Fresh Approaches to RT Improve Outcomes in Retroperitoneal Sarcoma

Krisha J. Howell, MD

Assistant Professor

Department of Radiation Oncology Residency and Fellowship Training Program

Fox Chase Cancer Center

Philadelphia, Pennsylvania

Each year, 10% to 15% of patients with soft-tissue carcinomas receive a diagnosis of rare retroperitoneal sarcoma (RPS), an aggressive disease that typically recurs in 26% of cases and has a 47% to 67% five-year overall survival rate (Table).^1-3

New radiation therapies (RTs) hold potential to decrease treatment time and provide local control of RPS. At Fox Chase Cancer Center, we are investigating the adverse events and effectiveness of 3 novel RT approaches: hypofractionated radiotherapy, unidirectional low-dose-rate (LDR) brachytherapy, and radiation treatments combined with an enzyme inhibitor.

Our goal with these trials is to increase the possibility that patients will receive therapies customized to their tumors and schedules, provide them flexibility, and deliver the best clinical outcomes.

Higher Doses in Fewer Sessions Are Well Tolerated

We conducted a retrospective study of patients with RPS whose results showed that giving higher radiation doses over a shorter time frame, 20-39 Gy doses in 5 to 13 fractions (standard administration is 44.0-57.5 Gy in 22-28 fractions), resulted in similar acute adverse events compared with standard-course RT, which typically spans 5 to 6 weeks.¹

Our team analyzed data from patients with RPS with metastatic or uncontrolled primary disease who had either received standard neoadjuvant RT or undergone hypofractionated RT because of constraints that prevented standard therapy.

The initial hypofractionated data demonstrated tolerable acute toxicity, with no patients experiencing grade ≥3 toxicity within the intended period. Our team is currently developing a hypofractionated RT protocol for this disease setting.

Key findings, which we presented at the Connective Tissue Oncology Society 2018 Annual Meeting,¹ showed:

• None of the patients experienced grade ≥3 acute toxicities. In the hypofractionated RT group, 14.29% of patients experienced grade 2 toxicity of any kind; 31.58% of patients in the standard RT group experienced grade 2 toxicity of any kind.
• Analysis of acute gastrointestinal (GI) toxicities (upper and lower) showed that 14.29% of patients who received hypofractionated RT experienced GI toxicity (grade ≥1), and 47.37% of patients on standard RT experienced GI toxicity (grade ≥1); P = .1904.
• Twenty (77%) of the 26 patients had surgery after RT, as intended, with 2 in the hypofractionated RT group and 18 in the standard RT group. Surgical margins were positive in 1 of 2 patients in the hypofractionated RT group; 22.2% (4 of 18) in the standard RT group had positive margins.

A New Brachytherapy Approach for RPS

Fox Chase is a leading center in a registry trial of a unidirectional LDR brachytherapy implant, CivaSheet, that investigators are evaluating to improve local control of recurrent retroperitoneal sarcomas. The implant is administered after surgical resection at the margin of residual microscopic disease.

We are trying this approach because a previous trial combining preoperative external beam radiation therapy (EBRT) with postoperative, omnidirectional brachytherapy found substantial toxicity, most notably within the upper abdomen.

Initial data from our institution were presented at the 2018 Annual Meeting of the American Society for Radiation Oncology and demonstrated the utility of this approach to treating RPS.²

The prescribed LDR brachytherapy dose averaged 34.7 Gy (range, 20-60 Gy) and covered an average area of 6060 mm² (~58 sources). Palladium-103 (Pd-103) half-life was 16.99 days, delivering the therapeutic radiation dose over several weeks.

The highlights of our findings were 3-fold:

• Application of unidirectional, planar Pd-103 LDR brachytherapy technology is safe and easy.
• Unidirectional brachytherapy should be considered a standard option to escalate high doses to the highrisk margins of RPS after resection.
• 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 the maximum EBRT dose to the regional organs at risk.

Treatment included the following outcomes:

• Patients tolerated the implant well, with no complications following surgery.
• No source movement was reported in patients with RPS.
• One patient was treated for local control on the left side; however, existing inoperable right-sided disease was also present at the time of surgery.
• At a median follow-up of 15 months (8-24 months), 0 of 6 patients have demonstrated local recurrence, defined as the targeted field of brachytherapy radiation.
• One patient (1 of 6) had recurrence outside the surgical/brachytherapy field.
• There were no reported incidences of acute or late radiation toxicity despite the surrounding organs at risk, which included the small intestine, the ureter, and the kidneys.

Table. Exploratory RT Approaches in Soft Tissue Sarcomas^1-3

Adverse Events of Combining an Enzyme Inhibitor With Radiation

The Fox Chase team is one of the first to open a new NRG Oncology trial (NCT03217266) investigating the adverse events of the MDM2 enzyme inhibitor AMG-232 combined with radiation therapy to treat patients with soft tissue sarcoma.³

The tumor suppressor gene TP53 is a commonly mutated gene in cancer. Therefore, inhibition of MDM2, which regulates p53 protein activity, is a viable strategy to treat wild-type TP53 tumors with neoadjuvant radiotherapy.

In the experimental arm of the study, patients will receive AMG-232 orally on day 2, days 2 and 4, days 2 to 4, days 2 to 5, or days 1 to 5 of weeks 1 to 5. Patients will also undergo radiation therapy daily on weeks 1 to 5. Treatment will continue in absence of disease progression or unacceptable toxicity.

The primary outcome measures will be maximumtolerated dose and recommended phase II dosage at 4 weeks after treatment completion. Secondary and other measures include disease-free survival, overall survival, tumor cell genetic mutations, tumor volume changes, and clinical outcomes by genomic biomarkers.

Advances in Radiation Therapy Hold Promise for RPS

With these 3 studies, the Fox Chase research team is exploring important developments in treating patients with RPS with novel radiation therapies.

The key takeaways are:

• Initial retrospective data on hypofractionated radiation therapy demonstrate tolerable, acute adverse events in well-selected patients with retroperitoneal disease.
• Unidirectional LDR brachytherapy may be a safe option for escalating to a high dose after surgical resection to decrease recurrence risk at the microscopic margin.
• Investigators are evaluating neoadjuvant radiation combined with the MDM2 enzyme inhibitor AMG-232 to increase tumor response to neoadjuvant therapy.

References

1. Yankey H, Hollawell C, Howell K, et al. Completion rate and toxicity of hypofractionated radiotherapy for retroperitoneal and pelvic soft tissue sarcomas. Poster presented at: Connective Tissue Oncology Society 2018 Annual Meeting; November 14-17, 2018; Rome, Italy. ctos.org/Portals/0/PDF/2018%20CTOS%20Final%20Program.pdf.
2. Howell KJ, Meyer JE, Rivard MJ, et al. Initial clinical experience with uni-directional LDR brachytherapy in the treatment of retroperitoneal sarcoma. Int J Radiat Oncol. 2018;102(3)(suppl 1):e256. doi:10.1016/j.ijrobp.2018.07.842
3. MDM2 Inhibitor AMG-232 and Radiation Therapy in Treating Patients With Soft Tissue Sarcoma. clinicaltrials.gov/ct2/show/NCT03217266?term=amg-232&rank=2. Updated June 28, 2019. Accessed July 1, 2019.