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Comparison of practice patterns and treatment techniques for regional nodal irradiation with breast conservation vs. postmastectomy in stage I-II breast cancer
S378
I. J. Radiation Oncology
● Biology ● Physics
Volume 60, Number 1, Supplement, 2004
2003]. In the current study, we explore the potential utility of Ly294002, a DNA-PK inhibitor, to enhance the cytotoxicity of combination of ionizing radiation and DNA topoisomerase I-targeted CPT in cultured mammalian cells. Materials/Methods: Clonogenic survival assays using various treatment protocols with combination of drugs and radiation were performed in Chinese hamster ovary V3, its DNA-PKcs-complemented V3⫹147b cells, and the human glioma D54-MG cells. DNA-PK activity of V3 and V3⫹147b cells was measured by dsDNA Cellulose Pull-down assay. DNA-PK activity in human D54-MG cells was determined by using SignaTECT DNA-PK assay system (Promega Corp., Madison, WI). Results: Analyzed by clonogenic survival assays, the DNA-PK inhibitor Ly294002 at 25, 50, 100 ?M had no enhancement effect on the cytotoxicity from combining radiation and CPT at 1 ?M in the Chinese hamster V3 cells, which expresses no DNA-PKcs and are deficient in DNA-PK activity. However, under the same conditions, Ly294002 markedly enhanced the cytotoxicity from combining radiation and CPT in the DNA-PKcs transfected Chinese hamster V3⫹147b cells, which are proficient in DNA-PK activity. There was no enhancement effect by Ly294002 on the cytotoxicity of CPT in both V3 and V3⫹147b cells. The enhancement effect on the cytotoxicity of combining radiation and CPT by Ly294002 correlates with its inhibitory effect on the DNA-PK activity in V3⫹147b cells. In addition, enhancement of the cytotoxicity of combining radiation and CPT was further examined in the human glioma D54-MG cells, which harbors wild-type DNA-PKcs and are proficient in DNA-PK activity. Consistently, Ly294002 at 25, 50 or 100 ?M had no enhancement effect on the cytotoxicity of CPT, but significantly enhanced the cytotoxicity of combining radiation and CPT in the D54-MG cells. Conclusions: Our findings indicate that Ly294002 can enhance cytotoxicity from combination of radiation and DNA topoisomerase I-targeted CPT in human glioma cells by inhibiting DNA-PK activity. Our data supports the notion that inhibitors of DNA-PK may be a useful adjuvant to combination therapy with radiation and TOP1-targeted drugs.
2071
Comparison of Practice Patterns and Treatment Techniques for Regional Nodal Irradiation with Breast Conservation vs. Postmastectomy in Stage I-II Breast Cancer
J. R. White,1 J. Moughan,2 L. J. Pierce,3 M. McNeese,4 J. Owen,2 J. F. Wilson1 1
Medical College of Wisconsin, Milwaukee, WI, 2ACR Patterns of Care Study, Philadelphia, PA, 3University of Michigan, Ann Arbor, MI, 4MD Anderson Cancer Center, Houston, TX Purpose/Objective: Regional nodal irradiation (RNI) after mastectomy has been the subject of much debate and has generated multiple guidelines about which population of node-positive breast cancer patients benefit most and how radiation should be executed. It is unclear whether similar criteria for RNI are being applied following breast conservation (BC) and mastectomy. The purpose of this study was to utilize the Patterns of Care Study (PCS) to examine how RNI was implemented in Stage I-II cases for BC compared to postmastectomy (PM). Materials/Methods: PCS used a two-staged stratified random sample to perform two separate surveys of breast cancer patients treated in 1998 –99:353 survey cases (71,877 weighted sample size [wss]) who underwent radiation after BC surgery and 405 survey cases (wss ⫽ 13,720) who received radiation PM. The surveys were conducted simultaneously at 59 randomly selected institutions. For this study, the analyzed population is node-positive and any node-negative breast cancer case that received RNI from both surveys. This resulted in 53 survey (wss ⫽ 11,105) BC cases and 208 survey (wss ⫽ 7,020) PM cases. Multivariate analysis was done to compare what factors were associated with the type of RNI utilized. Results: The populations that received RNI after BC and PM had statistically similar characteristics in terms of the distribution of ethnicity, principal payer, and menopausal status. Patients in the BC group who received RNI are slightly older: mean age was 59.3 yrs vs. 52.7 yrs in the PM group (p ⫽ 0.03). PM patients were more likely to be treated at higher volume facilities (treating ⬎500 cases/year, p ⫽ 0.01), and academic facilities (p ⫽ 0.0003) than their BC counterparts. Similar size tumors were treated with a mean tumor size of 2.1 cm for BC vs. 2.6 cm in the PM group (p ⫽ 0.10). Axillary dissection was performed for 72% of the BC cases and 100% of the PM cases (p ⫽ 0.004) with similar numbers of nodes within the specimen, (17.9 vs. 17.3 respectively; p ⫽ 0.76). After dissection in the BC group 25.4% were node-negative, 56.1% had 1–3 positive nodes, and 18.5% had ⱖ4 positive nodes compared to 10.9% node negative, 40.3% 1–3 positive nodes, and 48.8% ⱖ4 positive nodes for PM (p ⫽ 0.06). The distribution of nodal metastases differed significantly between BC and PM forⱖ4 positive nodes, (p ⫽ 0.02). Extra capsular extension was more frequent in the PM cases, 30.1% vs. 11.1% (p ⫽ 0.056). In the BC survey 47.4% of the patients with 1–3 and 90.6% of the ⱖ4 positive nodes underwent RNI. When RNI was performed in the BC survey, it included a supraclavicular field (SCL) 80.2%, an axillary (AX) field 36.7%, and internal mammary field (IM) 4.9% as compared to the PM survey, when RNI included a SCL for 98.8% (p ⫽ 0.0495), AX 42.5% (p ⫽ 0.64), and IM 28.2% (p ⫽ 0.005). CT based treatment planning for RNI was used for 35.8% for the BC patients compared to 21.1% for the PM (p ⫽ 0.26). In the PM group, lower energy (⬍8 MV/MEV) was used more frequently for the SCL (p ⫽ 0.0495) and AX (p ⫽ 0.10) fields. There were no other significant differences between the BC and PM groups in the radiation type (electron or photons), dose, and where the dose was recorded. On multivariate analysis of the BC cases, a T-2 tumor was associated with receiving RT to the SCL field (OR 4.3, p ⫽ 0.04). In the PM survey, a T-2 tumor size was associated with RNI to the AX field (OR 2.9, p ⫽ 0.03). When the two surveys are combined for multivariate analysis, patients with positive nodes (p ⬍ 0.0001) and patients in the PM survey (p ⫽ 0.004) had a higher chance of receiving RNI to the SCL field than negative node and BC patients respectively. Conclusions: Patients with Stages I-II breast cancer who received RNI in 1998 –99 after BC had similar size tumors but were less likely to have ⱖ4 positive nodes compared to those treated PM. RNI after BC was significantly less likely to include the internal mammary nodes. Having had a mastectomy rather than BCT was associated with the use of RNI.
I. J. Radiation Oncology
● Biology ● Physics
Volume 60, Number 1, Supplement, 2004
2003]. In the current study, we explore the potential utility of Ly294002, a DNA-PK inhibitor, to enhance the cytotoxicity of combination of ionizing radiation and DNA topoisomerase I-targeted CPT in cultured mammalian cells. Materials/Methods: Clonogenic survival assays using various treatment protocols with combination of drugs and radiation were performed in Chinese hamster ovary V3, its DNA-PKcs-complemented V3⫹147b cells, and the human glioma D54-MG cells. DNA-PK activity of V3 and V3⫹147b cells was measured by dsDNA Cellulose Pull-down assay. DNA-PK activity in human D54-MG cells was determined by using SignaTECT DNA-PK assay system (Promega Corp., Madison, WI). Results: Analyzed by clonogenic survival assays, the DNA-PK inhibitor Ly294002 at 25, 50, 100 ?M had no enhancement effect on the cytotoxicity from combining radiation and CPT at 1 ?M in the Chinese hamster V3 cells, which expresses no DNA-PKcs and are deficient in DNA-PK activity. However, under the same conditions, Ly294002 markedly enhanced the cytotoxicity from combining radiation and CPT in the DNA-PKcs transfected Chinese hamster V3⫹147b cells, which are proficient in DNA-PK activity. There was no enhancement effect by Ly294002 on the cytotoxicity of CPT in both V3 and V3⫹147b cells. The enhancement effect on the cytotoxicity of combining radiation and CPT by Ly294002 correlates with its inhibitory effect on the DNA-PK activity in V3⫹147b cells. In addition, enhancement of the cytotoxicity of combining radiation and CPT was further examined in the human glioma D54-MG cells, which harbors wild-type DNA-PKcs and are proficient in DNA-PK activity. Consistently, Ly294002 at 25, 50 or 100 ?M had no enhancement effect on the cytotoxicity of CPT, but significantly enhanced the cytotoxicity of combining radiation and CPT in the D54-MG cells. Conclusions: Our findings indicate that Ly294002 can enhance cytotoxicity from combination of radiation and DNA topoisomerase I-targeted CPT in human glioma cells by inhibiting DNA-PK activity. Our data supports the notion that inhibitors of DNA-PK may be a useful adjuvant to combination therapy with radiation and TOP1-targeted drugs.
2071
Comparison of Practice Patterns and Treatment Techniques for Regional Nodal Irradiation with Breast Conservation vs. Postmastectomy in Stage I-II Breast Cancer
J. R. White,1 J. Moughan,2 L. J. Pierce,3 M. McNeese,4 J. Owen,2 J. F. Wilson1 1
Medical College of Wisconsin, Milwaukee, WI, 2ACR Patterns of Care Study, Philadelphia, PA, 3University of Michigan, Ann Arbor, MI, 4MD Anderson Cancer Center, Houston, TX Purpose/Objective: Regional nodal irradiation (RNI) after mastectomy has been the subject of much debate and has generated multiple guidelines about which population of node-positive breast cancer patients benefit most and how radiation should be executed. It is unclear whether similar criteria for RNI are being applied following breast conservation (BC) and mastectomy. The purpose of this study was to utilize the Patterns of Care Study (PCS) to examine how RNI was implemented in Stage I-II cases for BC compared to postmastectomy (PM). Materials/Methods: PCS used a two-staged stratified random sample to perform two separate surveys of breast cancer patients treated in 1998 –99:353 survey cases (71,877 weighted sample size [wss]) who underwent radiation after BC surgery and 405 survey cases (wss ⫽ 13,720) who received radiation PM. The surveys were conducted simultaneously at 59 randomly selected institutions. For this study, the analyzed population is node-positive and any node-negative breast cancer case that received RNI from both surveys. This resulted in 53 survey (wss ⫽ 11,105) BC cases and 208 survey (wss ⫽ 7,020) PM cases. Multivariate analysis was done to compare what factors were associated with the type of RNI utilized. Results: The populations that received RNI after BC and PM had statistically similar characteristics in terms of the distribution of ethnicity, principal payer, and menopausal status. Patients in the BC group who received RNI are slightly older: mean age was 59.3 yrs vs. 52.7 yrs in the PM group (p ⫽ 0.03). PM patients were more likely to be treated at higher volume facilities (treating ⬎500 cases/year, p ⫽ 0.01), and academic facilities (p ⫽ 0.0003) than their BC counterparts. Similar size tumors were treated with a mean tumor size of 2.1 cm for BC vs. 2.6 cm in the PM group (p ⫽ 0.10). Axillary dissection was performed for 72% of the BC cases and 100% of the PM cases (p ⫽ 0.004) with similar numbers of nodes within the specimen, (17.9 vs. 17.3 respectively; p ⫽ 0.76). After dissection in the BC group 25.4% were node-negative, 56.1% had 1–3 positive nodes, and 18.5% had ⱖ4 positive nodes compared to 10.9% node negative, 40.3% 1–3 positive nodes, and 48.8% ⱖ4 positive nodes for PM (p ⫽ 0.06). The distribution of nodal metastases differed significantly between BC and PM forⱖ4 positive nodes, (p ⫽ 0.02). Extra capsular extension was more frequent in the PM cases, 30.1% vs. 11.1% (p ⫽ 0.056). In the BC survey 47.4% of the patients with 1–3 and 90.6% of the ⱖ4 positive nodes underwent RNI. When RNI was performed in the BC survey, it included a supraclavicular field (SCL) 80.2%, an axillary (AX) field 36.7%, and internal mammary field (IM) 4.9% as compared to the PM survey, when RNI included a SCL for 98.8% (p ⫽ 0.0495), AX 42.5% (p ⫽ 0.64), and IM 28.2% (p ⫽ 0.005). CT based treatment planning for RNI was used for 35.8% for the BC patients compared to 21.1% for the PM (p ⫽ 0.26). In the PM group, lower energy (⬍8 MV/MEV) was used more frequently for the SCL (p ⫽ 0.0495) and AX (p ⫽ 0.10) fields. There were no other significant differences between the BC and PM groups in the radiation type (electron or photons), dose, and where the dose was recorded. On multivariate analysis of the BC cases, a T-2 tumor was associated with receiving RT to the SCL field (OR 4.3, p ⫽ 0.04). In the PM survey, a T-2 tumor size was associated with RNI to the AX field (OR 2.9, p ⫽ 0.03). When the two surveys are combined for multivariate analysis, patients with positive nodes (p ⬍ 0.0001) and patients in the PM survey (p ⫽ 0.004) had a higher chance of receiving RNI to the SCL field than negative node and BC patients respectively. Conclusions: Patients with Stages I-II breast cancer who received RNI in 1998 –99 after BC had similar size tumors but were less likely to have ⱖ4 positive nodes compared to those treated PM. RNI after BC was significantly less likely to include the internal mammary nodes. Having had a mastectomy rather than BCT was associated with the use of RNI.