Phase i trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates

Janelle M. Meyer, Kelly S. Perlewitz, James B. Hayden, Yee Cheen Doung, Arthur Y. Hung, John T. Vetto, Rodney F. Pommier, Atiya Mansoor, Brooke R. Beckett, Alina Tudorica, Motomi Mori, Megan L. Holtorf, Aneela Afzal, William J. Woodward, Eve Rodler, Robin L. Jones, Wei Huang, Christopher W. Ryan

Research output: Contribution to journalArticle

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Abstract

Purpose: We conducted 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 undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced MRI (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 twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. Results: Eighteen 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%). Of note, 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker DKtrans ΔKtrans after 2 weeks of 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 soft tissue sarcoma.

Original languageEnglish (US)
Pages (from-to)6902-6911
Number of pages10
JournalClinical Cancer Research
Volume19
Issue number24
DOIs
StatePublished - Dec 15 2013
Externally publishedYes

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Sarcoma
Extremities
Epirubicin
Maximum Tolerated Dose
Chemoradiotherapy
Hypophosphatemia
Radiation Dosage
Ifosfamide
Limb Salvage
sorafenib
Neutropenia
Thrombocytopenia
Anemia
Neoplasms
Research Design
Fever
Necrosis
Pharmacokinetics
Perfusion
Biomarkers

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase i trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates. / Meyer, Janelle M.; Perlewitz, Kelly S.; Hayden, James B.; Doung, Yee Cheen; Hung, Arthur Y.; Vetto, John T.; Pommier, Rodney F.; Mansoor, Atiya; Beckett, Brooke R.; Tudorica, Alina; Mori, Motomi; Holtorf, Megan L.; Afzal, Aneela; Woodward, William J.; Rodler, Eve; Jones, Robin L.; Huang, Wei; Ryan, Christopher W.

In: Clinical Cancer Research, Vol. 19, No. 24, 15.12.2013, p. 6902-6911.

Research output: Contribution to journalArticle

Meyer, JM, Perlewitz, KS, Hayden, JB, Doung, YC, Hung, AY, Vetto, JT, Pommier, RF, Mansoor, A, Beckett, BR, Tudorica, A, Mori, M, Holtorf, ML, Afzal, A, Woodward, WJ, Rodler, E, Jones, RL, Huang, W & Ryan, CW 2013, 'Phase i trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates', Clinical Cancer Research, vol. 19, no. 24, pp. 6902-6911. https://doi.org/10.1158/1078-0432.CCR-13-1594
Meyer, Janelle M. ; Perlewitz, Kelly S. ; Hayden, James B. ; Doung, Yee Cheen ; Hung, Arthur Y. ; Vetto, John T. ; Pommier, Rodney F. ; Mansoor, Atiya ; Beckett, Brooke R. ; Tudorica, Alina ; Mori, Motomi ; Holtorf, Megan L. ; Afzal, Aneela ; Woodward, William J. ; Rodler, Eve ; Jones, Robin L. ; Huang, Wei ; Ryan, Christopher W. / Phase i trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 24. pp. 6902-6911.
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T1 - Phase i trial of preoperative chemoradiation plus sorafenib for high-risk extremity soft tissue sarcomas with dynamic contrast-enhanced MRI correlates

AU - Meyer, Janelle M.

AU - Perlewitz, Kelly S.

AU - Hayden, James B.

AU - Doung, Yee Cheen

AU - Hung, Arthur Y.

AU - Vetto, John T.

AU - Pommier, Rodney F.

AU - Mansoor, Atiya

AU - Beckett, Brooke R.

AU - Tudorica, Alina

AU - Mori, Motomi

AU - Holtorf, Megan L.

AU - Afzal, Aneela

AU - Woodward, William J.

AU - Rodler, Eve

AU - Jones, Robin L.

AU - Huang, Wei

AU - Ryan, Christopher W.

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N2 - Purpose: We conducted 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 undergoing limb salvage surgery. We conducted a correlative study of quantitative dynamic contrast-enhanced MRI (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 twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. Results: Eighteen 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%). Of note, 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker DKtrans ΔKtrans after 2 weeks of 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 soft tissue sarcoma.

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