Phase I trial of neoadjuvant conformal radiotherapy plus sorafenib for patients with locally advanced soft tissue sarcoma of the extremity Journal Article

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Authors: Canter, R. J.; Borys, D; Olusanya, A.; Li, C. S.; Lee, L. Y.; Boutin, R. D.; Christensen, S. D.; Tamurian, R. M.; Monjazeb, A. M.
Article Title: Phase I trial of neoadjuvant conformal radiotherapy plus sorafenib for patients with locally advanced soft tissue sarcoma of the extremity
Abstract: BACKGROUND: Despite effective local therapy with surgery and radiotherapy (RT), ~50 % of patients with high-grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when antiangiogenic targeted therapies such as sorafenib are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a phase I/II trial among patients with extremity STS amenable to treatment with curative intent. METHODS: For the phase I trial, eight patients with intermediate- or high-grade STS >5 cm in maximal dimension or low-grade STS >8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 twice daily, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during the entire period of RT as tolerated. Surgical resection was completed 4-6 weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT). RESULTS: Eight patients were enrolled in the phase I (five females, median age 44 years, two high-grade pleomorphic, two myxoid/round cell liposarcoma, four other). Median tumor size was 16 cm (range 8-29), and all tumors were located in the lower extremity. Two of five patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and supraventricular tachycardia. Radiation toxicity (grade 1 or 2 dermatitis; N = 8) and post-surgical complications (three grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (>/=95 % tumor necrosis) was observed in three patients (38 %). CONCLUSION: Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (ClinicalTrials.gov identifier NCT00805727).
Journal Title: Annals of surgical oncology
Volume: 21
Issue: 5
ISSN: 1534-4681; 1068-9265
Publisher: Unknown  
Journal Place: United States
Date Published: 2014
Start Page: 1616
End Page: 1623
Language: eng
DOI/URL:

10.1245/s10434-014-3543-7
Notes: JID: 9420840; 2013/09/01 [received]; 2014/02/20 [aheadofprint]; ppublish