Expert Elucidates the Role of Neoadjuvant Systemic Therapy in High-Risk Retroperitoneal Sarcoma

William W. Tseng, MD

Neoadjuvant systemic therapy was found to show a modest benefit in patients with retroperitoneal sarcoma, and the tumor response could be used as an indicator of disease biology to predict survival outcomes after surgery, according to results of a retrospective study.

In the multicenter Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) analysis, investigators sought to determine the frequency and potential predictors of tumor response to therapy and assessed the clinical outcomes of patients with high-risk RPS who were treated with neoadjuvant systemic therapy, followed by surgery.

In the analysis, data were collected retrospectively from patients with retroperitoneal sarcoma from 2008 to 2018 at 13 institutions within TARPSWG. A total 158 patients with retroperitoneal sarcoma were included, in whom a median 3 cycles of neoadjuvant chemotherapy was given. Results showed that 37 patients (23%) had a partial response (PR), 88 patients (56%) demonstrated stable disease, and 33 patients (21%) demonstrated progressive disease.

Moreover, patients with grade 3 dedifferentiated liposarcoma who received doxorubicin and ifosfamide, in comparison with another regimen, seemed to show a decrease in PR rates and an increase in overall survival (OS). In addition, patients with leiomyosarcoma who received doxorubicin, followed by dacarbazine, versus another regimen, had higher PR rates (37% vs 16%) and OS. However, these subtype-specific data did not reach statistical significance.

“Ultimately, these data help dispel the skepticism of neoadjuvant systemic therapy and it sets the stage for the prospective study that we are currently working on,” said lead study author William W. Tseng, MD.

In an interview with OncLive, Tseng, an associate professor of surgery, and leader of the Retroperitoneal Sarcoma Surgery Program at Keck School of Medicine at the University of Southern California, discussed the results of the retrospective TARPSWG study and the potential role of neoadjuvant therapy in high-risk retroperitoneal sarcoma.

OncLive: Could you discuss the patient population of retroperitoneal sarcoma and the rationale to conduct the TARPSWG study?

Tseng: This study investigated retroperitoneal sarcoma, which is a subset of soft tissue sarcomas. Soft tissue sarcomas are very rare and represent 1% of all adult cancers. Of these, 20% occur in the retroperitoneum., which is an anatomical space deep within the back of the abdomen.

The disease is very challenging to treat; these tumors can weigh 20to30 pounds; the largest I have removed was a 77-pound tumor. Due to their typically large size, these tumors often touch several vital structures within the abdomen, such as major blood vessels and organs. Surgery for these tumors are frequently long and challenging operations.

Unfortunately, reoccurrence rates in this patient population are high, and, in certain subtypes, there are also high distant metastatic rates. All in all, this cancer is tough to treat, and the outcomes are not good. Even at major referral centers, more must be done for patients with retroperitoneal sarcoma.

Could you discuss the design of the TARPSWG trial? What were your main objectives?

This was a retrospective study. It would have been more ideal to do a prospective study, which we are planning to do one in the near future. For this study, we wanted to get as many sarcoma referral centers involved as possible. Our overall question is: is there a benefit with neoadjuvant systemic therapy in retroperitoneal sarcoma?

The study was designed to be exploratory, so more work still has to be done. Additionally, the prospective study should give us the definitive answers we are seeking. In this exploratory study, we wanted to determine how many patients demonstrated a complete response (CR), PR, and progressive disease. We wanted to quantitate that data, especially since it has never been done before.

The secondary objective was to analyze the clinical outcomes of these patients, specifically recurrence rates, distant metastatic rates, and OS .

Could you elaborate on the findings from this analysis?

Our current results show that there is a modest response rate to systemic therapy. Prior to this study, when taking a look at the current available literature, there is quite a bit of skepticism in terms of whether or not systemic therapy, such as chemotherapy, is effective for this rare disease.

However, our exploratory study showed that chemotherapy does in fact work, although the response rate is modest. Overall, almost 30% of patients demonstrated a partial response to systemic therapy.

In terms of the clinical outcomes, we discovered that patients whose tumors showed progressive disease to neoadjuvant systemic therapy did much worse. Survival is almost 3-fold lower in these patients compared to those whose tumors had response. I think we can use this information to help counsel patients in terms of their prognosis.

I also think another question this raises is: should patients with progressive disease get second-line therapy? Surgery is an often challenging and some patients can have a prolonged recovery I personally believe that if the patient can tolerate it, we should try another line of therapy; however, this is still up for discussion.

What is the STRASS2 study?

STRASS2, the prospective study, is in the final stages of design and approval, so it has not started accruing patients yet. The first STRASS study was presented at the 2019 ASCO Annual Meeting; that trial tried to assess the benefit of neoadjuvant radiation therapy in retroperitoneal sarcoma, whereas STRASS2 will be focused on systemic therapy.

STRASS2 will be a randomized study, in which patients with retroperitoneal sarcoma are assigned to 2 arms: neoadjuvant systemic therapy followed by surgery versus surgery alone. This study will be limited to 2 subtypes: liposarcoma (high grade) and leiomyosarcoma.

Additionally, STRASS2 will focus on specific systemic therapy regimens in these 2 subtypes. This all ties back to our current study in which we found some indication of better outcomes with these hypothesized ideal regimens.

In closing, the data gathered in the current retrospective TARPSWG study can help assist us in the planning of the upcoming prospective STRASS2 study.

Reference

1. Tseng WW, Barretta F, Conti L, et al. Defining the role of neoadjuvant systemic therapy in high-risk retroperitoneal sarcoma: a multi-institutional TARPSWG study. J Clin Oncol. 2020;38(suppl 15):11513. doi:10.1200/JCO.2020.38.15_suppl.11513