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e15151 Background: We examined whether 133 germline polymorphisms (SNPs) in 15 candidate genes (CSF1R, IL8RA, TLR4, IL10, IL10RA, CTLA4, IL2, IL2RA, TGF b1, ICOS, IL13, IL13RA2, IFNgR, IL15 and IL15RA) would predict clinical outcome in the ACCORD-12 phase III trial which randomly compared neoadjuvant radiotherapy (RT) plus capecitabine (CAP45) with dose-intensified RT plus capecitabine and oxaliplatin (CAPOX50) in T3-4 Nx M0 resectable rectal cancer. Methods: A candidate-gene association study was conducted in 316 patients (n = 161 in the CAPOX50 and n = 155 in the CAP45 arm). The primary end-point was tumor response according to the Dworak score in each arm. Logistic regressions were used to assess univariate/multivariate associations. The Storey and Tibshirani method based on the control of false discovery rate was used ( q-value < 0.10 (adjusted p-value) considered as true discovery). Multivariate models adjusted on treatment arm and T stage were performed to determine prognostic and predictive values of SNPs for tumor response. Results: In univariate analysis, two SNPs in IL2RA (rs11256456: OR = 5.1 [2.38; 11] and rs706781: OR = 4.2 [1.98 ; 8.74]) were significantly associated with the Dworak score in the CAP45 arm, and one in IL2RA the CAPOX50 arm (rs2104286: OR = 0.11 [0.01 ; 0.90]. All were confirmed in the multivariate analysis. A significant haplotypic effect was observed in the CAP-45 arm (p = 0.0001). Interaction was significant for IL2RA rs11256456 ( p= 0.03) and rs706781 ( p= 0.002) and no significant for IL2RA rs2104286 ( p= 0.722), suggesting a predictive deleterious effect the first two ones for response to oxaliplatin-based chemoRT, and a prognostic effect of the third one for response to chemoRT (+/- oxaliplatin). None of the three IL2RA SNPs were correlated with survival in the multivariate analysis. Conclusions: This pharmacogenetic analysis shows that SNPs in IL2RA have a significant association with response to chemoRT with capecitabine in patients with locally advanced rectal cancer. Their predictive effect may identify patients in whom oxaliplatin addition to chemoRT is deleterious.

1094 Background: With the necessity of reducing randomized clinical trial (RCT) duration, cost and number of patients, surrogate endpoints of overall survival (OS) are increasingly being used in cancer RCTs. However, most of these endpoints currently lack of standardized definition enabling a comparison of RCT results. Some recommendations have been proposed for specific cancer sites but they do not rely on a formal consensus methodology. The objective of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project is to provide guidelines to standardize definitions of time-to-event endpoints in RCTs for different cancer sites. Here, we present results for BREAST cancer. Methods: We relied on the modified Delphi consensus method, a validated formalized consensus process for the development of practice guidelines. International experts with various backgrounds and expertises were involved. First, the coordinating committee, a group of statisticians and epidemiologists involved in the design and conduct of RCTs, led a comprehensive literature review to identify time-to-event endpoints, events of interest and the existence of guidelines in adjuvant and metastatic settings. The steering committee, which included additional medical experts, validated the list and prepared the questionnaire sent for rating to an independent expert committee. Results: The consensus process involved 2 rounds of scoring (31 experts) and 1 in-person meeting (in parallel to ASCO'12). Each expert had to rate on a 1-9 scale if s/he agreed or not for including events (e.g. death from breast cancer) in the definition of time-to-event endpoints (e.g. progression-free survival). 150 events had to be scored for the 11 selected endpoints. Consensus was reached for 57% of the events after the 2 rounds of scoring. After the in-person meeting, consensus was reached for all the remaining events except one. Conclusions: The DATECAN guidelines should help standardizing definitions of commonly used endpoints. This process should (i) facilitate the comparison of RCTs and (ii) improve the quality of future RCTs by providing better estimation of sample size and treatment effect.

4098 Background: The combination of radiotherapy and chemotherapy is a mainstay for anal cancer. Improving local control could avoid mutilating salvage. We evaluate the role of an intensified strat...

TPS131 Background: Ductal carcinoma in situ is defined as breast cancer confined to the ducts of the breast without evidence of penetration of the basement membrane. Local treatment quality represents one of the most prognostic factors as half of recurrences are invasive diseases. The main goal of adjuvant radiotherapy after conservative surgery is to decrease local recurrences and to permit breast conservation with low treatment-induced sequelae. Several randomized trials have established the impact of 50 Gy to the whole breast (WB) in terms of local control. Nevertheless, no randomized trial is still available concerning the role of the boost in this disease. The phase III randomized trial “BONBIS” is elaborated to evaluate the impact of a 16-Gy boost after 50 Gy delivered to the whole breast in 25 fractions and 33 days. Methods: A total of 1,950 DCIS breast cancer patients are planned to be enrolled in this trial. Patients will receive the following treatment: (A) WB radiotherapy of 50 Gy in 25 fractio...

LBA4007 Background: Following the results of randomized trials FFCD 9203 and EORTC 2291, neoadjuvant CT-RT is considered standard treatment for LARC. The ACCORD 12/0405 PRODIGE 2 trial was initiated to optimize this regimen. Methods: Pts with T3 or resectable T4 N0–1-2 M0, rectal adenocarcinoma were randomized to arm A: concurrent RT 45Gy/25f/5 weeks (w) + capecitabine (800mg/m2/bid) or arm B: concurrent RT 50Gy/25f/5w + capecitabine (800mg/m2/bid/5/7days) + oxaliplatine 50mg/m2/w. Resection with Total Mesorectum Excision was scheduled 6 weeks after the end of CT-RT. Adjuvant chemotherapy was optional. 590 patients were needed to show an increase in the pathological complete response (Dworak) rate from 11% (arm A) to 20% (arm B). Circumferential positive rectal margin (CRM R1) was defined as the presence of residual cancer cells within 0 to 1 mm from the perirectal surface. Results: This trial closed in 07/2008 after randomization of 598 pts since 11/2005. Patients characteristics of 586 eligible pts were well balanced: male 66%, median age 61 years, 66% low rectum, 87% T3 stage. Data base was locked in March 2009. Results are reported in Table . Conclusions: The RT 50 capox regimen is compatible with surgery in 98% of cases with no increase in postoperative complication. In the RT 50 arm, there is a trend in favour of a higher rate of pathological complete sterilization and lower rate of positive CRM. These data could contribute to design a new standard preoperative regimen for LARC. 50 Gy/25 F/5 weeks combined with concurrent chemotherapy could be proposed as an efficient schedule. [Table: see text] No significant financial relationships to disclose.

4527 Background: The role of adjuvant chemoradiotherapy (CRT) in resectable pancreatic cancer is debated. This randomized phase II intergroup study demonstrated the feasibility and tolerability of a gemcitabine-based CRT regimen after R0 resection of pancreatic head cancer (Proc ASCO 2008, 4514). Long term and survival data are now reported. Methods: Patients were randomized within 8 weeks after surgery to receive either 4 cycles of gemcitabine 1000 mg/m2 given over 30 minutes every 3 weeks (control arm) or gemcitabine 1000 mg/m2 for 2 cycles followed by weekly gemcitabine 300 mg/m2 with concurrent radiation of 50.4 Gy given in 28 fractions of 1.8 Gy (experimental arm). The co-primary endpoints were completion of treatment and tolerability. Secondary endpoints were late toxicity, DFS and OS. Results: Between 9/04 and 1/07, 90 patients were randomized by 29 centers (45:45). Treatment arms were balanced in terms of patient/tumour characteristics. Follow-up was equal for both arms with an overall median follow-up of 27.1 months. In the control arm, 5 patients were ineligible, including 2 not treated. In the experimental arm, CRT was delivered to 36 of 45 patients (80%). Treatment was completed per protocol by 86.7% and 73.3% (80% CI 63.1–81.9%) of randomized patients in the control and experimental arms, respectively. Grade 4 toxicity was 0% and 4.4%, respectively. In the CRT arm, 2 patients experienced grade 3 late toxicity (anorexia 1 and epigastric pain 1). In the CRT experimental arm, 33 DFS events were noted and 23 deaths versus 34 and 24, respectively, in the control arm. Median DFS was 12 months in the experimental arm vs. 11 months in the control arm (p=0.6). Median overall survival was 24 months both in the experimental arm and the control arm. Distant progression was similar in both arms while the rate of first local recurrence was lower in the chemoradiation arm (11 vs 24 %, p=0.16). Conclusions: Post-op modern gemcitabine-based CRT is feasible and well- tolerated after long-term follow-up, and a larger trial should assess its true benefit to that of standard gemcitabine alone. [Table: see text]

e20590 Background: Oropharyngeal candidiasis (OPC) is usually considered as a frequent and manageable complication of cancer treatments. International guidelines recommend the use of broad spectrum local antifungal agents as first line treatment using old published data. In 2008, we elaborated a prospective pharmaco- epidemiological survey (Candidoscope) to update the prevalence and the management of OPC in France. Methods: Candidoscope concerned patients suffering from solid tumors or non-Hodgkin's lymphoma (NHL) and still under treatments. Thirty-five French centres participated in this survey. Patients were screened during a consecutive period of 15 days and were included in a registry to estimate OPC prevalence. Exclusion criteria was the use of antifungal agents within the last 15 days before the beginning of the the present study. OPC was defined clinically. Patients diagnosed for OPC were selected to the second part of the study detailing OPC treatments. Results: Overall, 2,027 patients were registered. OPC prevalence was 9.6% (n=195). Breast cancer population was the most frequent disease presenting untreated OPC (n= 47, 24%). The prevalence of OPC in head and neck, digestive cancer, and NHL patients was 30%, 20%, and 20%, respectively. Patients with combined treatments presented the highest OPC prevalence (nearly 22%). The most common clinical presentation for OPC was the erythematous form (62%). Main OPC symptoms were dry mouth (63%), altered taste (60%), pain (43%), dysphagia (42%), and appetite disorders (31%) with an average weight loss of 4kg. Local antifungal agents (amphotericin B, nystatin, and miconazole muco-adhesive buccal tablet (MBT)) were given in 75% of patients (41%, 12%, and 22%, respectively). Compliance to treatment was respectively 19%, 40%, and 88% for nystatin, amphotericin B with mouthwashes, and MBT. Conclusions: The prevalence of OPC in treated cancer patients is frequent with important clinical consequences. Systemic treatment compliance delivered according to the international guidelines is often poor and are strongly improved by the use of daily MBT. No significant financial relationships to disclose.

15030 Background: To assess the role of pelvic radiotherapy (RT) in the outcome of patients treated with chemotherapy (CT) with or without surgery in the management of metastatic rectal cancer. Met...

4089 Background: Both the FFCD 9203 [J Clin Oncol 2006;24:4620–5] and the EORTC 22921 [NEJM 2006;355:1114–23] trials showed superiority of neoadjuvant chemoradiation (CT-RT) to radiotherapy (RT) al...

9629 Background: Locally advanced stage III or IV squamous cell carcinomas of head and neck warrant treatment concurrent chemoradiotherapy. In 45–50% of cases, mucositis grade NCI 3 or 4 underwent ...

614 Background: In experimental and clinical trials, tamoxifen (TAM) has been shown to increase radiation-induced lung fibrosis (RILF). Aromatase inhibitors (AI) are superior to TAM in the adjuvant setting, and preclinical data suggest that letrozole (LET) sensitizes breast cancer cells to ionizing radiation. However, poor data are available regarding the toxicity of concurrent use of AI and radiation therapy (RT). In this experimental study, we evaluated whether AI have any impact on the development of RILF in rats. Methods: 60 female wistar- albino rats were divided into 6 groups: control (group A), RT alone (group B), RT + TAM (group C), RT + anastrozole (ANA group D), RT + LET (group E), and RT + exemestane (EXE, group F). RT consisted of 30 Gy in 10 fractions to both lungs with an anterior field at 2-cm depth. Equivalent doses for 60 kg adult dose per day of TAM, ANA, LET, and EXE i.e. 20 mg, 1 mg, 2.5 mg, 25 mg, respectively, were calculated according to the mean weight of rats which was 200 gr and ...

8554 Purpose: A multicenter randomized study comparing after breast-conservative surgery, sequential versus concurrent adjuvant chemotherapy (CT) with radiation therapy (RT) was initiated (ARCOSEI). After a median follow-up of 6.7 (4.3–9) years, we assessed prospectively late effects and cosmesis satisfaction of these two strategies. Methods and material: After breast-conserving surgery, patients were treated either with sequential treatment with CT first followed by RT (arm A) or CT administered concurrently with the same normofractinnated breast RT (arm B).With structured questions, 214 patients (107 in each arm) rated their satisfaction considering cosmesis, the difference in overall appearance, and specific changes of the breast. Late toxicity (LENT/SOMA scale) and cosmesis were blinded to treatment and assessed by a radiation oncologist by a qualitative scale and another semi-qualitative and semi-quantitative evaluation. Results: Subcutaneous fibrosis (SF), telangectasia (T), skin pigmentation (SP), and breast atrophy (BA) were significantly increased in arm B. Patient’s cosmesis satisfaction was not statistically different between the two arms with 92.6% of good results in arm A and 86% in arm B (p=0.72); although patients have found more important differences in the treated breast in arm B than in arm A, with 28.8% vs 14.3% of bad results, respectively. Physician’s prospective assessment found less favorable cosmesis results with concomitant treatment than with sequential one, with 40% and 15% of unsatisfaction, respectively (p=0.0014) using a semi-quantitative and qualitative scale; The use of a subjective 5-point scale found also a worse physician’s cosmesis satisfaction in arm B than in arm A (p=0.0013) Conclusion: The concurrent use of CT with RT is significantly associated with an increase incidence of grade 2 or greater late side effects. Rating of cosmesis is also subjective. Patients’ satisfaction with cosmesis is greater than the doctors’ for concomitant radiochemotherapy in breast cancer, and is not only determined by radiation late effects. With two methods, physician found a worse cosmesis outcome for concomitant radiochemotherapeutic arm. No significant financial relationships to disclose.

630 Background: Trastuzumab (T) combined with chemotherapy (CT) has been recently shown to improve the outcome in patients with HER2-positive breast cancer. Its administration either weekly or every 3 weeks for one year is recommended as adjuvant therapy. Nevertheless, little is known about the toxicity of radiotherapy (RT) and T administered concurrently. Methods: Since June 2005, 95 patients (pts) with stage II-III HER2-positive breast cancer were treated concurrently with adjuvant T and RT. At this time, 53 have completed their combined therapy. Median age was 48y and 22 pts were menopausal. Twelve and 41 pts received T weekly or every 3 weeks, respectively. Neoadjuvant CT using anthracyclin/taxane regimen was administered in 27 pts. T was initiated after the last cycle of anthracyclin. Hormonal treatment was given to 17 hormone-receptor positive pts. RT was delivered to the whole breast (45–50 Gy ± a 10 to 16 Gy-boost, n=24) or to the chest wall (50 Gy, n=29). Internal mammary chain (IMC) and supraclavicular nodes were irradiated in 41 pts. Toxicity assessment (dermatitis, esophagitis and left ventricular dysfunction) was implemented according to the CTC v3.0 criteria. Results: Grade (G) 2 or more skin and esophageal toxicities were observed in 27/53 (51%) and 7/53 (13%) pts, respectively. Post-RT left ventricular dysfunction was observed in 22 pts (G1 in 14, G2 in 6, and G3 in 2). In univariate analyses, unfavorable factors influencing G2 or more cardiac toxicity were postmenopausal status (p=0.03), IMC irradiation (p=0.005) and weekly T administration (p=0.0001). Multivariate analysis revealed the concurrent administration of weekly T and RT (WTRT) as an unfavorable independent prognostic factor for cardiac toxicity (p=0.0001) and for G2 or more dermatitis (p=0.05). The two unfavorable prognostic factors for esophagitis (G2 or more) were concurrent administration of WTRT (p=0.008) and total mastectomy (p=0.004). Conclusion: Our preliminary results show that in addition to increased skin and esophageal acute toxicities, concurrent administration of weekly T and RT significantly decreases the left ventricular ejection fraction compared to the 3-week schedule. Results for the whole cohort will be presented at the meeting. No significant financial relationships to disclose.

10585 Background: The purpose of this study was to identify potential prognostic factors of early relapse among postmenopausal women with ER+ breast cancer treated at least by adjuvant tamoxifen therapy. Methods: This was a multi-center, retrospective study. Data was collected from 1588 subjects on demographic and subject characteristics and the subjects’ course of the disease using information from patient files. It was planned to have data to cover a follow-up period of ten years. Frequency distributions of the pre-specified potential prognostic factors were presented for subjects with relapse or death (RoD) below 3 years (early), RoD after at least 3 years (late) and without RoD recorded. Results: There were 1550 subjects included in the analysis population. The median age was 60 years [52–67]. There were 633 patients (40.8%) with an event for RoD. Median relapse-free survival time (RFS) was 165 months (no confidence interval calculation possible due to low event rate) and lower quartile relapse-free survival time was 68 months [95% CI, 59–76]. Concerning RFS 212 (13.7%) subjects had an early relapse and 421 (31.5%) had a late relapse. Out of 1550 subjects analyzed for overall survival, there were 344 (22.2%) with an event. Median survival time was not reached; lower quartile survival time was 143 months [131–176 months]. The Cox regression for RFS showed that prognostic factors for RFS overall and for early RFS seems to have similar patterns. Prognostic factors for late RFS differed from those for RFS overall and early RFS. The Cox regression for overall survival showed similar results. SBR grade 1 or 2 vs. 3 (p < 0.0001), No significant financial relationships to disclose.

4099 Background: We previously reported results a phase I trial of weekly docetaxel concurrently with radiation therapy in patients (pts) with locally advanced pancreatic adenocarcinoma (Pancreas, Vol 27, N°3, 2003). We prospectively explored this regimen in 34 pts with biopsy proven potentially resectable pancreatic adenocarcinoma. Methods: Treatment consisted of concomitant radiotherapy (45 Gy within 5 weeks directed at the pancreatic tumor and regional lymphatics) with 5 weekly doses of docetaxel (30 mg/m2/week) by 1-hour infusion, followed by a complete staging evaluation 3–4 weeks after chemo-radiation. Pts without disease progression underwent surgery. Results: From May, 2003 to July, 2005, this study enrolled 34 pts (59% men) with median age 62 years (range 45–72). Median tumor size was 3 cm. Pretreatment Endoscopic Ultrasound (EUS) staging was uT1 (7 pts), uT2 (25 pts), uT3 (2pts), uN0 (26 pts) and uN1 (8 pts). Median pretreatment CA 19.9 levels was 114 (range 1–9432). All pts (97%) but one completed radiation and 91% (31 pts) received the 5 weekly doses of docetaxel. Adverse events included grade 3/4 asthenia (28%), grade 3/4 nausea/vomiting (10%), grade 3/4 anemia (7%) and grade 3/4 neutropenia (7%). Median time between diagnosis and surgery was 3.7 months (range 2.8–8.7). Ten pts (29%) presented progressive disease after chemo-radiation and one additional patient (pt) voluntary stopped treatment procedure. Twenty three pts (68%) underwent surgical procedure, which was with curative intent in 17 pts (50%). One pt died within the 30-day post operative period. Pathological response was observed in 7 pts (30%), including 2 complete response. The median Disease Free Survival (DFS) was 11 months and the 2-year DFS was 21%. The median overall survival (OS) was 14 months. The 2-year DFS for the 17 pts resected with a curative intent was 50.4%. In this subgroup, median overall survival was not reached. Conclusions: Pre-operative combination of radiotherapy and docetaxel is feasible with tolerable toxicity and with promising pathological response. A randomized phase III study comparing this regimen (radiotherapy and docetaxel) and surgery versus surgery alone is starting. Supported in part by Sanofi Aventis, France. No significant financial relationships to disclose.

5516 Background: The concept of expecting radiosensitive tumors in patients genetically hypersensitive to radiation is not widely accepted. Here, we aim to assess whether the tumors of patients with increased lymphocyte apoptotic response with head and neck cancer have a better outcome than their normoresponsive counterparts. Methods: Seventy-five patients with head and neck cancer treated with curative radiation therapy (RT) were included in the KFS 00539–9-1997/SKL 00778–2-1999 prospective study aiming at assessing the value of CD8 T-lymphocyte apoptosis in predicting intrinsic radiosensitivity. Male to female ratio was 60/15, and median age was 59 years (35–85). Median radiation dose was 66 Gy (60–74.4) administered in median 41 days (37–58). Dose per fraction was 2 Gy in the majority of the patients (n = 70). Prior to RT, all patients were tested using a rapid (48 h) apoptosis assay where fresh blood samples were irradiated with 8-Gy X rays. Lymphocytes were collected and prepared for flow cytometric ...