(P 162) LONG TERM SAFETY AND EFFICACY OF COMBINED DOXORUBICIN-IFOSFAMIDE CHEMOTHERAPY WITH PREOPERATIVE HYPOFRACTIONATED RADIOTHERAPY IN MARGINALLY RESECTABLE SOFT TISSUE SARCOMAS

Objective: There is no consensus on most efficient treatment for marginally resectable soft tissue sarcomas (STS) of the extremities and trunk wall to achieve the highest number of R0 resections. Based on our phase II UN-RESARC trial we implemented multidisciplinary treatment where patient received 5x5 Gy radiotherapy combined with doxorubicin-ifosfamide chemotherapy. Here we describe the long-term safety of this treatment approach along with the ratio of conservative surgeries with negative microscopic margins (R0).

Methods: The patients with marginally resectable STS were treated within single-arm prospective clinical trial and routine clinical practice according to the same regimen afterwards. The patients received the first course of AI chemotherapy - doxorubicin 75 mg/sqm and ifosfamide 10 g/sqm followed by 5x5 Gy radiotherapy and two additional courses of AI chemotherapy in the gap between radiotherapy and delayed surgery. Surgery was planned after 9 weeks of neoadjuvant chemo-radiotherapy. Adult patients were treated with radical intent. The primary endpoint was to assess the number of patients in whom R0 en-bloc radical resection was achieved. The secondary endpoint was to describe the safety of treatment. Patients treated with other chemoregimens, fractionation regimens, or in a palliative setting were not eligible for analysis. Common Terminology Criteria for Adverse Events (CTCAE) 4.0 was used to describe toxicity. Descriptive statistics were used to summarize the demographic and clinical characteristics. Median follow-up was estimated by Kaplan-Meier analysis with the reversed meaning of status indicator. Relapse-free survival (RFS) was calculated from the day of resection to the last follow-up, death without relapse, confirmed local relapse, or distant metastases. Clinical local recurrence was confirmed with CT or MRI and biopsy. Overall survival (OS) was calculated from the date of surgery to the last follow-up or death. Data cut-off was 24th June 2023. All statistical analyses were performed using R version 4.2.3.

Results: Eighty-two patients with median age of 58 years (25-76) met the eligibility criteria. Six patients had resectable lung metastases at baseline. Most common sarcoma subtypes diagnosed in these patients were undifferentiated pleomorphic sarcoma (n=33; 40.2%), myxofibrosarcoma (n=15; 18.3%), and malignant peripheral nerve sheath tumor (n=9; 11%). Median tumor diameter was 14.85 cm. 43% of patients presented with anemia of chronic disease. R0 resections were achieved in 57 (69.5%) patients while only 3 (3.7%) patients had to undergo limb amputations. Surgery-related adverse events according to Clavien-Dindo classification were reported in 8 (10%) patients in grade 3a and in 2 (2.4%) patients in grade 3b. Systemic therapy-related adverse events of grade ≥3 were reported in 39 (47.5%) patients, with most common lymphopenia in 29 (35%) patients, neutropenia in 10 (12%), and febrile neutropenia in 4 (4.9%) patients. Due to toxicity doxorubicin dose was reduced in 19 (23.2%) patients and 4 (4.9%) patients received only one cycle of chemotherapy. No life-threatening complications were reported after surgery. Wound dehiscence occurred in 16 (20%) cases, but severe bleeding only in 3 (3.7%) patients. In total 10 (12%) patients required reoperation. Wound complications as per O’Sullivan criteria occurred in 22 (27%) patients. Nine patients (11%) experienced local recurrence. The median RFS was 20.8 (10.9 - 40) months with 43% of patients free of recurrence at 3 years. Median follow-up was 34.2 months, and median OS was not reached (3-year OS rate was 58%); while the longest overall survival was 81.6 months. None of the patients died before the surgery.

Conclusion: Although preoperative radiotherapy is usually associated with a higher risk of wound complications than postoperative radiotherapy and there is a fear of anthracycline administration with radiotherapy, hypofractionated radiotherapy combined with AI chemotherapy allows safe and efficient surgery in patients with marginally resectable STS.