Pazopanib Associated With Higher Wound Complication Rates in Non-rhabdomyosarcoma Soft Tissue Sarcoma

The addition of pazopanib (Votrient) to neoadjuvant chemotherapy and radiotherapy was associated with a higher rate of wound complications in patients with non-rhabdomyosarcoma soft tissue sarcoma, according to data from a subgroup analysis of the phase 2/3 ARST1321 trial (NCT02180867).¹

The multicenter, open-label trial evaluated the addition of pazopanib to neoadjuvant radiotherapy with ifosfamide plus doxorubicin in pediatric and adult patients with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma that was larger than 5 cm in diameter and intermediate or high grade. Previously reported findings from the randomized portion of the trial showed that 58% of patients in the pazopanib group (n = 24) experienced a 90% pathological response or higher, compared with 22% of patients in the control group treated with radiotherapy and chemotherapy alone (n =18).²

The subgroup analysis included 85 evaluable patients from the dose-finding and randomized portions of ARST1321 who received radiotherapy with or with pazopanib, and with or without chemotherapy. Forty-one percent of all patients experienced postoperative wound complications, and 57% were grade 3 events. Additionally, patients who were randomly assigned to receive pazopanib plus radiotherapy and chemotherapy had a 50% would complication rate; 47% of these complications were grade 3. Moreover, patients given pazopanib with radiotherapy experienced a 59% wound complication rate, compared with 25% for those treated with radiotherapy alone. Wound complications occurred at a median of 35 days following surgery.¹

“Whether you are a medical oncologist, a pediatric oncologist, or radiation oncologist, [if you are] using pazopanib for any setting—not just for non-rhabdomyosarcoma soft tissue sarcoma—that involves surgery, be aware of the wound healing issues and make sure you are [communicating with] the surgeon,” R. Lor Randall, MD, FACS, said.

In an interview with OncLive^®, Randall, the David Linn Endowed Chair for Orthopedic Surgery, the chair of the Department of Orthopedic Surgery, and a professor at UC Davis Comprehensive Cancer Center in Sacramento, California, discussed the use of neoadjuvant pazopanib in patients with non-rhabdomyosarcoma soft tissue sarcoma, expanded on findings from the subgroup analysis of ARST1321, and detailed the implications of these findings.

OncLive: What was the rationale conducting this subgroup analysis on wound complication rates in patients with non-rhabdomyosarcoma soft tissue sarcoma who were treated with neoadjuvant pazopanib?

Randall: This is part of the ARST 1321 trial, using neoadjuvant pazopanib in non-rhabdomyosarcoma soft tissue sarcoma. This is a subgroup analysis looking at wound complications. Pazopanib is a TKI that has been shown to be associated with wound complications, and we were able to show that [wound complication rates] were not insignificant in this study. Therefore, [these complications] need to be a consideration for the use of this drug in patients with non-rhabdomyosarcoma soft tissue sarcoma.

What were the key findings from the subgroup analysis regarding wound complication rates?

There were 85 evaluable patients, and 41% experienced some sort of wound complications. Most of those [57%] were grade 3. A grade 3 [complication] generally means that a surgical intervention is necessary to address that wound complication. A grade 1 [complication] is something that is minor that may deviate [recovery] a little bit but doesn’t really require any intervention. A grade 2 [complication] is something that may be treated with something such as antibiotics. Grade 4 means a life-threatening [complication].

Grade 3 complications are serious because it means taking patients back to surgery for repeat incision and drainage. The use of pazopanib, radiation, and ifosfamide/doxorubicin had a 50% [wound] complication rate, [47%] of which were grade 3; that's not insignificant.

What do these findings mean for the use of pazopanib in patients with non-rhabdomyosarcoma soft tissue sarcoma?

While there may be some benefits to pazopanib, it does come at a cost for wound complications. Surgeons need to be very vigilant in communicating with their medical and pediatric oncologists, as well as radiation therapists, in the multimodality treatment of these patients.

Are there current guidelines around the use of pazopanib? What are the current selection criteria for treatment with the TKI?

In terms of actual use of [pazopanib], this study showed some improvement [in responses], but it hasn't been entrenched in the conventional management of non-rhabdomyosarcoma soft tissue sarcoma. For more aggressive cases, it is sometimes used. When it is employed, we recommend waiting at least 2 weeks after surgery before any resumption, and [patients should] visit the orthopedic oncologist before they resume any adjuvant therapy.

References

1. Kayton ML, Weiss AR, Xue W, et al. Neoadjuvant pazopanib in nonrhabdomyosarcoma soft tissue sarcomas (ARST1321): A report of major wound complications from the Children's Oncology Group and NRG Oncology. J Surg Oncol. 2023;127(5):871-881. doi:10.1002/jso.27205
2. Weiss AR, Chen Y-L, Scharschmidt TJ, et al. Pathologic response in children and adults with large unresected intermediate- or high-grade soft tissue sarcoma receiving preoperative chemoradiation with or without pazopanib (ARST1321; PAZNTIS): a multicentre, randomised, open-label, phase 2 trial. Lancet Oncology. 2020;21(8):1110–1122. doi:10.1016/S1470-2045(20)30325-9