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The Mechanism behind Tumor Regression during Radiation Therapy of Cervical Cancer - The Role of Tumor Perfusion
Proceedings of the 51st Annual ASTRO Meeting However, repopulation onset time remains an unsolved issue for cervical cancer. The purpose of this study is to determine the onset time of accelerated repopulation in cervical cancer using clinical data. Materials/Methods: The linear-quadratic (LQ) model extended for tumor repopulation was used to analyze the clinical data and MRI-based 3D tumor volumetric regression data of 80 cervical cancer patients, who received external beam radiotherapy (EBRT) and low-dose rate (LDR) brachytherapy. Overall treatment times ranged from 38–76 days. The LDR dose was converted to EBRT dose in 1.8 Gy fractions using the LQ formula, and the total dose ranged from 61.4–99.7 Gy. The patients were divided into 11 groups according to total dose and treatment time. The tumor control probability (TCP) was calculated for each group. The least chi-square method was used to fit the TCP data with two free parameters: the onset time (Tk) of accelerated tumor repopulation and the number of clonogens (K) while other LQ model parameters were adopted from the literature (a = 0.16 Gy-1, a/b = 14 Gy and Td = 4.5 days, Td-tumor effective doubling time) were fixed, due to the limited patient data. The uncertainty of the onset time Tk was estimated by varying a in the range of (0.14, 0.18) Gy-1 and a/b in (12, 16) Gy based on S2 data derived in a separate study. Results: Among the 11 patient groups, TCP varied from 33–100% as a function of radiation dose and overall treatment time. Higher dose and shorter treatment durations were associated higher TCP. Using the LQ model, the best fit was achieved with the onset time Tk = 19 days, clonogen number K = 139, with uncertainty ranges of (11, 22) days for Tk, and (48, 1822) for K, respectively. Conclusions: This is the first report of accelerated repopulation onset time in cervical cancer, derived directly from the clinical data using the LQ model. Our study validated clinically that accelerated repopulation does exist in cervical cancer and has a relatively short onset time. Therefore, dose escalation may be required to compensate for the effects of tumor repopulation if the radiation therapy course is protracted. Supported in part by NIH R01 CA 71906. Author Disclosure: Z. Huang, None; N.A. Mayr, None; M. Gao, None; D. Zhang, None; W.T.C. Yuh, None; J.Z. Wang, None.
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The Mechanism behind Tumor Regression during Radiation Therapy of Cervical Cancer - The Role of Tumor Perfusion
J. Z. Wang, N. A. Mayr, Z. Huang, L. Lu, D. Zhang, J. F. Montebello, S. S. Lo, W. T. C. Yuh The Ohio State University, Columbus, OH Purpose/Objective(s): Tumor regression during radiation therapy (RT) strongly correlates with treatment outcome in cervical cancer. This gradual tumor volume reduction depends not only on radiosensitivity, but also clearance of dead cells from the tumor. However the mechanisms of dead cell resolving are poorly understood. The purpose of this study was to develop a kinetic model of tumor regression and to investigate mechanisms of dead cell resolving during the RT course. Materials/Methods: Data of 3D volumetric tumor regression and tumor perfusion from dynamic contrast enhanced MRI (DCEMRI) from 61 patients with Stage IB2–IVA cervical cancer were analyzed. Four sequential MRI scans were performed pre-RT, every 2–2.5 weeks during RT and post-RT. Based on the signal intensity (SI) curves of the DCE-MRI, poorly perfused tumor regions were quantified by the low-DCE tumor pixels with SI below the 10th percentile of the entire tumor pixel population (SI10), and by mean SI (mSI) of the entire tumor. A kinetic model incorporating effects of radiation cell killing, tumor repopulation, and resolution of dead/inactivated cells, was developed to analyze the tumor regression data and estimate the radiation sensitivity and the half-time (T1/2) of dead-tumor-cell resolving for individual patients. Correlation with local tumor control and disease-specific survival was conducted for model and perfusion parameters (T1/2, SI10, mSI) using the Mann-Whitney rank-sum test. To explore the tumor regression mechanism, a correlation study was performed between T1/2 and perfusion parameters using Pearson’s correlation. Median follow-up time was 5.2 (range, 0.2–9.4) years. Results: The dead-cell resolving half-time T1/2 correlated with the perfusion parameter SI10 at the third MRI obtained at 45–50 Gy (p = 0.03). Short T1/2, indicative of fast dead-cell resolving, was associated with high SI10, consistent with high perfusion. Both T1/ 2 and SI10 correlated with local control (p\0.001 and p = 0.02, respectively) and disease-specific survival (p = 0.004 and p = 0.05, respectively). The T1/2 did not correlate with the SI10 at the earlier imaging time points, pre-RT or at 20-25 Gy of RT (p . 0.1), nor with mSI at any time (p . 0.1). Conclusions: These results suggest that the speed of dead-cell resolving is influenced by the tumor perfusion status in mid-RT (at 45–50 Gy), but not in the earlier phases of therapy. The complex pathophysiology of dead-cell resolving remains unclear. However, the current finding suggest that in the early RT phase other mechanisms, including surface sloughing/bleeding, may predominate, while in the later RT phase, blood perfusion is critical for the dead-cell resolving and tumor volume reduction. Supported in part by NIH R01 CA 71906. Author Disclosure: J.Z. Wang, None; N.A. Mayr, None; Z. Huang, None; L. Lu, None; D. Zhang, None; J.F. Montebello, None; S.S. Lo, None; W.T.C. Yuh, None.
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Impact of MR on CT-based Treatment Planning and Acute Toxicity for Prostate Cancer Patients Treated with Intensity-modulated Radiotherapy (IMRT)
A. N. Ali1, P. J. Rossi1, K. Godette1, S. Liauw2, S. Vijayakumar3, S. Cooper1, A. B. Jani1 1
Emory University, Atlanta, GA, 2University of Chicago, Chicago, IL, 3University of Mississippi, Jackson, MS
Purpose/Objective(s): Registration of MR to simulation CT images (to create CT-MR targets) has been shown to reduce the delineated prostate volume and improve dosimetric endpoints. However, no direct comparison of CT-MR vs. CT plans in the IMRT era has included an analysis of clinical endpoints. Our objectives were to evaluate rectal and bladder dosimetric endpoints and acute (genitourinary [GU] and gastrointestinal [GI]) toxicity for prostate patients treated with IMRT using CT-MR vs. CT target volumes. Materials/Methods: The charts of 155 consecutive patients treated with IMRT at our institution from 2004–2008 were reviewed. Postprostatectomy and brachytherapy patients were excluded, leaving 81 patients (28 CT-MR and 53 CT). Demographic, anatomic (including ultrasound prostate size - 43.8 vs. 38.7 cm3; p = 0.523), disease, and treatment factors were generally balanced; median
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The Mechanism behind Tumor Regression during Radiation Therapy of Cervical Cancer - The Role of Tumor Perfusion
J. Z. Wang, N. A. Mayr, Z. Huang, L. Lu, D. Zhang, J. F. Montebello, S. S. Lo, W. T. C. Yuh The Ohio State University, Columbus, OH Purpose/Objective(s): Tumor regression during radiation therapy (RT) strongly correlates with treatment outcome in cervical cancer. This gradual tumor volume reduction depends not only on radiosensitivity, but also clearance of dead cells from the tumor. However the mechanisms of dead cell resolving are poorly understood. The purpose of this study was to develop a kinetic model of tumor regression and to investigate mechanisms of dead cell resolving during the RT course. Materials/Methods: Data of 3D volumetric tumor regression and tumor perfusion from dynamic contrast enhanced MRI (DCEMRI) from 61 patients with Stage IB2–IVA cervical cancer were analyzed. Four sequential MRI scans were performed pre-RT, every 2–2.5 weeks during RT and post-RT. Based on the signal intensity (SI) curves of the DCE-MRI, poorly perfused tumor regions were quantified by the low-DCE tumor pixels with SI below the 10th percentile of the entire tumor pixel population (SI10), and by mean SI (mSI) of the entire tumor. A kinetic model incorporating effects of radiation cell killing, tumor repopulation, and resolution of dead/inactivated cells, was developed to analyze the tumor regression data and estimate the radiation sensitivity and the half-time (T1/2) of dead-tumor-cell resolving for individual patients. Correlation with local tumor control and disease-specific survival was conducted for model and perfusion parameters (T1/2, SI10, mSI) using the Mann-Whitney rank-sum test. To explore the tumor regression mechanism, a correlation study was performed between T1/2 and perfusion parameters using Pearson’s correlation. Median follow-up time was 5.2 (range, 0.2–9.4) years. Results: The dead-cell resolving half-time T1/2 correlated with the perfusion parameter SI10 at the third MRI obtained at 45–50 Gy (p = 0.03). Short T1/2, indicative of fast dead-cell resolving, was associated with high SI10, consistent with high perfusion. Both T1/ 2 and SI10 correlated with local control (p\0.001 and p = 0.02, respectively) and disease-specific survival (p = 0.004 and p = 0.05, respectively). The T1/2 did not correlate with the SI10 at the earlier imaging time points, pre-RT or at 20-25 Gy of RT (p . 0.1), nor with mSI at any time (p . 0.1). Conclusions: These results suggest that the speed of dead-cell resolving is influenced by the tumor perfusion status in mid-RT (at 45–50 Gy), but not in the earlier phases of therapy. The complex pathophysiology of dead-cell resolving remains unclear. However, the current finding suggest that in the early RT phase other mechanisms, including surface sloughing/bleeding, may predominate, while in the later RT phase, blood perfusion is critical for the dead-cell resolving and tumor volume reduction. Supported in part by NIH R01 CA 71906. Author Disclosure: J.Z. Wang, None; N.A. Mayr, None; Z. Huang, None; L. Lu, None; D. Zhang, None; J.F. Montebello, None; S.S. Lo, None; W.T.C. Yuh, None.
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Impact of MR on CT-based Treatment Planning and Acute Toxicity for Prostate Cancer Patients Treated with Intensity-modulated Radiotherapy (IMRT)
A. N. Ali1, P. J. Rossi1, K. Godette1, S. Liauw2, S. Vijayakumar3, S. Cooper1, A. B. Jani1 1
Emory University, Atlanta, GA, 2University of Chicago, Chicago, IL, 3University of Mississippi, Jackson, MS
Purpose/Objective(s): Registration of MR to simulation CT images (to create CT-MR targets) has been shown to reduce the delineated prostate volume and improve dosimetric endpoints. However, no direct comparison of CT-MR vs. CT plans in the IMRT era has included an analysis of clinical endpoints. Our objectives were to evaluate rectal and bladder dosimetric endpoints and acute (genitourinary [GU] and gastrointestinal [GI]) toxicity for prostate patients treated with IMRT using CT-MR vs. CT target volumes. Materials/Methods: The charts of 155 consecutive patients treated with IMRT at our institution from 2004–2008 were reviewed. Postprostatectomy and brachytherapy patients were excluded, leaving 81 patients (28 CT-MR and 53 CT). Demographic, anatomic (including ultrasound prostate size - 43.8 vs. 38.7 cm3; p = 0.523), disease, and treatment factors were generally balanced; median
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