Phase II prospective study of dose-dense doxorubucin and ifosfamide in high-grade, locally advanced or metastatic soft tissue sarcoma (STS) patients

Abstract

20509 Background: High grade STS is expected to benefit from dose-dense doxorubicin/ifosfamide (doxo/ifo) sequential chemotherapy. This trial was designed using the two-stage Minimax design, in which 6 responses were needed among the first 19 pts to proceed to the second stage of the trial (a=0.05, β=0.20) to detect a 20% difference in RR as compared to expected 30%. Preliminary results of the first 20 pts are presented. Patients and Methods: Eligible pts had untreated, metastatic or locally advanced, high-grade STS, > 5 cm; age 18- 60 y; ECOG-PS 0–2; normal cardiac, renal and hepatic function; and signed informed consent. Pts were treated with doxo 30 mg/m2/d, D1–3, every 14 d, 3 cycles, followed by ifo 2.5 g/m2/d, D1–5, every 21 d, 3 cycles, with mesna and G-CSF support. Results: 20 pts were enrolled (7 in the neo-adjuvant setting with curative intent, 13 palliative). Median age: 39y (23–60); 5 synovial, 5 leiomyo, 4 sarcoma NOS, 2 MFH, 4 others. Primary site: 11 lower extremity; mean tumor size 13 cm. Median number of cycles was 3 for both drugs. 12 pts completed all planned chemotherapy cycles, and the mean relative dose intensity was 92±15% and 89±16% for doxo and ifo, respectively. Anemia was the most frequent toxicity (18 pts). 75 cycles were administered and grade 3/4 toxicities (CTC NCI 2.0) were observed in 27. G3 neutropenia was observed in 4 pts, none fatal. Thromboembolic events occurred in 4 pts (2 DVT, 2 PE). One pt presented a LVEF drop from 60% to 34% and developed symptomatic cardiac failure. Among 10 evaluable pts who completed chemotherapy, no response (CR or PR) was observed; eight pts had stable and 2 progressive disease. Surgery was performed in 6 pts, 4 of them limb-sparing, without changing the previous surgical plan. None of these pts presented complete pathologic response, with rate of necrosis ranging from 0–60%. At a median follow-up of 6 mo (1–16), 6 pts had died: 4 of disease progression, one sudden death (unknown cause) after 2 wks from the last chemotherapy cycle, and one patient died from pulmonary embolism. Conclusion: Sequential high-dose doxorubicin followed by ifosfamide failed in demonstrating any response in high grade STS, in addition to an unacceptable toxicity profile. Results of overall survival are pending. No significant financial relationships to disclose.