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II Trial of Multitargeted Tyrosine Kinase Inhibitor Sunitinib in Combination with Image-guided Radiotherapy for Patients with Oligometastases
Proceedings of the 51st Annual ASTRO Meeting Conclusions: For tumors such as head-and-neck squamous carcinomas that show only modest responses to inhibitors of specific angiogenic pathways, targeting NO-dependent prosurvival and angiogenic mechanisms in both tumor and supporting stromal cells may present a potential new strategy for tumor control. Author Disclosure: R.B. Mikkelsen, None; R.J.G. Cardnell, None.
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Phase I/II Trial of Multitargeted Tyrosine Kinase Inhibitor Sunitinib in Combination with Image-guided Radiotherapy for Patients with Oligometastases
J. Kao1, S. Kulkarni2, S. Packer1, M. Sung1, J. A. Cesaretti3, S. Chen1 1 Mount Sinai School of Medicine, New York, NY, 2Michigan State School of Medicine, East Lansing, MI, 3Florida Radiation Oncology Group, Jacksonville, FL Purpose/Objective(s): To determine the toxicity and efficacy of concurrent sunitinib and image-guided radiotherapy (IGRT) in patients with oligometastases. Based on preclinical evidence that sunitinib reverses immune suppression (Ozao-Choy, Cancer Research 2009;69:2514), we investigated its effect on myeloid cells in treated patients. Materials/Methods: Eligible patients had 1 to 5 sites of metastatic cancer measuring #6 cm. The most common treatment sites were bone, liver, and lung. Patients were treated with concurrent sunitinib (Days 1–28) and IGRT (40–50 Gy in 10 fractions starting on Day 8). This was followed by maintenance sunitinib (50 mg daily, 4 weeks on/2 weeks off starting on Day 43) in 10 patients. The starting dose was sunitinib 25 mg and IGRT 40 Gy and doses were escalated in a ping-pong design with incremental increases in either sunitinib or IGRT. The Phase II dose is sunitinib 37.5 mg and IGRT 50 Gy. Results: Between February 2007 and November 2008, 29 patients with 51 metastatic lesions were enrolled, with a median followup of 11 months. Dose limiting toxicity consisting of neutropenia and thrombocytopenia was noted at a dose level 4 (sunitinib 50 mg, IGRT 50 Gy), particularly in patients with large liver tumors. At last follow-up, 11 patients (38%) are alive without evidence of progression. The 1-year local, event-free, and overall survival were 84%, 42%, and 66%, respectively. Among leukocyte subtypes, sunitinib causes a rapid decrease in monocytes (mean 43%). A decrease in monocytes within 7 days of sunitinib is associated with significantly increased 1-year progression-free survival (67% vs. 0%; p = 0.003). Flow cytometric analysis suggests that the observed effect of sunitinib on monocytes are primarily due to decreased Lin-CD33+CD11b+ myeloid derived suppressor cells (MDSC) and plasmacytoid dendritic cells. Functional assays suggested reversion of MDSC-mediated immune suppression in treated patients. Conclusions: These data demonstrating major antitumor responses suggest that adding sunitinib to radiotherapy can achieve clinically significant radiosensitization without potentiating radiation toxicity. The prognostic value of an early decline in monocytes, which appears attributable to myeloid derived suppressor cells, suggests that reversion of immune suppression may contribute to better response to therapy. Author Disclosure: J. Kao, Pfizer, B. Research Grant; S. Kulkarni, None; S. Packer, None; M. Sung, None; J.A. Cesaretti, None; S. Chen, None.
150
An Online Replanning Technique for Breast Adaptive Radiation Therapy
X. Li, E. Ahunbay, A. Godley, N. Morrow, J. F. Wilson, J. White Medical College of Wisconsin, Milwaukee, WI Purpose/Objective(s): Daily setup errors and anatomic changes are significant in breast irradiation, and cannot be completely corrected by the repositioning with the current standard IGRT. We have previously proposed an online adaptive scheme based on aperture morphing. In this work, we report the effectiveness for using this online scheme to account for the interfractional variations in partial breast irradiation (PBI). Materials/Methods: The proposed online replanning process includes: (1) acquiring the CT of the day prior to the treatment, (2) generating contours of target and normal structures by registering the CT of the day with the planning CT using deformable registration, (3) verifying/modifying new contours to agree with the anatomy of the day, (4) rapidly adjusting (morphing) beam/segment apertures, (5) computing dose distributions for the new apertures, (6) optimizing weights of the new apertures and computing and comparing DVHs, and (7) transferring new apertures and weights for delivery. This process was evaluated with a series of daily CT sets collected for the patients who underwent the daily CT-guided PBI using a linac and CT-on-Rails combination (CTVision, Siemens). These patients were treated in either prone or supine position with either 3D-CRT or IMRT based on direct aperture optimization (Panther, Prowess). The daily CT sets were selected so that surgical clips and/or lumpectomy cavities were evident in these CTs. Several parameters including the maximum overlap ratio (MOR) were used to quantify the daily anatomic change. The dosimetry benefits, time required, and work flows for the online replanning process were evaluated. The DVHs generated for the online replanning were compared with those generated for the repositioning and for the full-scale reoptimization based on the CT of the day. Results: The positions, shapes, and volumes of lumpectomy cavities can change significantly from day-to-day (up to 2 cm displacement and 0.7 MOR). The plan quality (target coverage and normal tissue sparing) for the online replanning scheme was better than that for the repositioning, and comparable to that for the reoptimization based on the CT of the day. The larger the breast deformation (MOR \0.8), the larger the benefits from the online replanning. The minimum dose and D95 for lumpectomy cavity increased by up to 35% and 15%, respectively. The times required to complete the online replanning ranged 7–10 minutes. Conclusions: The proposed online replanning scheme can effectively correct interfraction errors in partial breast irradiation with a practically acceptable timeframe. This online scheme enables ‘‘image-plan-treat’’, a new paradigm for IGRT that will permit shrinking PTV margins (allowing more patients suitable for PBI) and facilitate the delivery of hypofractionated PBI. Author Disclosure: X. Li, None; E. Ahunbay, None; A. Godley, None; N. Morrow, None; J.F. Wilson, None; J. White, None.
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149
Phase I/II Trial of Multitargeted Tyrosine Kinase Inhibitor Sunitinib in Combination with Image-guided Radiotherapy for Patients with Oligometastases
J. Kao1, S. Kulkarni2, S. Packer1, M. Sung1, J. A. Cesaretti3, S. Chen1 1 Mount Sinai School of Medicine, New York, NY, 2Michigan State School of Medicine, East Lansing, MI, 3Florida Radiation Oncology Group, Jacksonville, FL Purpose/Objective(s): To determine the toxicity and efficacy of concurrent sunitinib and image-guided radiotherapy (IGRT) in patients with oligometastases. Based on preclinical evidence that sunitinib reverses immune suppression (Ozao-Choy, Cancer Research 2009;69:2514), we investigated its effect on myeloid cells in treated patients. Materials/Methods: Eligible patients had 1 to 5 sites of metastatic cancer measuring #6 cm. The most common treatment sites were bone, liver, and lung. Patients were treated with concurrent sunitinib (Days 1–28) and IGRT (40–50 Gy in 10 fractions starting on Day 8). This was followed by maintenance sunitinib (50 mg daily, 4 weeks on/2 weeks off starting on Day 43) in 10 patients. The starting dose was sunitinib 25 mg and IGRT 40 Gy and doses were escalated in a ping-pong design with incremental increases in either sunitinib or IGRT. The Phase II dose is sunitinib 37.5 mg and IGRT 50 Gy. Results: Between February 2007 and November 2008, 29 patients with 51 metastatic lesions were enrolled, with a median followup of 11 months. Dose limiting toxicity consisting of neutropenia and thrombocytopenia was noted at a dose level 4 (sunitinib 50 mg, IGRT 50 Gy), particularly in patients with large liver tumors. At last follow-up, 11 patients (38%) are alive without evidence of progression. The 1-year local, event-free, and overall survival were 84%, 42%, and 66%, respectively. Among leukocyte subtypes, sunitinib causes a rapid decrease in monocytes (mean 43%). A decrease in monocytes within 7 days of sunitinib is associated with significantly increased 1-year progression-free survival (67% vs. 0%; p = 0.003). Flow cytometric analysis suggests that the observed effect of sunitinib on monocytes are primarily due to decreased Lin-CD33+CD11b+ myeloid derived suppressor cells (MDSC) and plasmacytoid dendritic cells. Functional assays suggested reversion of MDSC-mediated immune suppression in treated patients. Conclusions: These data demonstrating major antitumor responses suggest that adding sunitinib to radiotherapy can achieve clinically significant radiosensitization without potentiating radiation toxicity. The prognostic value of an early decline in monocytes, which appears attributable to myeloid derived suppressor cells, suggests that reversion of immune suppression may contribute to better response to therapy. Author Disclosure: J. Kao, Pfizer, B. Research Grant; S. Kulkarni, None; S. Packer, None; M. Sung, None; J.A. Cesaretti, None; S. Chen, None.
150
An Online Replanning Technique for Breast Adaptive Radiation Therapy
X. Li, E. Ahunbay, A. Godley, N. Morrow, J. F. Wilson, J. White Medical College of Wisconsin, Milwaukee, WI Purpose/Objective(s): Daily setup errors and anatomic changes are significant in breast irradiation, and cannot be completely corrected by the repositioning with the current standard IGRT. We have previously proposed an online adaptive scheme based on aperture morphing. In this work, we report the effectiveness for using this online scheme to account for the interfractional variations in partial breast irradiation (PBI). Materials/Methods: The proposed online replanning process includes: (1) acquiring the CT of the day prior to the treatment, (2) generating contours of target and normal structures by registering the CT of the day with the planning CT using deformable registration, (3) verifying/modifying new contours to agree with the anatomy of the day, (4) rapidly adjusting (morphing) beam/segment apertures, (5) computing dose distributions for the new apertures, (6) optimizing weights of the new apertures and computing and comparing DVHs, and (7) transferring new apertures and weights for delivery. This process was evaluated with a series of daily CT sets collected for the patients who underwent the daily CT-guided PBI using a linac and CT-on-Rails combination (CTVision, Siemens). These patients were treated in either prone or supine position with either 3D-CRT or IMRT based on direct aperture optimization (Panther, Prowess). The daily CT sets were selected so that surgical clips and/or lumpectomy cavities were evident in these CTs. Several parameters including the maximum overlap ratio (MOR) were used to quantify the daily anatomic change. The dosimetry benefits, time required, and work flows for the online replanning process were evaluated. The DVHs generated for the online replanning were compared with those generated for the repositioning and for the full-scale reoptimization based on the CT of the day. Results: The positions, shapes, and volumes of lumpectomy cavities can change significantly from day-to-day (up to 2 cm displacement and 0.7 MOR). The plan quality (target coverage and normal tissue sparing) for the online replanning scheme was better than that for the repositioning, and comparable to that for the reoptimization based on the CT of the day. The larger the breast deformation (MOR \0.8), the larger the benefits from the online replanning. The minimum dose and D95 for lumpectomy cavity increased by up to 35% and 15%, respectively. The times required to complete the online replanning ranged 7–10 minutes. Conclusions: The proposed online replanning scheme can effectively correct interfraction errors in partial breast irradiation with a practically acceptable timeframe. This online scheme enables ‘‘image-plan-treat’’, a new paradigm for IGRT that will permit shrinking PTV margins (allowing more patients suitable for PBI) and facilitate the delivery of hypofractionated PBI. Author Disclosure: X. Li, None; E. Ahunbay, None; A. Godley, None; N. Morrow, None; J.F. Wilson, None; J. White, None.
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