Proceedings of the 49th Annual ASTRO Meeting S81

141 Liver Regeneration in Patients With Intrahepatic Malignancies Treated with Focal Liver Radiation Therapy

C. C. Pan, U. Krishnan, D. Normolle, T. S. Lawrence, R. K. Ten Haken

University of Michigan, Ann Arbor, MI

Purpose/Objective(s): Hepatocytes display regenerative capabilities following partial tissue loss, such as after surgical resection.We have noted anecdotally that within 6 months of treatment, the liver undergoes fibrosis in the high dose region and regenerates inthe low dose region. The aim of this study was to quantify liver segment volume changes following radiotherapy (RT) and deter-mine any relationship to radiation dose.

Materials/Methods: Serial CT scans (pre-RT and 1–6 months post-RT) of patients with intrahepatic malignancies treated withfocal liver 3D-conformal RT and intrahepatic arterial chemotherapy were used for this retrospective study. Stable, anatomical land-marks were used to delineate the left lateral and medial segments, right anterior and posterior segments, and caudate lobe. Volumechanges and mean radiation doses delivered to liver segments are reported. The change in volume (% DV) between pre-RT and 1–6months post-RT as a function of mean dose to a segment was modeled using a repeated measures ANOVA.

Results: 54 patients were studied, including 12 hepatocellular carcinomas (HCC), 16 cholangiocarcinomas (CC), and 26 metastaticcolorectal carcinomas (CRC). In 31 patients, both liver atrophy and hypertrophy were observed in different segments, with a radi-ation dose dependency. Eighty-seven percent (27/31) had hypertrophy in the segment receiving the lowest radiation dose. Seventy-four percent (23/31) had the most atrophy in the segment receiving the highest radiation dose. At 60 days post-RT, the atrophyingsegments had a mean volume change (range) of �145.8 cm3 (�79.3, �212.3) and a mean dose of 43.7 Gy (39.9, 47.5). The hy-pertrophying segments showed a mean increase of 115.7 cm3 (88.7, 142.7), with a mean dose of 17.8 Gy (14.7, 20.9). Thesechanges persisted when measured .100 days post-RT. A mixed linear model for liver %DV between pre-RT and 1–6 monthspost-RT versus dose revealed a slope of �1.1%/Gy (�1.3%/Gy, �1.0%/Gy) with an intercept of 26.8% (21.6%, 31.9%), p \0.0001. This model was most significant regardless of liver segment or histology. On average, liver regeneration may be inhibitedfor mean liver segment doses .23.9 Gy.

Conclusions: Initial results suggest that liver regeneration can occur in the minimally irradiated liver segments following high-dosefocal RT. A model based on these data may predict volume changes in specific liver segments as a function of radiation dose. Thismodel can help guide future IMRT treatment planning in patients with limited liver function.

Author Disclosure: C.C. Pan, None; U. Krishnan, None; D. Normolle, None; T.S. Lawrence, None; R.K. Ten Haken, None.

142 Update of the Results of the Dutch Multicenter Dose Escalation Trial of Radiotherapy for Localized

Prostate Cancer

A. Al-Mamgani1, W. van Putten1, W. Heemsbergen2, M. Hoogeman1, A. Slot3, M. Dielwart4, J. Lebesque2, L. Incrocci1

1Department of Radiotherapy-Erasmus Medical Center, Rotterdam, The Netherlands, 2The Netherlands Cancer Institute, Antonivan Leeuwenhoek Hospital, Amsterdam, The Netherlands, 3Radiotherapeutic Institute Friesland, Leeuwarden, The Netherlands,4Zeeuws Radiotherapeutic Institute, Vlissingen, The Netherlands

Background: The Dutch Multicenter Dose Escalation Trial has shown, after a median follow-up of 51 months, that an increase inthe dose of radiotherapy by 10 Gy (68 v 78 Gy) is beneficial for patients with localized prostate cancer in terms of Freedom FromFailure (FFF), without statistically significant differences in Freedom From Clinical Failure (FFCF) and Overall survival (OS).

Purpose: We report on an updated analysis of this trial after a median follow-up of 69 months.

Materials/Methods: This study entered 669 patients with stage T1a-4 prostate cancer between June 1997 and February 2003. Pa-tients were randomly assigned to receive 68 or 78 Gy with external beam radiotherapy. Follow-up data were available until June2006. The median follow-up time was 69 months (range 9–115 months). Patients were stratified by age, institution, use of (neo)-adjuvant hormonal therapy, and treatment groups. The primary end point was FFF, which was defined as clinical or biochemicalfailure, according to the American Society of Therapeutic Radiation Oncology definition. Secondary end points were FFCF, OS,Genitourinary (GU) and Gastrointestinal (GI) toxicities.

Results: FFF is still significantly better in the 78-Gy arm compared with the 68-Gy arm (at 7-year follow-up, FFF rate is 57% v45%, respectively), with an adjusted hazard ratio of 0.75 (p = 0.015). However, no differences in OS (75% v 74% at 7 years, HR =0.93, p = 0.66) and FFCF (70% v 69% at 7 years, HR = 0.99, p = 0.96) were observed. The cumulative incidence of late GU toxicityof RTOG/EORTC grade 2 or higher was the same in both arms (36% at 5 years and 40% at 7 years), while the cumulative incidenceof late GI toxicity of RTOG/EORTC grade 2 or higher was increased in the 78-Gy arm (36% v 25% at 7 years, p = 0.04).

Conclusions: This Multicenter Randomized Trial still shows a statistically significant improvement in FFF in prostate cancerpatients treated with 78 Gy of external beam radiotherapy without statistically significant differences in FFCF and OS. LateGU toxicity was similar in both treatment arms, but there is a higher rate of late GI toxicity in the 78-Gy arm.

Author Disclosure: A. Al-Mamgani, None; W. van Putten, None; W. Heemsbergen, None; M. Hoogeman, None; A. Slot, None;M. Dielwart, None; J. Lebesque, None; L. Incrocci, None.

143 Surrogate Endpoints for Prostate Cancer Survival: A Secondary Analysis of RTOG 9202

M. E. Ray1, K. Bae2, M. H. A. Hussain3, G. E. Hanks4, W. U. Shipley5, H. M. Sandler3

1Radiology Associates of Appleton, Appleton, WI, 2Radiation Therapy Oncology Group, Philadelphia, PA, 3University ofMichigan, Ann Arbor, MI, 4Fox Chase Cancer Center, Philadelphia, PA, 5Massachusetts General Hospital, Boston, MA

Purpose/Objective(s): The identification of surrogate endpoints for survival would accelerate the conduct of prostate cancerclinical trials. We evaluated the incidence of distant metastasis (DM) and general clinical failure (GCF) as potential surrogatemarkers for cause-specific survival (CSS) using data from RTOG 9202.

S82 I. J. Radiation Oncology d Biology d Physics Volume 69, Number 3, Supplement, 2007

Materials/Methods: Men with locally-advanced prostate cancer were treated with 4 months of neoadjuvant and concurrent an-drogen deprivation (AD) with external beam radiation therapy (RT) followed by no additional therapy (standard arm) or 24 addi-tional months of AD (experimental arm). General clinical failure (GCF) was defined as local progression, regional/distantmetastasis, initiation of hormonal therapy, or PSA $ 25 ng/mL after completion of RT (Taylor et al, IJROBP 50:1212, 2001).DM and GCF with 5 years follow up were formally tested for surrogacy for CSS at 10 years. Surrogacy testing utilized Prentice’scriteria: 1) that the treatment is prognostic for the true endpoint; 2) that the treatment is prognostic for the surrogate endpoint; 3) thatthe surrogate endpoint is prognostic for the true endpoint; and 4) that the full effect of treatment on the true endpoint is explained bythe surrogate. Landmark analyses at 3 and 5 years were performed to address potential follow up length bias.

Results: Among 1521 eligible, randomized patients, there were 218 cause-specific deaths, 291 DMs and 726 GCFs. The 10-yearCSS was 85% in the standard arm, compared with 89% in the experimental arm (p = 0.0089). The 5-year DM and GCF rates were14% and 43% in the standard arm, compared with 9% and 33% in the experimental arm (HR = 1.7 [1.2–2.4] and 1.6 [1.3–1.9],respectively). Both 5-year DM and 5-year GCF were significantly associated with 10-year CSS (p \ 0.0001 and p = 0.0005,respectively). 10-year CSS was independent of treatment among patients who experienced DM (p = 0.63) or GCF (p = 0.23),and 10-year CSS was independent of treatment among patients who did not experience DM (p = 0.60) or GCF (p = 0.69), indicatingthat the 5-year surrogates both capture the full effect of treatment on 10-year CSS. Therefore, without adjusting for length bias,5-year DM and GCF both satisfied all of Prentice’s criteria for 10-year CSS. The analysis using only the 1364 patients alive atlandmark time 3 years, showed that both 3-year DM and GCF satisfied all of Prentice’s criteria for 10-year CSS. In the 1178 patientsalive at a landmark time of 5 years, there was no statistical difference in CSS between the treatment arms (p = 0.08). Nonetheless,5-year DM and GCF met the most important of the remaining Prentice’s criteria for 10-year CSS.

Conclusions: This analysis of patient data from RTOG 9202 demonstrates that DM and GCF at 5 years satisfy Prentice’s surrogacycriteria for CSS at 10 years. These endpoints should be validated in future randomized clinical trials for localized prostate cancer.

Supported by NCI grants U10 CA21661, U10 CA37422, U10 CA32115.

Author Disclosure: M.E. Ray, None; K. Bae, None; M.H.A. Hussain, None; G.E. Hanks, None; W.U. Shipley, None; H.M.Sandler, None.

144 Radiation Therapy in Prostate Cancer Patients and Survival–A Population-Based Study

E. H. Zhou1,2, R. J. Ellis2,3, F. Xu1, E. Cherullo2, S. Gupta2, A. Storfer-Isser1, W. Chen4, V. Collussi5, D. A. Kaminsky3,S. M. Koroukian1, et al.1Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, 2Department of Urology,University Hospital of Cleveland, Cleveland, OH, 3Department of Radiation Oncology, Aultman Hospital, Canton, OH,4Department of Medicine, Case Western Reserve University, Cleveland, OH, 5Department of Radiation Oncology,Case Western Reserve University, Cleveland, OH

Purpose/Objective(s): The optimal therapy for management of prostate cancer is still debatable. Through the use of a large pop-ulation-based retrospective cohort study of prostate cancer patients, we investigated the association of overall survival (OS) anddisease specific survival (DSS) with standard treatment modalities including: brachytherapy (BT), external beam radiation therapy(EBRT), radical prostatectomy (RP), hormonal therapy (HT), and watchful waiting/active surveillance (WW/AS).

Materials/Methods: Using the Ohio Cancer-Aging Linked Database developed by linking records from the Ohio Cancer Inci-dence Surveillance System with Medicare and Death Certificate files, we identified a cohort of N = 11,453 men 65 years and olderwith incident prostate cancer diagnosed between 1999 and 2001. We analyzed the 7-year OS and DSS among the 5 different clin-ically accepted procedures including curative therapies such as BT, EBRT, and RP, versus HT alone used for conservative man-agement of disease progression or by WW/AS observation. The patient attributes that were accounted for included: age, race,comorbidities, cancer stage, Gleason score, and treatment method.

Results: OS and DSS rates were 65.8% and 89.7% for the whole cohort at 7-year, respectively. DSS rates were 93.0% and 30.1%for the patients with localized disease versus patients who presented with distant adenocarcinoma of the prostate, respectively. Forthe localized-disease cohort, the DSS rates were 97.8%, 97.0%, 92.8%, 91.6%, and 89.1% at 7-year, for RP, BT, EBRT, WW/AS,or HT treatment groups; respectively. After controlling for age, race, comorbidities, stage, and Gleason score, the hazard of prostatecancer specific death was similar in patients receiving EBRT compared to RP; and marginally better for men receiving BT than RP(Hazard ratio = 0.7, 0.47–1.03). Additionally, a 1.6–2.1 folds higher hazard ratio was identified among those who did not undergoa curative interventions such as RP, BT, or EBRT within 6 months following initial diagnosis of localized disease.

Conclusions: Large population-based studies on survival may provide useful and important insights for use by physicians andpatients in determining appropriate disease management. After controlling for patient age, race, comorbidities, cancer stage andGleason score, we show in this study that patients in the treatment groups for curative therapy (BT, RP or EBRT) demonstrateimproved DSS compared to those without curative therapy initiated within 6 months of presenting with localized disease. Thesedata indicate that additional study is warranted, to improve clinical determinates in the selection of appropriate management ofprostate cancer, and to improve predictive modeling for which patient subsets may benefit most from definitive therapy, versusconservative management and/or observation.

Author Disclosure: E.H. Zhou, None; R.J. Ellis, None; F. Xu, None; E. Cherullo, None; S. Gupta, None; A. Storfer-Isser, None; W.Chen, None; V. Collussi, None; D.A. Kaminsky, None; S.M. Koroukian, National Cancer Institute (K07 CA096705), B. ResearchGrant.

145 Does Image Guidance Need to be Performed Daily in the Treatment of Localized Prostate Cancers?

Implications on Treatment Margins

S. Meeks, P. A. Kupelian, C. Lee, T. Willoughby, O. Zeidan, K. Langen

M. D. Anderson Cancer Center Orlando, Orlando, FL

Purpose/Objective(s): To compare the residual localization errors with different image-guidance (IG) strategies utilized in thealignment of prostate cancer patients. Using data from patients who were treated with daily IG, the remaining set-up errors forseveral different strategies were retrospectively calculated.