synovial sarcomas. We now have been able to demonstrate quite nicely that despite very attentive risk stratification, and maximizing systemic chemotherapy, these patients do poorly.

A basic question of, "Should we be doing other methods of local control either in the form of surgery, or ablations, or something of that sort, if we really want to give a small number of patients a chance of survival?"

Are there any other takeaways that might be important for the practicing physician?

For the practicing medical oncologist for synovial sarcoma diagnoses, or patients who present to a medical oncologist with a lesion that is concerning for soft tissue sarcoma, one should we should think about synovial sarcoma, and therefore, cross reference with pediatric oncologists. This is speculative, but they probably have the largest experience with synovial sarcoma, at least at major centers. They should be a point of reference. They can talk about dose modification of the radiotherapy, and they can talk about the chemotherapy.

Reference

1. Venkatramani R, Xue W, Randall RL, et al. Synovial Sarcoma in Children, Adolescents, and Young Adults: A Report From the Children’s Oncology Group ARST0332 Study. J Clin Oncol. Published online October 8, 2021. doi:10.1200/JCO.21.01628