Author Disclosure: L. Geng, None; K.C. Cuneo, None; S. Konjeti, None; A. Fu, None; M. Cooper, None; D.E. Hallahan, None.

2639 Risk of Second Malignant Neoplasm After Cancer in Childhood Treated by Radiotherapy: CorrelationWith the Integral Dose

T. V. F. Nguyen1, C. Rubino1, S. Guerin1, I. Diallo1, A. Samand1, M. Hawkins2, O. Oberlin1, D. Lefkopoulos1,F. De Vathaire1

1Institut Gustave Roussy, Villejuif, France, 2University of Birmingham, Birmingham, United Kingdom

Purpose/Objective(s): After successful treatment of malignant diseases in childhood, the problem of long-term complicationscame to the fore. Few studies have focused on the relationship between the radiation dose received and the risk of developinga second malignant neoplasm (SMN). Most of them estimated risk coefficients according to the radiation dose received at thesite of the second cancer: thus, the estimated relative risk (RR) is the ratio between the risk of developing a cancer at a givensite that received a given dose and the risk of developing a cancer at the same site in the absence of this dose of radiation.

Materials/Methods: This approach does not really correspond to needs in clinical practice, where a global evaluation of therisk is required. In order to investigate the influence of radiotherapy on the overall risk of SMN after a childhood cancer in acohort of 4401 patients treated in 8 centres in France and UK between 1947 and 1986, we used another dose distributionparameter, defined as the Integral Dose, which provides an estimate of the total energy (in joules) delivered to the patient’s bodyduring radiotherapy. We also calculated the integral dose per kilogram (kg) by dividing each integral dose by the patient’sweight in order to obtain an average dose (in grays) delivered throughout the body. The superiority of these new parametersin the risks estimate is that they take into account the deposit of a given dose to a given volume of the body whatever theirradiated site. In our cohort, we highlighted a significant linear relationship between the integral dose and the risk of SMN.

Results: According to the linear model, after adjustment on chemotherapy (mainly alkylating and intercalating agents), theexcess risk of SMN was of 0.008 per unity of the integral dose. This coefficient increased to 0.017 if a negative exponentialterm was taken into account. With the integral dose per kg, these coefficients became respectively 0.23 and 0.48. For 20% ofthe patients who received the higher dose, the risk of SMN, compared to the non-irradiated patients, was 5.43 and 4.97,respectively for the integral dose and the integral dose per kg. Nevertheless, if we focus on patients who were treated byradiotherapy, only those who had received the highest integral dose had a higher risk and indeed, among the other patients,including 80% of the variability of the integral dose, no increased risk was evidenced. One of the main reasons is probably dueto the wide heterogeneity in our cohort which included patients treated for all types of solid cancers and inadequate adjustmenton chemotherapy whose combinations varied considerably. Finally, the estimated risk with the integral dose, in our study,cannot be considered as a good predictor of a later risk of SMN.

Conclusions: Modern radiotherapy techniques such as intensity modulated radiation therapy (IMRT) or tomotherapy involvea greater number of treatment beams exposing a larger volume of normal tissue to lower doses. It is therefore of paramountimportance to take into account the irradiated volume when evaluating the long-term adverse effect of these radiotherapytechniques. Thus, other studies with the same study design are obviously needed to evaluate the usefulness of the integral doseas a new tool of decision-making aid for choosing between different radiation therapy plans.

Author Disclosure: T.V.F. Nguyen, None; C. Rubino, None; S. Guerin, None; I. Diallo, None; A. Samand, None; M. Hawkins,None; O. Oberlin, None; D. Lefkopoulos, None; F. De vathaire, None.

2640 p53-Regulated Transcriptional Response to Radiation in the Cerebral Cortex

J. F. Dorsey, J. P. Plastaras, W. S. El-Deiry

University of Pennsylvania, Philadelphia, PA

Purpose/Objective(s): Recent investigations have revealed that p53 activates downstream targets in a highly regulated,selective, and tissue-specific manner. We therefore sought to characterize the p53-mediated transcriptional response to radiationin the CNS with the goal of increasing our understanding of the therapeutic index of radiation and potential toxicities. Acomprehensive gene expression analysis was performed.

S566 I. J. Radiation Oncology ● Biology ● Physics Volume 66, Number 3, Supplement, 2006

Materials/Methods: p53 is activated after irradiation and transcriptionally regulates selected targets in a tissue-specific manner.A global gene profile was obtained in the mouse cerebral cortex. Cohorts of 8–10 week old female p53�/� and p53-/- wereirradiated (5 Gy total body) or mock irradiated. Six hours later, mice were euthanized according to an approved IACUCprotocol. Cortex was rapidly dissected, isolated and flash-frozen in TRIZOL. Total RNA was isolated, purified, amplified,labeled, and hybridized to MOE430v2 gene chips (Affymetrix, Santa Clara, USA) containing probes for over 39,000 transcripts.Analysis was performed using Genespring and Affymetrix Microarray Suite version 5.0. All RNA processing and hybridizationwas carried out at the University of Pennsylvania School of Medicine Microarray Core Facility (Philadelphia, PA).

Results: We confirmed known p53 targets of transcriptional regulation in our microarray screen including p21-Waf1 andTrp53inp1. Other p53-dependent, pro-apoptotic mediators such as PUMA and NOXA were not upregulated to a significantdegree in contrast to our previous findings in the irradiated mouse colon. These findings are in line with the tissue-specific natureof p53 targets in response to DNA damage and the relative radioresponsiveness of early and late responding tissues. Selectedgenes upregulated in a p53-dependent manner after 5 Gy of radiation included SIN3B, Psmb3, Prss11, metallothionein 1 and2, and Beclin 1 (BECN1). Selected genes downregulated in a 53-dependent manner after 5 Gy of radiation includedSNRPN-Snurf, Cyclin I, and eukaryotic translation initiation factor 5A.

Conclusions: p53 profoundly regulates the transcription of multiple genes in the cerebral cortex in response to radiation.Although known apoptotic mediators PUMA and NOXA were not upregulated to an appreciable degree, the prominentautophagy gene BECN1 was identified as a p53 target of upregulation in this microarray screen. Examination of the promotersequence of BECN1 reveals putative p53 binding sites, reinforcing the validity of this finding. The potential role of autophagyin radiation-induced cell death, cell survival, and/or late-term toxicities remains unclear. However, one may speculate that thismechanism if important in the cortex in response to radiation, may potentially involve BECN1 in a p53-dependent manner.Further studies are currently ongoing to confirm the results of the microarray screen and to identify and characterize potentialmechanisms of p53-mediated radioresponsiveness and toxicity.

Author Disclosure: J.F. Dorsey, None; J.P. Plastaras, None; W.S. El-Deiry, None.

2641 Long Term Results Using Hypo-Fractionated Stereotactic Radiosurgery (HFSR) for Acoustic Neuroma(AN)

G. Lederman, G. Qian, M. Fastaia, B. Gilson, L. Cangiane

Cabrini Medical Center, New York, NY

Purpose/Objective(s): HFSR offers the potential advantage of relatively few divided low dose treatments with the precisionof stereotaxy for AN. HFSR is appealing because of radiobiological repair of normal surrounding structures while attemptingto maintain efficacy of treatment using a non-invasive relocatable frame.

Materials/Methods: 547 patients with 566 acoustic neuromas were treated between November 1993 and November 2005.Described are patients (pts) aged 21 - 88 years (mean 54) with unilateral AN ranging in volume from 0.05 - 33.6cc (mean 3.45).2000 Centigray (cGy) divided in 4 or 5 fractions was delivered utilizing stereotactic radiosurgery technique. Control after FSRis defined as cessation of growth, shrinkage or disappearance of the tumor in the treated field.

Results: Radiographic follow-up ranged from 6 - 121 mos (mean 37). Patients were followed with MRI and hearing tests in6 month intervals for the first two years and annually thereafter. Overall control rate for AN with radiographic follow-up was97%. Of pts(n�28) with follow-up greater than 7 years, control rate was 100%. Of pts with pure tone audiometry followupgreater than 12 months(mean 35, median 36), 84% had preservation of any testable hearing (Class I-IV Gardner-Robertson) and62% had preservation of serviceable hearing (Class I-II).

Conclusions: The majority of pts, after FSR maintain, serviceable hearing, avoid facial or trigeminal neuropathy and remainin remission years after treatment.

Author Disclosure: G. Lederman, None; G. Qian, None; M. Fastaia, None; B. Gilson, None; L. Cangiane, None.

2642 SAFORIS™ Decreases the Duration and Severity of Radiation-Induced Oral Mucositis (OM) in theHamster

A. L. Kiorpes1, B. Watkins2, S. Sonis2

1MGI PHARMA, Bloomington, MN, 2Biomodels, LLC, Cambridge, MA

Purpose/Objective(s): SAFORIS™ (glutamine in UpTec™) Powder for Oral Suspension is in development for the preventionand treatment of OM in patients receiving mucotoxic cancer therapy. This study evaluated and compared the effectiveness ofSAFORIS (500 mg/mL glutamine) when administered topically as a 0.2 mL suspension TID on 3 different treatment schedulesin a hamster cheek-pouch model of OM.

Materials/Methods: Mucositis was induced in Male Golden Syrian hamsters by a single dose of radiation (40 Gy/dose)administered on Day 0. Radiation was generated with a 160 kilovolt potential (18.75-ma) source at a focal distance of 21 cm,hardened with a 3.0 mm Al filtration system. Irradiation was targeted to the left buccal pouch mucosa at a rate of 3.32Gy/minute. Animals were anesthetized with xylazine and ketamine prior to irradiation and allocated to 5 groups of 8/group. InGroups 1 and 2, water and vehicle, respectively, were administered from Days -3 through 20 into the irradiated cheek pouches.Group 3 hamsters were administered SAFORIS from Days -3 through -1 (pre-radiation). Group 4 animals were treated withSAFORIS from Day 0 through Day 20 (post-radiation), and Group 5 animals were treated with SAFORIS from Days -3 through20 (pre- and post-radiation). Starting on Day 6 and continuing every other day through Day 28 (n � 12 observation days), cheekpouches were evaluated for OM on a scale of 0 (normal) to 5 (entire pouch ulcerated) and photographed. Two independentobservers scored the lesions in a blinded fashion from the photographs. A score �3 indicated clinical mucositis. Statisticalanalyses were performed using �2 and ANOVA.

Results: There was no evidence of toxicity, and no animals died during the study. There were significantly fewer days withmucositis scores of �3 (P�0.001) in the Group 4 and 5 hamsters compared with both water and vehicle control groups. There

S567Proceedings of the 48th Annual ASTRO Meeting