2033 (64) Cu-ATSM microPET Imaging of Tumor Hypoxia in Mammary Tumor Model: CompartmentalModeling and Immunohistochemistry Analysis

H. Yuan,1 Z. Wang,1 T. Schroeder,1 J.E. Bowsher,2,3 L.W. Hedlund,2,3 F. Yin,1 M.W. Dewhirst1

1Dept. Radiation Oncology, Duke University Medical Center, Durham, NC, 2Dept. Radiology, Duke University MedicalCenter, Durham, NC, 3The Center for In Vivo Microscopy, Duke University Medical Center, Durham, NC

Purpose/Objective: (64)Cu-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) is a recently developed PET imagingmarker for tumor hypoxia. However, its accuracy, reliability, and sensitivity have not been fully characterized in vivo. Also,activities from intravascular (64) Cu-ATSM that are not related to hypoxia, can also contribute to the PET signal. The purposeof this study is to validate its ability of hypoxia marker in animal mammary tumor model by comparing to immunostaining ofa well-known hypoxia marker, EF5, and further characterize the dynamic uptake of 64Cu-ATSM in tumors using compart-mental modeling to separate the intravascular signal contribution.

Materials/Methods: R3230 mammary adenocarcinoma (R3230Ac) was used as tumor model and was implanted in the flankof Fisher344 rat. A dynamic (64) Cu-ATSM microPET scan was performed with a microPET R4 system. Tumor/muscle ratioand time activity curves were acquired from PET imaging. To validate the spatial correlation between (64) Cu-ATSM uptakeand hypoxia area, EF5 and a vascular perfusion marker, Hoechst33342, were also administrated into the same animal duringmicroPET scanning for subsequent histological imaging. Electronic autoradiography was conducted on tumor sections from thesame animals. Images from microPET, autoradiography, EF5 immunostaining, Hoechst vascular perfusion, and H&E histologywere aligned, and the distribution of (64) Cu-ATSM in the tumor was compared to the EF5/Hoechst fluorescent images. Tofurther characterize the dynamic uptake of (64) Cu-ATSM in the tumor, a two-compartment model was used. In the model, the64Cu-ATSM concentration is separated into an intravascular concentration (Cp) with vascular volume fraction (Vp) andextravascular concentration (Ce) with effective interstitial volume fraction (Ve). The transfer between the intra- and extra-vascular compartments is described by rate constant k(in) and k(out). After non-linear least square (NLLS) fitting to thedynamic scan data, the overall radioisotope signal in the tumor was separated into intravascular and extravascular components.Vascular volume fraction Vp and rate constant k were also obtained from the fitting.

Results: The tumor-muscle ratio (T/M) of (64) Cu-ATSM measured by microPET in R3230Ac was 2.23 � 0.11, indicatinghigher uptake in the tumor. The comparison between autoradiography and EF5/Hoechst staining showed high correlationsbetween (64) Cu-ATSM uptake and hypoxia area (image correlation coefficient � 0.76). The area fraction of (64) Cu-ATSMuptake closely followed the area fraction of EF5 staining (0.24 � 0.04 vs. 0.21 � 0.03). The (64) Cu-ATSM uptake curves fromPET imaging were fitted well by a two-compartment model for the R3230Ac tumor. The time courses of the intravascular andextravascular (64) Cu-ATSM signals were obtained from the NLLS fitting. Vascular volume fraction (Vp) and transfer constant(kin) were (2.50 � 0.15) % and 0.045 � 0.001 1/min, respectively.

Conclusions: The distribution of (64) Cu-ATSM is closely correlated to tumor hypoxia in R3230Ac tumor. The uptake of(64)Cu-ATSM in R3230Ac can be also characterized by a compartmental model, which can effectively remove the intravas-cular radioisotope signal from the overall tissue signals, reflecting more accurately the tissue uptake and tumor hypoxia. Thecalculated tumor vascular volume fraction and transfer rate constant can be used to characterize the change of tumor hypoxiain the future study.

The work is supported by grants from the DOD (DAMD17-03-01-0367) and NIH/NCI (CA42745, R24 CA92656, and R24CA86307).

2034 The Use of Radiation in the Treatment of DCIS Is Not Influenced by the Type of Health Care System

E. Rakovitch, L. Paszat, C. Chartier, J. Pignol, W. Hanna

Sunnybrook & Women’s College Health Sciences Centre, Toronto, ON, Canada

Purpose/Objective: The efficacy of adjuvant radiation (XRT) in reducing the risk of breast recurrence following breast-conserving surgery (BCS) for DCIS has been demonstrated in three randomized controlled trials. Current treatment guidelinesreport that most women with DCIS will be candidates for XRT following lumpectomy. However, according to SEER data, inthe United States, only half of DCIS cases treated by lumpectomy in 1999 received XRT. The use of XRT varied significantlyby geographic location and demographic features such as age and race. The extent to which variations in the use of XRT occurin other populations with DCIS remains unknown. In Ontario, the delivery of radiotherapy services is provided by nine regionalcancer centers and permanent residents of Ontario have universal health care coverage. However, it remains unknown ifdifferences in health care systems result in increased utilization of radiotherapy in the management of women with DCIS.

Objective: To evaluate the use of adjuvant radiation following lumpectomy in a population of women diagnosed with DCISand to identify the factors associated with the use of adjuvant XRT.

Materials/Methods: We conducted a retrospective cohort study of all participants of the Ontario Breast Screening Program(OBSP) diagnosed with DCIS without microinvasion between 1991–2000. The following data has been collected: demographicdata (age, socioeconomic status, rural vs. urban), treatment data (type of breast surgery, axillary node dissection, received XRT)and tumor characteristics (tumor size, presence of comedo necrosis, nuclear grade, multifocality, margin status). Descriptivestatistics were used to characterize the patterns of XRT. Proportional differences were tested using chi-square tests forcategorical variables and mean differences for continuous variables by Students t-tests. Multivariate analysis with odds ratioestimates and their corresponding 95% confidence intervals were calculated while adjusting for confounders using logisticregression.

Results: From 1991 to 2000, a total of 320,236 women attended the OBSP for screening mammography. 727 cases of DCISwere identified and included in the study. The median age of the cohort is 62.7 yr (Range: 49 to 87 yr) with most womenpresenting with an abnormal mammogram (N�576 (79%)). Most cases were treated by breast-conserving surgery (N� 529(74%)), although mastectomy was performed in 187 cases (26%).

Over the time period of this study, referral rates to a cancer center increased from 59% in 1991–1993 to 81% in 2000(p�0.02). Overall, 49% (261/529) of cases of DCIS treated with BCS received radiation. The use of radiation increased from39% in 1991–1993 to 56% in 1997 and remained stable reaching 60% in 2000 (p� 0.04). Among women with high risk DCIS

S251Proceedings of the 47th Annual ASTRO Meeting