Clear cell sarcoma (CCS) is a rare but highly malignant tumor of soft tissues often appearing as a small tender mass in the deep tissues of the distal extremities. We have studied 17 patients with such lesions treated since 1986 and have a high incidence of local recurrence and metastasis with a survival rate of only 47% despite surgery and for many of the patients, adjuvant therapy. The purpose of this article is to warn the readers of the dangers related to treating this seemingly benign lesion and urge them to perform wide surgery and utilize adjuvant therapy.
Purpose
We performed a phase I trial of the addition of sorafenib to a chemoradiotherapy regimen in patients with high-risk (intermediate/high grade, >5 cm) extremity soft tissue sarcoma (STS) undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess response to treatment.
Experimental Design
Patients were treated at increasing dose levels of sorafenib (200 mg daily, 400 mg daily, 400 mg BID) initiated 14 days prior to 3 preoperative and 3 postoperative cycles of epirubicin/ifosfamide. 28 Gy of radiation was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was performed at baseline, after 2 weeks of sorafenib, and prior to surgery. The imaging data were subjected to quantitative pharmacokinetic analyses.
Results
18 subjects were enrolled, of which 16 were evaluable. The MTD of sorafenib was 400 mg daily. Common grade 3–4 adverse events included neutropenia (94%), hypophosphatemia (75%), anemia (69%), thrombocytopenia (50%), and neutropenic fever/infection (50%). 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker ΔKtrans after 2 weeks sorafenib correlated with histologic response (R2=0.67, p = 0.012) at surgery.
Conclusion
The addition of sorafenib to preoperative chemoradiotherapy is feasible and warrants further investigation in a larger trial. DCE-MRI detected changes in tumor perfusion after 2 weeks of sorafenib and may be a minimally-invasive tool for rapid assessment of drug effect in STS.
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