Gregory M Cote1, Constance M Barysauskas2, Thomas F DeLaney3, Joseph Schwab4, Kevin Raskin4, Santiago Lozano-Calderon4, Karen Bernstein3, John T Mullen5, Alex B Haynes5, Francis Hornicek6, Yen-Lin E Chen3, Edwin Choy7. 1. Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts; Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: gcote@mgh.harvard.edu. 2. Department of Biostatistics at Dana-Farber Cancer Institute, Boston, Massachusetts. 3. Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts; Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. 4. Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts; Orthopaedic Oncology, Massachusetts General Hospital, Boston, Massachusetts. 5. Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts; Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts. 6. Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts; Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, California. 7. Division of Hematology-Oncology, Massachusetts General Hospital, Boston, Massachusetts; Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts.
Abstract
PURPOSE: Chordomas are malignant tumors arising from remnant notochordal tissue. Despite improved local control with preoperative/postoperative radiation therapy (RT), progression-free survival and overall survival (OS) remain poor in patients with high-risk features. Chordoma has been identified to express and activate platelet-derived growth factor receptor signaling. We conducted a phase 1 trial to identify the maximum tolerated dose (MTD), safety, and feasibility of nilotinib with RT as either preoperative or definitive treatment for patients with high-risk chordoma. METHODS AND MATERIALS: We recruited 23 patients with high-risk, nonmetastatic chordoma. High risk was defined as the presence of any of the following: local recurrence after surgery, previous intralesional resection, unplanned incomplete resection, unresectable or marginally resectable disease based on locally advanced stage, or declining surgery because of excessive morbidity. Patients were treated with nilotinib and concurrent RT to 50.4 Gy relative biological effectiveness (RBE) followed by surgery and postoperative RT to a cumulative dose up to 70.2 Gy RBE or definitively up to 77.4 Gy RBE without surgery. On completion of RT, patients were eligible to continue nilotinib until disease progression. RESULTS: In patients receiving nilotinib 200 mg twice daily with RT, 3 dose-limiting toxicities (DLT) occurred in 5 patients. One DLT was seen among 6 patients receiving nilotinib 200 mg daily with RT. Therefore, 200 mg daily was declared the maximum tolerated dose. Eleven additional patients received nilotinib with RT at the maximum tolerated dose, and 1 additional DLT occurred. The objective best response rate was 6% (1 of 18 patients, 95% confidence interval [CI], 0.1%-27%). The median progression-free survival was 58.15 months (95% CI, 39.10-∞). The median OS was 61.5 months (43.1-∞), and the 2-year OS rate was 95%. CONCLUSIONS: Nilotinib 200 mg/d with RT is safe and tolerated in patients with high-risk chordoma. Long-term follow-up is needed to understand whether nilotinib combined with RT, with or without surgery, adds greater improvement to progression-free survival or OS than with RT with or without surgery alone in patients with high-risk chordoma.
PURPOSE: Chordomas are malignant tumors arising from remnant notochordal tissue. Despite improved local control with preoperative/postoperative radiation therapy (RT), progression-free survival and overall survival (OS) remain poor in patients with high-risk features. Chordoma has been identified to express and activate platelet-derived growth factor receptor signaling. We conducted a phase 1 trial to identify the maximum tolerated dose (MTD), safety, and feasibility of nilotinib with RT as either preoperative or definitive treatment for patients with high-risk chordoma. METHODS AND MATERIALS: We recruited 23 patients with high-risk, nonmetastatic chordoma. High risk was defined as the presence of any of the following: local recurrence after surgery, previous intralesional resection, unplanned incomplete resection, unresectable or marginally resectable disease based on locally advanced stage, or declining surgery because of excessive morbidity. Patients were treated with nilotinib and concurrent RT to 50.4 Gy relative biological effectiveness (RBE) followed by surgery and postoperative RT to a cumulative dose up to 70.2 Gy RBE or definitively up to 77.4 Gy RBE without surgery. On completion of RT, patients were eligible to continue nilotinib until disease progression. RESULTS: In patients receiving nilotinib 200 mg twice daily with RT, 3 dose-limiting toxicities (DLT) occurred in 5 patients. One DLT was seen among 6 patients receiving nilotinib 200 mg daily with RT. Therefore, 200 mg daily was declared the maximum tolerated dose. Eleven additional patients received nilotinib with RT at the maximum tolerated dose, and 1 additional DLT occurred. The objective best response rate was 6% (1 of 18 patients, 95% confidence interval [CI], 0.1%-27%). The median progression-free survival was 58.15 months (95% CI, 39.10-∞). The median OS was 61.5 months (43.1-∞), and the 2-year OS rate was 95%. CONCLUSIONS: Nilotinib 200 mg/d with RT is safe and tolerated in patients with high-risk chordoma. Long-term follow-up is needed to understand whether nilotinib combined with RT, with or without surgery, adds greater improvement to progression-free survival or OS than with RT with or without surgery alone in patients with high-risk chordoma.
Authors: Samantha E Hoffman; Sally A Al Abdulmohsen; Saksham Gupta; Blake M Hauser; David M Meredith; Ian F Dunn; Wenya Linda Bi Journal: Front Neurol Date: 2020-07-08 Impact factor: 4.003
Authors: Christopher E Lietz; Cassandra Garbutt; William T Barry; Vikram Deshpande; Yen-Lin Chen; Santiago A Lozano-Calderon; Yaoyu Wang; Brian Lawney; David Ebb; Gregory M Cote; Zhenfeng Duan; Francis J Hornicek; Edwin Choy; G Petur Nielsen; Benjamin Haibe-Kains; John Quackenbush; Dimitrios Spentzos Journal: Sci Rep Date: 2020-03-10 Impact factor: 4.379