- Email: [email protected]
Improved Radiation Pneumonitis Risk Modeling Using a Nonlinear Approach
I. J. Radiation Oncology d Biology d Physics
S180
Volume 69, Number 3, Supplement, 2007
MTS Score Self Report
Overall Health Self Report 0 (worst) - 10 (perfect health) Adjusted* Mean score (SE1)
FACT-E Quality of Life 0 (worst) - 176 (best) Adjusted* Mean score (SE1)
Functional Wellbeing 0 (worst) - 28 (best) Adjusted* Mean score (SE1)
None - 0 A little - 1 Moderate - 2 Quite a bit - 3 Extreme - 4
7.6 (0.1) 6.9 (0.1) 6.1 (0.1) 5.4 (0.1) 4.7 (0.1)
145.5 (2.0) 129.4 (1.8) 113.4 (1.7) 97.4 (1.8) 81.4 (2.1)
19.5 (0.5) 17.0 (0.5) 14.5 (0.5) 11.9 (0.5) 9.4 (0.6)
* Adjusted for baseline ECOG performance status, ctx use, and cancer site. 1 Adjusted for within-pt correlation.
Author Disclosure: A.S. Garden, None; R.B. Tishler, None; A. Barasch, None; M.T. Brennan, None; P.M. Harari, None; M.R. Kudrimoti, None; C.J. Schultz, None; D.G. Brachman, None; M. Vera-Llonch, None; D. Keefe, None.
1077
Second Malignancies in 15,500 Irradiated Patients Since 1981: A Mono-institutional Experience
B. Welte, P. Suhr, D. Bottke, T. Wiegel Clinic for Radiation Oncology, University of Ulm, 89081 Ulm, Germany Purpose/Objective(s): Few data about the induction of secondary neoplasms by irradiation are available. The aim of this study was to investigate the incidence of second malignancies following irradiation in the Clinic for Radiation Oncology, University of Ulm, and to define subgroups of possibly radiation-induced second cancers. Materials/Methods: 15,503 patients were irriadiated in Ulm from 1981–2003. 11,758 patients were still alive one year after completion of radiotherapy. By long-term follow-up of the irradiated patients, information about the development of a second cancer was obtained. The location of the second malignancy was compared to the former irradiation volume. Patients with a second malignancy within or near the margin of the former irradiation portals and a latency of at least one year were selected for further analysis. Results: During follow-up of the 11,758 one-year-survivors, 937 second cancers were observed. 100 of the second malignancies were located in the former irradiation volume or at the field margins (66 f, 34 m, age median 52 yrs. (range 2–80 yrs., at time of first cancer diagnosis)). The median follow-up period was 13.3 years. Primary tumors of the 100 patients had mostly been breast cancer (27%), lymphoma (24%), gynecological tumors of pelvis (17%). The latency of the 100 field-associated second tumors was median 7.4 yrs. (1–42 yrs., including 2 pts. irradiated in childhood alio loco). Most of the second tumors were upper gastrointestinal carcinomas (18%) and colorectal carcinomas (12%), both with short latency of 5.6 resp. 3.5 years. Other second cancers were head and neck tumors (10%, incl few cases of thyroid cancer), lymphoma (10%), breast cancer (9%), sarcoma (9%) and lung cancer (8%). Second breast cancer and sarcoma had a long latency of 17.1 and 11.7 yrs. 5 years after diagnosis of the second tumor, only 35 of 100 patients were still alive. Conclusions: 100 of 11,758 irradiated patients (0.85%) developed a second malignancy in or near the irradiated region, suspicious for being induced by former therapy. The median follow-up of the 100 pts. had been 13.3 yrs., the median latency of the second tumor was 7.4 yrs. The second tumors occured mostly following irradiation of breast or chest wall with lymph nodes, extended field lymphoma radiotherapy or pelvic irradiation in gynecological tumors. Most of the second cancers were carcinomas, especially of the gastrointestinum. Only 35% of the patients were alive 5 years after diagnosis of the second cancer. Author Disclosure: B. Welte, None; P. Suhr, None; D. Bottke, None; T. Wiegel, None.
1078
Improved Radiation Pneumonitis Risk Modeling Using a Nonlinear Approach
I. El Naqa, J. D. Bradley, J. O. Deasy Washington University Medical School, St. Louis, MO Purpose/Objective(s): Individualized and patient-specific treatment planning decisions require accurate estimates of tumor control or complication risk to surrounding normal tissues. However, the inherent complexity and heterogeneity of the variables that characterize treatment response to radiation therapy require more robust methods for outcome-model building. In this work, we adapt a new form of statistical model-building known as kernel learning. We demonstrate the prognostic potential of this method in modeling radiation pneumonitis (RP) in a cohort of non-small cell lung cancer (NSCLC) patients. Materials/Methods: We considered a cohort of 219 patients diagnosed with NSCLC treated with 3D conformal radiation therapy with median dose of 70 Gy. 24% of the patients developed RP (RTOG grade $ 3). In our previous analysis (Hope et al., IJROBP ’06), from a pool of 58 variables that included dosimetric, spatial, and clinical factors, the following were found to be clinically significant on logistic regression analysis: superior-inferior mean tumor position (COM-SI) (p = 0.009), minimum dose to hottest 35% lung volume (D35) (p = 0.002), and the ICRU maximum dose (p = 0.038). A nonlinear support vector machine (SVM) was constructed using radial basis kernel. The SVM is characterized by width of the kernel (s) and a regularization parameter (C) that controls trade-off between complexity and fitting error. The main idea of the technique is to accurately distinguish between patients who are at low risk versus patients who are at high risk of RP in a higher dimensional space defined by the assortment of patient and treatment characteristics available. Results: To demonstrate the prediction power of the kernel-based method, we compared its discriminant ability with V20 (percentage lung volume receiving at least 20 Gy) and our previous best 3-parameter logistic regression model predictions using actuarial analysis of RP as shown in Figure 1. The complication-free rates were estimated using the Kaplan-Meier method. The figure indicates the strong discrimination power of SVM (p = 0.0005) compared to V20 (p = 0.201) and multi-metric logistic regression
Proceedings of the 49th Annual ASTRO Meeting (p = 0.029 for stratifying patients based on RP risk. Using Spearman correlation (Rs), SVM classifier achieved an Rs of 0.37 on cross-validation testing data compared to V20 (Rs = 0.18) and the logistic regression model (Rs = 0.22). Conclusions: We have demonstrated a new method for model building in radiotherapy based on nonlinear kernel-based statistical learning. The method effectively handles a high dimensional space of potentially important features. The method significantly improved (68%) on our previous best technique with respect to predicting RP.
Author Disclosure: I. El Naqa, None; J.D. Bradley, None; J.O. Deasy, None.
1079
Aluminum Hydroxide Plus Magnesium Hydroxide Plus Oxetacaine Suspension Versus Aluminum Hydroxide Plus Magnesium Hydroxide Suspension for Acute Radiation-Induced Esophagitis in Cancer Treatment: Final Results of a Double-Blind Randomized Trial
F. Bruns1, D. Riesenbeck2, R. Mu¨cke3, M. Klasser4, N. Willich2 1 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany, 2Department of Radiotherapy–Radiooncology, Muenster University Hospital, Muenster, Germany, 3Department of Radiotherapy, St. Josef Hospital, Wiesbaden, Germany, 4GWD Consult – contract research, Muehlheim, Germany
Purpose/Objective(s): To assess whether oral administered oxetacaine-containing suspension is effective in treating acute radiation-induced esophagitis in cancer patients. Materials/Methods: A double-blind, prospective-randomized clinical trial was conducted across 20 radiotherapy institutions in Germany. Patients with head and neck or thoracic cancer without dysphagia/odynophagia received definitive or postoperative radiotherapy [RT] (minimal total dose: 40 Gy; daily dose: #2.0 Gy) including at least 5 cm of the esophagus in the high dose volume and with or without chemotherapy. Patients were randomized to receive oral aluminum hydroxide plus magnesium hydroxide plus oxetacaine (TepiltaÒ) suspension or aluminum hydroxide plus magnesium hydroxide suspension without oxetacaine (MagaldratÒ) as first-line treatment for acute radiation-induced esophagitis. Primary endpoint(s) were the interval between begin of RT and failure of first-line treatment of esophagitis defined as need for additional systemic analgesics. Data on patients’ symptoms were collected during and for at least 2 weeks after treatment. Results: A total of 158 patients were enrolled in the study. 105 of them developed an acute esophagitis $grade 2 (CTC) and took at least one dose of study medication. 103 patients were eligible for statistical analysis according to the ITT principles; 51 patients received TepiltaÒ and 52 MagaldratÒ. The cumulative incidence of acute esophagitis $grade 2 (CTC) was 25% for the TepiltaÒ and 22% for the MagaldratÒ arm. A Kaplan-Meier survival analysis in which the time is taken into account, at which the pain therapy was delivered, reveals a statistically significant difference between the two groups with regard to the need for additional systemic analgesics in favor of TepiltaÒ (p = 0.032). No statistically significant difference was found between the two groups with respect to the secondary endpoints: need respective delay of additional parenteral nutrition (p = 0.28 respective p = 0.12), and patient’s respective investigator’s estimation of global effectivity of the study medication (0.08 and 0.12). Conclusions: This trial validated the effectivity of oral aluminum hydroxide plus magnesium hydroxide plus oxetacaine suspension (TepiltaÒ) in the first-line treatment of acute radiation-induced esophagitis. Author Disclosure: F. Bruns, Valeant Pharmaceuticals Germany, C. Other Research Support; D. Riesenbeck, None; R. Mu¨cke, None; M. Klasser, None; N. Willich, None.
S181
S180
Volume 69, Number 3, Supplement, 2007
MTS Score Self Report
Overall Health Self Report 0 (worst) - 10 (perfect health) Adjusted* Mean score (SE1)
FACT-E Quality of Life 0 (worst) - 176 (best) Adjusted* Mean score (SE1)
Functional Wellbeing 0 (worst) - 28 (best) Adjusted* Mean score (SE1)
None - 0 A little - 1 Moderate - 2 Quite a bit - 3 Extreme - 4
7.6 (0.1) 6.9 (0.1) 6.1 (0.1) 5.4 (0.1) 4.7 (0.1)
145.5 (2.0) 129.4 (1.8) 113.4 (1.7) 97.4 (1.8) 81.4 (2.1)
19.5 (0.5) 17.0 (0.5) 14.5 (0.5) 11.9 (0.5) 9.4 (0.6)
* Adjusted for baseline ECOG performance status, ctx use, and cancer site. 1 Adjusted for within-pt correlation.
Author Disclosure: A.S. Garden, None; R.B. Tishler, None; A. Barasch, None; M.T. Brennan, None; P.M. Harari, None; M.R. Kudrimoti, None; C.J. Schultz, None; D.G. Brachman, None; M. Vera-Llonch, None; D. Keefe, None.
1077
Second Malignancies in 15,500 Irradiated Patients Since 1981: A Mono-institutional Experience
B. Welte, P. Suhr, D. Bottke, T. Wiegel Clinic for Radiation Oncology, University of Ulm, 89081 Ulm, Germany Purpose/Objective(s): Few data about the induction of secondary neoplasms by irradiation are available. The aim of this study was to investigate the incidence of second malignancies following irradiation in the Clinic for Radiation Oncology, University of Ulm, and to define subgroups of possibly radiation-induced second cancers. Materials/Methods: 15,503 patients were irriadiated in Ulm from 1981–2003. 11,758 patients were still alive one year after completion of radiotherapy. By long-term follow-up of the irradiated patients, information about the development of a second cancer was obtained. The location of the second malignancy was compared to the former irradiation volume. Patients with a second malignancy within or near the margin of the former irradiation portals and a latency of at least one year were selected for further analysis. Results: During follow-up of the 11,758 one-year-survivors, 937 second cancers were observed. 100 of the second malignancies were located in the former irradiation volume or at the field margins (66 f, 34 m, age median 52 yrs. (range 2–80 yrs., at time of first cancer diagnosis)). The median follow-up period was 13.3 years. Primary tumors of the 100 patients had mostly been breast cancer (27%), lymphoma (24%), gynecological tumors of pelvis (17%). The latency of the 100 field-associated second tumors was median 7.4 yrs. (1–42 yrs., including 2 pts. irradiated in childhood alio loco). Most of the second tumors were upper gastrointestinal carcinomas (18%) and colorectal carcinomas (12%), both with short latency of 5.6 resp. 3.5 years. Other second cancers were head and neck tumors (10%, incl few cases of thyroid cancer), lymphoma (10%), breast cancer (9%), sarcoma (9%) and lung cancer (8%). Second breast cancer and sarcoma had a long latency of 17.1 and 11.7 yrs. 5 years after diagnosis of the second tumor, only 35 of 100 patients were still alive. Conclusions: 100 of 11,758 irradiated patients (0.85%) developed a second malignancy in or near the irradiated region, suspicious for being induced by former therapy. The median follow-up of the 100 pts. had been 13.3 yrs., the median latency of the second tumor was 7.4 yrs. The second tumors occured mostly following irradiation of breast or chest wall with lymph nodes, extended field lymphoma radiotherapy or pelvic irradiation in gynecological tumors. Most of the second cancers were carcinomas, especially of the gastrointestinum. Only 35% of the patients were alive 5 years after diagnosis of the second cancer. Author Disclosure: B. Welte, None; P. Suhr, None; D. Bottke, None; T. Wiegel, None.
1078
Improved Radiation Pneumonitis Risk Modeling Using a Nonlinear Approach
I. El Naqa, J. D. Bradley, J. O. Deasy Washington University Medical School, St. Louis, MO Purpose/Objective(s): Individualized and patient-specific treatment planning decisions require accurate estimates of tumor control or complication risk to surrounding normal tissues. However, the inherent complexity and heterogeneity of the variables that characterize treatment response to radiation therapy require more robust methods for outcome-model building. In this work, we adapt a new form of statistical model-building known as kernel learning. We demonstrate the prognostic potential of this method in modeling radiation pneumonitis (RP) in a cohort of non-small cell lung cancer (NSCLC) patients. Materials/Methods: We considered a cohort of 219 patients diagnosed with NSCLC treated with 3D conformal radiation therapy with median dose of 70 Gy. 24% of the patients developed RP (RTOG grade $ 3). In our previous analysis (Hope et al., IJROBP ’06), from a pool of 58 variables that included dosimetric, spatial, and clinical factors, the following were found to be clinically significant on logistic regression analysis: superior-inferior mean tumor position (COM-SI) (p = 0.009), minimum dose to hottest 35% lung volume (D35) (p = 0.002), and the ICRU maximum dose (p = 0.038). A nonlinear support vector machine (SVM) was constructed using radial basis kernel. The SVM is characterized by width of the kernel (s) and a regularization parameter (C) that controls trade-off between complexity and fitting error. The main idea of the technique is to accurately distinguish between patients who are at low risk versus patients who are at high risk of RP in a higher dimensional space defined by the assortment of patient and treatment characteristics available. Results: To demonstrate the prediction power of the kernel-based method, we compared its discriminant ability with V20 (percentage lung volume receiving at least 20 Gy) and our previous best 3-parameter logistic regression model predictions using actuarial analysis of RP as shown in Figure 1. The complication-free rates were estimated using the Kaplan-Meier method. The figure indicates the strong discrimination power of SVM (p = 0.0005) compared to V20 (p = 0.201) and multi-metric logistic regression
Proceedings of the 49th Annual ASTRO Meeting (p = 0.029 for stratifying patients based on RP risk. Using Spearman correlation (Rs), SVM classifier achieved an Rs of 0.37 on cross-validation testing data compared to V20 (Rs = 0.18) and the logistic regression model (Rs = 0.22). Conclusions: We have demonstrated a new method for model building in radiotherapy based on nonlinear kernel-based statistical learning. The method effectively handles a high dimensional space of potentially important features. The method significantly improved (68%) on our previous best technique with respect to predicting RP.
Author Disclosure: I. El Naqa, None; J.D. Bradley, None; J.O. Deasy, None.
1079
Aluminum Hydroxide Plus Magnesium Hydroxide Plus Oxetacaine Suspension Versus Aluminum Hydroxide Plus Magnesium Hydroxide Suspension for Acute Radiation-Induced Esophagitis in Cancer Treatment: Final Results of a Double-Blind Randomized Trial
F. Bruns1, D. Riesenbeck2, R. Mu¨cke3, M. Klasser4, N. Willich2 1 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany, 2Department of Radiotherapy–Radiooncology, Muenster University Hospital, Muenster, Germany, 3Department of Radiotherapy, St. Josef Hospital, Wiesbaden, Germany, 4GWD Consult – contract research, Muehlheim, Germany
Purpose/Objective(s): To assess whether oral administered oxetacaine-containing suspension is effective in treating acute radiation-induced esophagitis in cancer patients. Materials/Methods: A double-blind, prospective-randomized clinical trial was conducted across 20 radiotherapy institutions in Germany. Patients with head and neck or thoracic cancer without dysphagia/odynophagia received definitive or postoperative radiotherapy [RT] (minimal total dose: 40 Gy; daily dose: #2.0 Gy) including at least 5 cm of the esophagus in the high dose volume and with or without chemotherapy. Patients were randomized to receive oral aluminum hydroxide plus magnesium hydroxide plus oxetacaine (TepiltaÒ) suspension or aluminum hydroxide plus magnesium hydroxide suspension without oxetacaine (MagaldratÒ) as first-line treatment for acute radiation-induced esophagitis. Primary endpoint(s) were the interval between begin of RT and failure of first-line treatment of esophagitis defined as need for additional systemic analgesics. Data on patients’ symptoms were collected during and for at least 2 weeks after treatment. Results: A total of 158 patients were enrolled in the study. 105 of them developed an acute esophagitis $grade 2 (CTC) and took at least one dose of study medication. 103 patients were eligible for statistical analysis according to the ITT principles; 51 patients received TepiltaÒ and 52 MagaldratÒ. The cumulative incidence of acute esophagitis $grade 2 (CTC) was 25% for the TepiltaÒ and 22% for the MagaldratÒ arm. A Kaplan-Meier survival analysis in which the time is taken into account, at which the pain therapy was delivered, reveals a statistically significant difference between the two groups with regard to the need for additional systemic analgesics in favor of TepiltaÒ (p = 0.032). No statistically significant difference was found between the two groups with respect to the secondary endpoints: need respective delay of additional parenteral nutrition (p = 0.28 respective p = 0.12), and patient’s respective investigator’s estimation of global effectivity of the study medication (0.08 and 0.12). Conclusions: This trial validated the effectivity of oral aluminum hydroxide plus magnesium hydroxide plus oxetacaine suspension (TepiltaÒ) in the first-line treatment of acute radiation-induced esophagitis. Author Disclosure: F. Bruns, Valeant Pharmaceuticals Germany, C. Other Research Support; D. Riesenbeck, None; R. Mu¨cke, None; M. Klasser, None; N. Willich, None.
S181