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Phase I Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients with Locally Advanced Soft Tissue Sarcoma of the Extremity

  • Bone and Soft Tissue Sarcomas
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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).

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Acknowledgment

The study was supported by University of California Davis’ Clinical and Translational Science Award UL1 TR000002, Bayer-Onyx Pharmaceuticals, the National Center for Advancing Translational Sciences (NCATS) and the NIH through Grant number 1K12CA138464-01A2. We also thank Dr. Philip Mack and William S. Holland from the Molecular Pharmacology Core Laboratory at the University of California Davis Comprehensive Cancer Center for support in the development and conduct of the serum biomarker correlative studies.

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Authors and Affiliations

  1. Division of Surgical Oncology, UC Davis Comprehensive Cancer Center, University of California Davis Medical Center, Sacramento, CA, USA

    Robert J. Canter MD & Abimbola Olusanya PhD

  2. Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA, USA

    Dariusz Borys MD

  3. Division of Biostatistics, Department of Public Health Sciences, University of California Davis, Sacramento, CA, USA

    Chin-Shang Li PhD

  4. Department of Psychology, University of Michigan, Ann Arbor, MI, USA

    Li-Yuan Lee BA

  5. Department of Radiology, University of California Davis Medical Center, Sacramento, CA, USA

    Robert D. Boutin MD

  6. Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, USA

    Scott D. Christensen MD

  7. Division of Orthopedic Oncology, Department of Orthopedic Surgery, University of California Davis Medical Center, Sacramento, CA, USA

    Robert M. Tamurian MD

  8. Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA, USA

    Arta M. Monjazeb MD, PhD

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  1. Robert J. Canter MD
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Correspondence to Robert J. Canter MD.

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Canter, R.J., Borys, D., Olusanya, A. et al. Phase I Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients with Locally Advanced Soft Tissue Sarcoma of the Extremity. Ann Surg Oncol 21, 1616–1623 (2014). https://doi.org/10.1245/s10434-014-3543-7

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  • DOI: https://doi.org/10.1245/s10434-014-3543-7

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