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Retroperitoneal Sarcoma’s Radiation Therapy Options Are Expanding

For patients with rare retroperitoneal sarcomas (RPS), new radiation therapy (RT) options are being explored to decrease treatment time and provide local control of this aggressive disease, which typically has a 26% local recurrence rate and a 47–67% five-year overall survival rate.

Fox Chase Cancer Center radiation oncologist Krisha J. Howell, MD, is researching the side effects and effectiveness of three approaches: hypofractionated radiotherapy, uni-directional LDR brachytherapy, and combining radiation treatments with an enzyme inhibitor.Krisha J. Howell, MDKrisha J. Howell, MD

“Our goal with the different radiation therapy trials is to increase the possibility of patients receiving therapies that are customized to their tumor and schedules,” said Howell. “We have options here that go beyond standard treatments.”

Higher Doses in Fewer Sessions Are Well Tolerated

Howell’s retrospective study of RPS patients showed that giving higher dosages over a shorter time frame — 20–39 Gy doses in 5–13 fractions (standardly administered as 44–57.5 Gy in 22–28 fractions) — had similar acute side effects to standard course RT, which typically spans 5–6 weeks. Data was analyzed from RPS patients with metastatic or uncontrolled primary disease who either received standard neoadjuvant RT or underwent hypofractionated RT due to constraints preventing standard therapy.

“The initial hypofractionated data demonstrated tolerable acute-toxicity, with no patients experiencing grade 3 or higher toxicity within the intended time period.” said Howell, who presented the findings at CTOS in November 2018. The team is currently developing a hypofractionated RT protocol for the disease at this site.

Key Study Findings:

1. None of the patients experienced toxicity at grade 3 or higher. Within the hypofractionated RT group, 14.29% of patients experienced grade 2 toxicity of any kind, while 31.58% of standard RT patients experienced grade 2 toxicity of any kind.

2. Analysis of GI toxicities (upper and lower) showed 14.29% of hypofractionated patients experienced GI toxicity (grade ≥1), while 47.37% of standard RT patients experienced GI toxicity (grade ≥1); p = 0.1904.

3. Twenty (77%) of the 26 patients had surgery after RT, as intended, with two in the hypo-fractionated RT group and 18 in the standard RT group. Surgical margins were positive in 1 of 2 patients in the hypo-fractionated RT group, while 22.2% (4 of 18) in the standard RT group had positive margins.

A New Brachytherapy Approach for RPS

Howell and colleagues are participating in a registry trial of a uni-directional low-dose rate (LDR) brachytherapy implant, CivaSheet, being investigated to improve local control in the setting of recurrent retroperitoneal sarcomas. The implant is administered after surgical resection, at the margin of concerned residual microscopic disease.

“We are trying this approach to prevent the gastrointestinal toxicity found in previous trials of omni-directional brachytherapy implants.” Howell said.

The study is called “Initial Clinical Experience with Uni-Directional LDR Brachytherapy in the Treatment of Retroperitoneal Sarcoma.”

Howell’s poster at ASTRO shared these findings:

1. Application of uni-directional, planar Pd-103 LDR brachytherapy technology is safe and easy in initial findings.

2. Uni-directional brachytherapy should be considered as an option to escalate high doses to the high-risk margins of RPS after resection.

3. In the setting of previous therapy, the directional source distribution allows for re-irradiation or adjuvant brachytherapy boost radiation therapy in patients who have had maximum EBRT dose to the regional organs at risk.

Investigating Side Effects of Combining an Enzyme Inhibitor with Radiation for Soft Tissue Sarcomas

Howell’s team is one of the first to open a new NRG trial researching the side effects of the MDM2 enzyme inhibitor AMG-232 when combined with radiation therapy to treat patients with soft tissue sarcoma.

“Tumor suppressor gene p53 is a commonly mutated gene in cancer,” Howell said. “Therefore, inhibition of MDM2, which regulates the amount of p53, is a viable strategy to treat WT p53 tumors with neoadjuvant radiotherapy.”

Important highlights of treating retroperitoneal sarcomas with radiation:

1. Initial retrospective data on hypofractionated radiation therapy demonstrates tolerable, acute side effects in well-selected retroperitoneal patients.

2. Uni-directional LDR brachytherapy may be a safe option for escalating to a high dose after surgical resection to decrease recurrence risk at the microscopic margin.

3. Neoadjuvant radiation combined with MDM2 enzyme inhibitor AMG-232 is being investigated to increase tumor response to neoadjuvant therapy.

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