underwent total abdominal hysterectomy, bilateral salpingo-ophorectomy and lymph node dissection. 34 patients receivedadjuvant pelvic or extended field radiation therapy (RT) using 4 fields of 18 MV photons; in most cases, 45 Gy was given toareas at risk for microscopic disease. Selected areas of gross disease or high risk received additional RT to a total dose of upto 57 Gy. The median follow-up of patients not dying of disease was 60 months and all patients but one were followed for 5years or until death, or to within 12 months of analysis. Survival rates were calculated using the Kaplan-Meier method, withdifferences assessed using log-rank tests.

Results: Of 41 patients, 18 (44%) had only pelvic lymph nodes involved, 8 (19%) had only paraaortic lymph nodes (PANs)and 14 had both pelvic and PAN involvement. Most patients (25, 60%) had grade 2 cancers; 12 patients had grade 3, and 2patients had grade 1 cancers. 61% had deep (�50%) myometrial invasion and 32% had involvement of the cervix.

Of the 41 patients in this study, 33 (80%) were treated with curative intent using RT; 3 also received concurrentchemotherapy and 5 received adjuvant chemotherapy or hormonal therapy. For these 33 patients, the 5-year disease-specificsurvival (DSS) was 73%. At 5 years, the DSS of patients treated with RT for positive pelvic nodes only was 63% vs. 79% forthose with PANs (P � NS). Eleven patients relapsed after RT; the sites of first relapse were in the distal vagina (4 patients),pelvic wall (1 patient), supraclavicular nodes (3 patients), PANs (2 patients), and brain (1 patient). There was one recurrencewithin the irradiated field. Four recurrances were salvaged with re-irradiation. Two of these were patients recurred above thepelvic radiation field in the PANs and two were distal vaginal recurrances. There were two grade 4 small bowel obstructionsin patients treated with RT for an overall major complication rate of 5.7%.

Seven of 43 patients (18.6%) did not receive RT. Two patients died of perioperative cardiac complications. Of the remainingfive, three received adjuvant carboplatin and one was treated with Megace alone. Two received no further treatment. Of the fiveremaining patients that did not receive radiation, four developed progressive pelvic disease in the vagina (2) and pelvic wall(2). Two of the four recurrences were salvaged; one in the pelvis with radiation therapy the second in the vagina with hormonaltherapy.

Conclusions: Treatment with lymph node dissection and postoperative RT achieved a high rate of cure in patients with stageIIIC adenocarcinoma of the endometrium. Locoregional failures were common in patients who did not receive RT. In somecases, isolated recurrences occurring in unirradiated sites may be cured with salvage RT.

Author Disclosure: P.J. Eifel, None; A.H. Klopp, None; L.M. Ramondetta, None; D.M. Gershenson, None; A. Jhingran, None.

1066 Tissue Transglutaminase Expression in Early-Stage Cervical Cancer

Z. N. Rabbani, J. P. Kirkpatrick, F. K. Salahuddin, R. C. Bentley, A. A. Secord, C. S. Greenberg, L. J. Havrilesky,Z. Vujaskovic, E. Jones, M. W. Dewhirst

Duke University Medical Center, Durham, NC

Purpose/Objective(s): Tissue transglutaminase (tTG) is a ubiquitously expressed enzyme that modifies proteins by crosslink-ing or polyamination. It is implicated in apoptosis, signal transduction, drug-resistance, cell growth, endocytosis, cell adhesion,cataract formation, and wound healing. It also plays an important role in metastasis and extracellular matrix assembly.

Objective: To investigate the expression of tTG and its role in the carcinogenesis of operable cervical tumors.

Materials/Methods: We reviewed the charts of women who underwent a radical hysterectomy (RH) at our institution between1986 and 2001 as definitive treatment for early-stage cervical cancer. A total of 315 patients, predominantly FIGO stage IB,were identified. Pathologic specimens from any patient who recurred or who had a follow-up of at least three years andremained disease-free were examined. The blocks from patients with adequate tumor specimens were cut and the slides stainedfor tTG. The extent and intensity of staining in the tumor specimen were measured in tumor cells/stroma, and an immuno-histochemical (IHC) score determined from the product of the extent (0-100%) and intensity (0-3). All reading pathologistswere blinded to clinical outcome. Survival curves were generated and the outcome compared by the log-rank method.

Results: Forty-two relapsing patients and 76 non-relapsing patients with a minimum of 3 years follow-up were included in theanalysis. In the overall group, the median follow-up was 59.6 months (range 4-195 months), the median age 44.9 years (range19.4-79.8 years), and 27 patients were found to have positive lymph nodes at the time of surgery. The histology was squamouscell, adencarcinoma, adenosquamous and other in 84, 22, 7 and 5 patients, respectively. FIGO stage was IA, IB and IIA in 3,105, and 5 patients; it could not be determined from the clinical data in 5 patients. Stratifying patients by extent of tumor cellsexpressing tTG less than versus greater than or equal to 50%, freedom from recurrence was significantly poorer for specimenswith elevated extent of expression (p �0.020, 5-year FFR 68 versus 38%). For the same stratification, freedom from distantmetastases approached but did not reach statistical significance (p�0.066, 5-year FFDM 84 versus 58%), while freedom fromlocal recurrence (FFLR) was not different (p�0.18). Intensity of staining and IHC score, in either the tumor or stroma did notpredict for FFR, FFDM or FFLR.

Conclusions: Elevated tTG expression in tumor cells was a statistically significant prognostic factor of freedom from recurrencein early-stage cervical cancer. As in other organ sites, the data also suggest that tTG is associated with increased metastaticpotential. tTG expression in tumor specimens obtained at RH could be an indication for more aggressive adjuvant therapy.

Support for this work came from a grant from Varian Corporation.

Author Disclosure: Z.N. Rabbani, None; J.P. Kirkpatrick, None; F.K. Salahuddin, None; R.C. Bentley, None; A.A. Secord,None; C.S. Greenberg, None; L.J. Havrilesky, None; Z. Vujaskovic, None; E. Jones, None; M.W. Dewhirst, None.

1067 Predictors of Tumor Response and Downstaging in Patients Treated with Preoperative Chemoradiationfor Rectal Cancer

P. Das, J. M. Skibber, M. A. Rodriguez-Bigas, B. W. Feig, G. J. Chang, R. A. Wolff, C. Eng, N. A. Janjan, S. Krishnan,C. H. Crane

U.T. M.D. Anderson Cancer Center, Houston, TX

Purpose/Objective(s): To identify predictive factors for pathologic complete response and tumor downstaging in patientstreated with preoperative chemoradiation for rectal cancer.

S167Proceedings of the 48th Annual ASTRO Meeting

Materials/Methods: Between 1989 and 2004, 562 patients with rectal adenocarcinoma and no evidence of distant metastasiswere treated with preoperative chemoradiation followed by mesorectal excision. Clinical T stage was T2 in 6%, T3 in 84%, T4in 9% and unknown in 1%. Clinical nodal stage was N0 in 44%, N1-2 in 55% and unknown in 2%. Median radiation dose was45 Gy (range 19.8-58.6 Gy), 99% received � 45 Gy, 77% received concurrent infusional 5-FU, 20% received concurrentcapecitabine, and 3% received other fluoropyrimidine-based regimens. Chi-square tests and logistic regression analysis wereused to identify univariate and multivariate predictors of pathologic complete response (CR) and T stage downstaging. Thefollowing potential predictors were evaluated: age, sex, race, clinical T stage, clinical N stage, presence of mucinous features,grade, distance from the anal verge, circumferential extent of tumor, tumor size, anal canal involvement, pretreatmentcarcinoembryonic antigen (CEA) level, radiotherapy dose and type of chemotherapy.

Results: Among the 562 patients, 115 (20%) had a pathologic CR, 107 (19%) had only microscopic residual disease at surgery,and 340 (61%) had gross residual disease at surgery. Downstaging of the T stage occurred in 316 (57%) patients. PathologicT stage was T0 in 20%, T1 in 6%, T2 in 28%, T3 in 39%, and T4 in 5%. Univariate analysis showed that tumor circumferentialextent �60% (P�0.033) and pretreatment CEA level �2.5 ng/ml (P�0.015) were significantly associated with a higherpathologic CR rate. Univariate analysis also showed that tumor circumferential extent �60% (P�0.001), pretreatment CEAlevel �2.5 ng/ml (P�0.006), and distance from the anal verge �5 cm (P�0.035) were significantly associated with a higherdownstaging rate. Multivariate logistic regression analysis showed that lower circumferential extent of tumor (odds ratio,OR�0.43, P�0.033) independently predicted for a higher pathologic CR rate. The pathologic CR rate was 24% for tumors withcircumferential extent �60%, and 15% for those with circumferential extent �60%. Multivariate logistic regression analysisalso showed that lower circumferential extent of tumor (OR�0.49, P�0.020) and lower distance from the anal verge(OR�0.46, P�0.010) independently predicted for a higher downstaging rate. The downstaging rate was 65% for tumors withcircumferential extent �60%, and 49% for those with circumferential extent �60%. The downstaging rate was 61% for tumorslocated �5 cm from the anal verge, and 52% for those located �5 cm from the anal verge.

Conclusions: Circumferential extent of tumor appears to be a significant clinical predictor of pathologic response topreoperative chemoradiation for rectal cancer. Circumferential extent of tumor could, therefore, be used to target patients formore aggressive preoperative regimens, and to stratify patients in trials on newer preoperative regimens.

Author Disclosure: P. Das, None; J.M. Skibber, None; M.A. Rodriguez-Bigas, None; B.W. Feig, None; G.J. Chang, None; R.A.Wolff, None; C. Eng, None; N.A. Janjan, None; S. Krishnan, None; C.H. Crane, None.

1068 Chemoradiation With Infusional 5FU and ZD1839 (Gefitinib - Iressa TM) in Patients With LocallyAdvanced Rectal Cancer: a Phase II Trial

V. Valentini1, A. De Paoli2, M. A. Gambacorta1, G. C. Mattiucci1, C. Ratto1, G. Boz2, R. Innocente2, C. Rossi2,M. Lupattelli3, G. B. Doglietto1

1Universityersita Cattolica S. Cuore, Rome 00168, Italy, 2Centro Riferimento Oncologico, Aviano, Italy, 3Universityersitadegli Studi, Perugia, Italy

Purpose/Objective(s): The recent reports of European randomized trials (CAO/ARO/AIO 94, EORTC 22921 FFCD 9203)support the use of preoperative chemoradiation in locally advanced rectal cancer. New chemotherapeutic agents in combinationof preoperative radiotherapy are tested in randomized phase II-III trials. The new targeted therapies (bevacizumab, cetuximab)are currently incorporated into phase I/II preoperative chemoradiation programs. We report the final data of a phase II studyon the combination of an anti-EGFR drug (gefitinib), plus infusional 5-fluorouracil, plus preoperative radiotherapy in T3 lowmedium rectal cancer.

Materials/Methods: Eligibility criteria included: histologically proven rectal carcinoma,T2-T3N0-2 stage, no comorbidity,age � 18 years; PS � 60 ; written informed consent. Patients (pts) received 50,4 Gy in the posterior pelvis (1.8 Gy/die).Infusional 5-Fluorouracil (225 mg/m2 die) and gefitinib (250 mg/die first 6 pts, 500 mg/die (MTD) the following pts) weredelivered during all radiotherapy course. An IORT boost of 10 Gy was allowed. The main endpoint of the study waspathological downstaging according to TRG Mandard Score: favourable events were classified as any TRG1 (no residualtumour) or TRG2 (residual isolated tumour cells). Fleming’s method was used to calculate the number of patients required. Asample size of 35 patients at the MTD is sufficient to give an 80% probability of rejecting the baseline pathological downstagingrate of 20% when the true rate is at the clinically relevant level of 40%. Toxicity was evaluated according CTC/RTOG scoresystems. Dose Limiting Events (DLT) were considered any Grade 3� GI, Skin and Haematological toxicity. Objective tumourresponse was based on RECIST criteria.

Results: 41 pts were enrolled in 3 Italian Centres between December 2002 and September 2005. 28 pts (68%) were male and13 female (32%); the mean age was 63.7 years (SD �9.1). 9 pts (22%) were stage II and 32 pts (78%) were stage III. The first6 pts didn’t show any DLT, the remaining 35 pts were available for the main endpoint of the study. 40 patients had at least oneo more adverse events, and overall 7 patients had one o more serious adverse event (17.5% ). Grade 3� diarrhoea was reportedin 5 pts (12%), and grade 3� skin toxicity in 6 pts (15%). 11 patients (27.5%) had Grade 1-2 proctitis, 5 patients had ALT levelincrease (12.5%), 4 (10%) experienced CTC 3-4 event. 25 pts (62.5%) had gefitinib dose interruption or reduction. 2 pts refusedthe experimental drug after the written consent and were not considered for the TRG analysis. TRG 1 was recorded in 10 pts(30.3%) and TRG 2 in 5 pts (15.2 %), overall 15/33 pts (45.5%) had a favourable endpoint. Looking at the 39 pts accordingto the intention to treatment (ITT) the rate of major response was 42.9% (15/39). The hypothesis that the baseline pathologicaldownstaging rate was about 20% can be reject at a level of probability less than 1% (p�0.01). Objective tumour response (CRand PR) based on RECIST criteria was 66.7%. All treated patients, except one, (97.4%) had a sphincter saving surgery.

Conclusions: The proportion of responder patients (42.9%) (ITT Group) results statistically (p�0.01) different as compared tothe baseline downstaging rate of 20%. The 95% Confidence Interval is within 30% and 56%. 25 pts (62.5%) had gefitinib doseinterruption or reduction.

Author Disclosure: V. Valentini, None; A. De Paoli, None; M.A. Gambacorta, None; G.C. Mattiucci, None; C. Ratto, None;G. Boz, None; R. Innocente, None; C. Rossi, None; M. Lupattelli, None; G.B. Doglietto, None.

S168 I. J. Radiation Oncology ● Biology ● Physics Volume 66, Number 3, Supplement, 2006