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Purpose: The identification of a robust IHC marker to predict the response to antiangiogenic bevacizumab in ovarian cancer is of high clinical interest. VEGF-A, the molecular target of bevacizumab, is expressed as multiple isoforms with pro- or antiangiogenic properties, of which VEGF-A165b is the most dominant antiangiogenic isoform. The balance of VEGF-A isoforms is closely related to the angiogenic capacity of a tumor and may define its vulnerability to antiangiogenic therapy. We investigated whether the expression of VEGF-A165b could be related to the effect of bevacizumab in advanced ovarian cancer patients. Experimental Design: Formalin-fixed paraffin-embedded tissues from 413 patients of the ICON7 multicenter phase III trial, treated with standard platinum-based chemotherapy with or without bevacizumab, were probed for VEGF-A165b expression by IHC. Results: In patients with low VEGF-A165b expression, the addition of bevacizumab to standard platinum-based chemotherapy significantly improved progression-free (HR: 0.727; 95% CI, 0.538–0.984; P = 0.039) and overall survival (HR: 0.662; 95% CI, 0.458–0.958; P = 0.029). Multivariate analysis showed that the addition of bevacizumab in low VEGF-A165b–expressing patients conferred significant improvements in progression-free survival (HR: 0.610; 95% CI, 0.446–0.834; P = 0.002) and overall survival (HR: 0.527; 95% CI, 0.359–0.775; P = 0.001), independently from established risk factors. Conclusions: We demonstrate for the first time that bevacizumab may differentially improve the prognosis of advanced ovarian cancer patients with low expression of VEGF-A165b, an antiangiogenic VEGF-A splice variant. We envision that this novel biomarker could be implemented into routine diagnostics and may have direct clinical implications for guiding bevacizumab-related treatment decisions in advanced ovarian cancer patients.

Purpose:The identification of a robust IHC marker to predict the response to antiangiogenic bevacizumab in ovarian cancer is of high clinical interest. VEGF-A, the molecular target of bevacizumab, is expressed as multiple isoforms with pro- or antiangiogenic properties, of which VEGF-A165b is the most dominant antiangiogenic isoform. The balance of VEGF-A isoforms is closely related to the angiogenic capacity of a tumor and may define its vulnerability to antiangiogenic therapy. We investigated whether the expression of VEGF-A165b could be related to the effect of bevacizumab in advanced ovarian cancer patients.Experimental Design:Formalin-fixed paraffin-embedded tissues from 413 patients of the ICON7 multicenter phase III trial, treated with standard platinum-based chemotherapy with or without bevacizumab, were probed for VEGF-A165b expression by IHC.Results:In patients with low VEGF-A165b expression, the addition of bevacizumab to standard platinum-based chemotherapy significantly improved progression-free (HR: 0.727; 95% CI, 0.538–0.984; P = 0.039) and overall survival (HR: 0.662; 95% CI, 0.458–0.958; P = 0.029). Multivariate analysis showed that the addition of bevacizumab in low VEGF-A165b–expressing patients conferred significant improvements in progression-free survival (HR: 0.610; 95% CI, 0.446–0.834; P = 0.002) and overall survival (HR: 0.527; 95% CI, 0.359–0.775; P = 0.001), independently from established risk factors.Conclusions:We demonstrate for the first time that bevacizumab may differentially improve the prognosis of advanced ovarian cancer patients with low expression of VEGF-A165b, an antiangiogenic VEGF-A splice variant. We envision that this novel biomarker could be implemented into routine diagnostics and may have direct clinical implications for guiding bevacizumab-related treatment decisions in advanced ovarian cancer patients.

Supplementary Figure from Bevacizumab May Differentially Improve Prognosis of Advanced Ovarian Cancer Patients with Low Expression of VEGF-A165b, an Antiangiogenic VEGF-A Splice Variant

PURPOSE To compare standard versus extended duration of bevacizumab treatment in combination with front-line chemotherapy in women with newly diagnosed stage IIB-IV ovarian cancer. METHODS In this multicenter, open-label, randomized phase III trial (ClinicalTrials.gov identifier: NCT01462890 ), patients with newly diagnosed International Federation of Gynecology and Obstetrics stage IIB-IV epithelial ovarian, fallopian tube, or peritoneal cancer underwent primary cytoreductive surgery followed by six cycles of chemotherapy (paclitaxel 175 mg/m2 plus carboplatin area under the curve 5 once every 3 weeks) and bevacizumab (15 mg/kg once every 3 weeks). Patients were randomly assigned 1:1 to receive bevacizumab for either 15 or 30 months, stratified by International Federation of Gynecology and Obstetrics stage/residual tumor. The primary end point was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary end points included overall survival (OS), safety, and tolerability. RESULTS Between November 11, 2011, and August 6, 2013, 927 women were randomly assigned. There was no difference in PFS between treatment arms (hazard ratio, 0.99; 95% CI, 0.85 to 1.15; unstratified log-rank P = .90). Median PFS was 24.2 versus 26.0 months with standard versus extended duration of bevacizumab, respectively; restricted mean PFS was 39.5 versus 39.3 months, respectively. There was no OS difference between treatment arms (hazard ratio, 1.04; 95% CI, 0.87 to 1.23; P = .68). Serious/nonserious adverse events of special interest occurred in 29% versus 34% of patients in the standard versus experimental arms, respectively, and were consistent with the known safety profile of standard bevacizumab. CONCLUSION Longer treatment duration with bevacizumab for up to 30 months did not improve PFS or OS in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer. A bevacizumab treatment duration of 15 months remains the standard of care.

BackgroundThere is limited information about the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer.ObjectiveTo evaluate the impact of radical surgery including pelvic and para-aortic lymphadenectomy and subsequent platinum-based chemotherapy on sexuality in patients with advanced ovarian cancer as a sub-protocol of the prospectively randomized LION trial.MethodsThe Sexual Activity Questionnaire was applied to assess sexual function according to its sub-scales activity, pleasure, and discomfort. The 'orgasm' sub-scale from the Female Sexual Function Index was also added. The questionnaire was administered in combination with the EORTC QLQ-C30 questionnaire at baseline prior surgery, after 6, 12, and 24 months. The primary endpoint was changes in sexual function.ResultsOverall, 495 patients received the questionnaires. 254 (51%) responded at baseline. Of these, 55 (22%) patients were sexually active, 182 (72%) were sexually inactive, and for 17 (7%) patients' data were not available. There was a total of 55/495 (11%) patients at 6 months, 139 (28%) patients at 12 months, and 81 (16%) patients at 24 months. Median age was 60.5 years (range 21.4–75.8). At baseline, sexually active responders were significantly younger (median age 51.5 years,) than sexually inactive responders (median age 61.8 years) and tended to have a better performance status. Discomfort evaluated as dryness of the vagina and pain during sexual intercourse was significantly worse at 12 months than at baseline (pConclusionThe majority of patients were sexually inactive; however, in those who were sexually active, pain during intercourse was worse at 12 months. In addition, the orgasm sub-scale demonstrated worse results in patients who underwent complete lymphadenectomy. The study suggests that surgery in the retroperitoneal space may influence sexual function.

Purpose: Predicting surgical outcome could improve individualizing treatment strategies for patients with advanced ovarian cancer. It has been suggested earlier that gene expression signatures (GES) might harbor the potential to predict surgical outcome. Experimental Design: Data derived from high-grade serous tumor tissue of FIGO stage IIIC/IV patients of AGO-OVAR11 trial were used to generate a transcriptome profiling. Previously identified molecular signatures were tested. A theoretical model was implemented to evaluate the impact of medically associated factors for residual disease (RD) on the performance of GES that predicts RD status. Results: A total of 266 patients met inclusion criteria, of those, 39.1% underwent complete resection. Previously reported GES did not predict RD in this cohort. Similarly, The Cancer Genome Atlas molecular subtypes, an independent de novo signature and the total gene expression dataset using all 21,000 genes were not able to predict RD status. Medical reasons for RD were identified as potential limiting factors that impact the ability to use GES to predict RD. In a center with high complete resection rates, a GES which would perfectly predict tumor biological RD would have a performance of only AUC 0.83, due to reasons other than tumor biology. Conclusions: Previously identified GES cannot be generalized. Medically associated factors for RD may be the main obstacle to predict surgical outcome in an all-comer population of patients with advanced ovarian cancer. If biomarkers derived from tumor tissue are used to predict outcome of patients with cancer, selection bias should be focused on to prevent overestimation of the power of such a biomarker. See related commentary by Handley and Sood, p. 9

Background:\ud State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin–paclitaxel or carboplatin–gemcitabine) or the most active non-bevacizumab regimen: carboplatin–pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin–pegylated liposomal doxorubicin combined with bevacizumab.\ud Methods:\ud This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m 2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m 2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251.\ud Findings:\ud Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin–pegylated liposomal doxorubicin–bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin–gemcitabine–bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3–21·7) in the experimental group and 11·3 months (8·0–18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7–14·2) in the experimental group versus 11·6 months (11·0–12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68–0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (

Introduction/Background Predicting surgical outcome could improve individualizing treatment strategies for pts with AOC. Several earlier papers have proposed that debulking signatures using RNA expression analyses might help in this regard. Methodology FFPE tumor tissue of FIGO stage IIIC/IV pts of AGO-OVAR 11 were used to generate whole-exome data. Previously identified molecular signatures (MS), including TCGA molecular subtype and three other published MPG, were tested. We used state-of the art biostatistical approaches for analyses. A theoretical model using data of a tertiary gynecologic cancer center was implemented to evaluate the impact of predictive factors for RD not directly related to tumor biology on the performance of a debulking signature model that predicts RD status (RD0 and RD Results Of the 266 pts that met inclusion criteria, 104 (39.1%) underwent complete resection. Previously reported MPG did not predict RD in this cohort. Best Area under the Curve (AUC) was generated using LR: 0.53±0.04. Similarly, TCGA molecular subtypes (AUC=0.56±0.04), an independent de novo signature (AUC=0.51±0.04), and the total gene expression data set using all 21,000 genes (AUC=0.55±0.03) were not able to predict RD status. We identified reasons unrelated to tumor biology that serve as potential limiting factors in the ability to use MS for predicting RD. Even in a centre with a complete resection rate higher than 65% in all comers, a debulking signature which perfectly predicts RD (100%) would have a predictive performance of only AUC 0.83, due to UTB. Conclusion Previously identified MPG cannot be generalized. Our theoretical model showed that factors unrelated to tumor biology limit the ability to identify a molecular debulking signature for RD. UTB may be the main obstacle to predict surgical outcome in an all comer Population. Disclosure FH: Advisory board: Roche, Tesaro, Honoraria: AstraZeneca, Roche, Tesaro, Clovis, travel/accommodation expenses: PharmaMar; Tesaro; SK: none ; RT: none; AG: none; LU: none; CA: none; AB:none; CW: none; UC: Advisory board/honoraria: Roche, Astra Zeneca; JW:none; AB: none; SP: none; LH:none; SM: none; BA: Advisory board: Roche, Tesaro, Amgen; honoraria: Celgene, Clovis, Astra Zeneca; travel/accommodation expenses: PharmaMar; FH: Honoraria: Roche, Tesaro, Clovis, Astra Zeneca, PharmaMar travel/accommodations/expenses: Astra Zeneca, Pharmamar; SS: none; JS:; RK: Advisory Role: Medtronic, Roche, Teva; Honoraria: AstraZeneca, Intuitive Surgical, Prostrakan, RIEMSER; travel/accommodations/expenses: Cambridge Medical Robotics; CK: none; BS: none; IB: Honoraria: Roche Pharma, CLOVIS, Tesaro, AstraZeneca, Seattle Genetics, Amgen; PH: Advisory Board: Astra Zeneca, Roche, Tesaro, Lilly, Clovis, Immunogen, MSD/Merck; Honoraria: Astra Zeneca, Roche, Sotio, Tesaro, Stryker, ASCO, Zai Lab, MSD; Research funding (Inst): Astra Zeneca, Roche, GSK, Boehringer Ingelheim, Medac, DFG, European Union, DKH, Tesaro, Genmab; SD: none; BW: none; JP: Advisory board: Clovis, Roche, AstraZeneca, Tesaro; Honoraria: Roche, AstraZeneca, Tesaro, Amgen, Clovis, MSD; travel/accommodations/expenses: Roche, Tesaro; AdB: advisory board: Roche, Astra Zeneca, Tesaro, Clovis, Pfizer, Biocad, Genmab, Seattle Genetics, MSD; Honoraria: Roche, Astra Zeneca, Tesaro, Clovis, Pfizer, Biocad, Genmab, Seattle Genetics, MSD.

Patients with non-platinum-sensitive recurrent ovarian cancer have a poor prognosis. Non-pegylated liposomal doxorubicin (Myocet®) is a promising drug that may be able to improve treatment for such patients. In the current study, patients with recurrent ovarian cancer relapsing within 12 months after primary treatment received non-pegylated liposomal doxorubicin at 75 mg/m2 d1q22 and 60 mg/m2 d1q22 after study dose modification, respectively. There were 29 patients enrolled in the trial, and 124 cycles of non-pegylated liposomal doxorubicin were administered in total. All 29 patients were evaluable for toxicity. The clinical benefit rate (defined as the proportion of patients with either complete remission or partial remission, or with stable disease for >6 months) was 50%. The predominant non-hematological toxicity was nausea and vomiting (18 patients, grade I/II), whilst no palmar plantar erythrodysesthesia was observed. In 3 patients, a grade III hematological toxicity occurred, and the treatment schedule was consequently modified to 60 mg/m2 d1q22. The findings suggest that non-pegylated liposomal doxorubicin administered in a schedule of 60 mg/m2 d1q22 is well-manageable and is associated with tolerable non-hematological toxicities (predominantly nausea).

Objective The aim of this study was to determine the response rate, toxicity, operability, and surgical complication rate of neoadjuvant concomitant radiochemotherapy (cRCH) (ifosfamide + carboplatin) followed by radical hysterectomy plus external-beam radiotherapy with curative intention in locally advanced primary inoperable stages IIB and IIIB squamous cell cervical cancer. Methods Patients with cervical cancer from 8 departments were enrolled. Patients received 3 cycles of ifosfamide 1.2 mg/m2 (+mesna 20%) plus carboplatin (area under the curve = 4), every 21 days, and concomitant external-beam radiotherapy (50.4 Gy [1.8 Gy/d]). Operability and remission were evaluated by clinical gynecological examination in general anesthesia (magnetic resonance imaging was optional), 4 weeks after the third cycle of cRCH. In case of achieved operability, a radical hysterectomy with pelvic lymphadenectomy was performed within 6 weeks after cRCH. If surgery was not performed because of incomplete remission or patient preferences, vaginal brachytherapy (15 Gy [5 Gy/d]) was given additionally. Results Forty-four patients were enrolled. Distribution of FIGO (International Federation of Gynecology and Obstetrics) tumor stage was as follows: IIB (19 patients) and IIIB (25 patients). All patients completed cRCH. Grade 3/4 hematologic toxicities (% of all cycles) were moderate: leukopenia, 7.3; thrombocytopenia, 2.4; and anemia, 3.2. In 13.8%, treatment cycles were delayed because of hematologic toxicity. Blood transfusions were given in 17.7% and granulocyte colony-stimulating factor in 39.5%. Overall, grade 3/4 nonhematologic toxicities were seldom (6.5%). Clinical overall response rate was 95.2%. Operability was achieved in 85.7%. Surgery was performed in 83.3%. Pathological response rates were as follows: pathological complete remission, 33.3%; partial remission, 63.3%; stable disease, 3.3%. Conclusions Our study demonstrates that cRCH is an effective and tolerable regimen in locally advanced cervical cancer treatment.

Purpose Bisphosphonates prevent skeletal-related events in patients with metastatic breast cancer. Their effect in early breast cancer is controversial. Ibandronate is an orally and intravenously available amino-bisphosphonate with a favorable toxicity profile. It therefore qualifies as potential agent for adjuvant use. Patients and Methods The GAIN (German Adjuvant Intergroup Node-Positive) study was an open-label, randomized, controlled phase III trial with a 2 × 2 factorial design. Patients with node-positive early breast cancer were randomly assigned 1:1 to two different dose-dense chemotherapy regimens and 2:1 to ibandronate 50 mg per day orally for 2 years or observation. In all, 2,640 patients and 728 events were estimated to be required to demonstrate an increase in disease-free survival (DFS) by ibandronate from 75% to 79.5% by using a two-sided α = .05 and 1-β of 80%. We report here the efficacy analysis for ibandronate, which was released by the independent data monitoring committee because the futility boundary was not crossed after 50% of the required DFS events were observed. Results Between June 2004 and August 2008, 2,015 patients were randomly assigned to ibandronate and 1,008 to observation. Patients randomly assigned to ibandronate showed no superior DFS or overall survival (OS) compared with patients randomly assigned to observation (DFS: hazard ratio, 0.945; 95% CI, 0.768 to 1.161; P = .589; OS: HR, 1.040; 95% CI, 0.763 to 1.419; P = .803). DFS was numerically longer if ibandronate was used in patients younger than 40 years or older than 60 years compared with patients age 40 to 59 years (test for interaction P = .093). Conclusion Adjuvant treatment with oral ibandronate did not improve outcome of patients with high-risk early breast cancer who received dose-dense chemotherapy.

The management of high-risk endometrial cancer (HREC) remains controversial. We conducted a prospective multicenter phase-II clinical trial to evaluate an adjuvant chemotherapy (CT) with sequential radiotherapy (RT) in patients with HREC.Patients with HREC from 8 institutions in Germany were enrolled. After surgery, patients received four cycles of paclitaxel 175 mg/m² (P) and carboplatin AUC5 (C) (d1, q21d) and subsequent external pelvic radiation therapy (1.8 Gy/d, d1-5) at a total dose of 45 Gy with vaginal brachytherapy (3 × 5 Gy). Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Primary endpoints were tolerability, toxicity and QoL. Progression-free survival (PFS) was defined as secondary endpoint.Thirty-five patients were enrolled from 2004 through 2008. Median follow-up was 24 months (range 3-24 months). All patients received 4 cycles of P and C and completed RT. Overall, grade 3/4 haematological toxicity was 25.6 %. Three cycles were delayed because of leukopenia. Grade 3/4 non-haematologic toxicities were rare (≤3 %). No overall change in QoL occurred during treatment. Two-year median PFS and OS rates were both 75.8 %.Adjuvant combination CT with P + C and sequential RT is well tolerated and a feasible regimen in patients with HREC. Subsequent phase-III trials are warranted.

Background: Several studies showed that pathologic complete response (pCR) is a surrogate for disease free survival (DFS) and overall survival (OS). Combinations of trastuzumab and anthracyclines in HER2-positive breast cancer are highly active but associated with a high incidence of cardiotoxicity. The risk of cardiac damage can be significantly reduced through liposomal encapsulation of anthracyclines. This phase I/II study was initiated to evaluate the combination of non-pegylated liposomal doxorubicin (NPLD), paclitaxel and lapatinib as primary treatment for patients with early stage, HER2-positive primary breast cancer. Patients and Methods: Patients with newly diagnosed HER2-positive (IHC 3+ or FISH+) early stage (T1c N1-2 or T2 N0-2) breast cancer were treated with NPLD (60mg/m2; day 1), paclitaxel (175mg/m2, day 1) and lapatinib (750–1500 mg orally daily) in 3-week intervals for up to 6 cycles. The primary endpoints were dose-limiting toxicities (DLT) and pathological complete response (pCR). Secondary endpoints include safety, incidence of cardiac events, and clinical response. Exploratory endpoints include molecular markers for sensitivity or resistance to chemotherapy and/or lapatinib evaluated. Results: A total of 84 patients have been included. No dose-limiting toxicity were observed and the maximum tolerated doses were NPLD 60mg/m2, paclitaxel 175mg/m2 and lapatinib 1500mg. Recommended phase 2 doses (P2D) were NPLD 60mg/m2, paclitaxel 175mg/m2 and lapatinib 1250mg. The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents. No cardiac event has been observed to date. Preliminary efficacy data confirm a pCR breast rate of 41.7% and pCR rate in breast and lymph nodes of 37.5%, in 32 evaluable patients treated at ≥P2D. Conclusions: The combination of NPLD, paclitaxel and lapatinib is well tolerated and has high antitumor activity in patients with HER2-positive primary breast cancer. Updated results of all 84 patients will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-05.

The combination of carboplatin and topotecan in platinum-sensitive relapsed ovarian cancer could not improve progression-free survival or overall survival compared with established standard regimens. Background Randomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC). Patients and methods Patients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m2/ days 1–3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes [(PC) paclitaxel plus carboplatin; (GC) gemcitabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin] which could be chosen by individual preference but before randomization. The primary end point was progression-free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points. Results A total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a median follow-up of 20 months, the median PFS was 10 months [95% confidence interval (CI) 9.4–10.6] and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4–27.6 resp. 26.0–36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P Conclusion The combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens.

Background: Bevacizumab has been reported to increase the risk of surgical complications, especially in pts treated with neoadjuvant chemotherapy. Methods: In January 2010 it was decided to collect surgical complications prospectively on a specifically developed from. All patients received chemotherapy with epirubicin/cyclophosphamide (EC) followed by docetaxel (T) with or w/o bevacizumab. Patients not responding to the first 4 cycles of EC+/−B were enrolled in another setting. All patients receiving bevacizumab were supposed to be operated at 5 weeks after the last infusion of bevacizumab. Results: Data from 699 patients have been prospectively collected, 329 received EC-T and 370 ECB-TB. Median age was 48 years in both arms. Median tumor size was 30mm in the ET-C arm vs 35mm in the ECB-TB arm (p=0.13). Multifocal or multicentric disease was present in 21% in the EC-T arm vs 22.4% (p=0.74). 36% of the patients received a sentinel node biopsy prior to start of neoadjuvant chemotherapy in both groups. 68.7% of patients received breast conserving therapy in the EC-T arm compared to 71.1% in the ECB-TB arm (p=0.54). The rate of pathological complete response was 19.5% with EC-T compared to 23.2% with ECB-TB (p=0.26). The median time from last CHT+/− bevacizumab to surgery was 29 days in EC-T and 34 days in ECB-TB. Bleeding or hematoma were reported in 6.7% of the patients treated by EC-T and 7.1% with ECB-TB (p=0.88). Wound infections or abscess were reported in 2.5% with EC-T and 3.9% with ECB-TB (p=0.39). Delayed wound healing was reported in 3.4% with EC-T and 6.3% with ECB-TB (p=0.11). Necrosis was reported in 1.9% with EC-T and 2.5% with ECB-TB (p=0.80). Any complication was reported in 11% with EC-T compared to 15.3% with ECB-TB (p=0.12). Conclusion: In general the rate of surgical complications was low. Patients treated with bevacizumab had a numerical increase of surgical complications. However, none of the differences were statistically significant. The intervals from last infusion to surgery as defined by the study protocol appear to be safe. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-14-05.

5575Background: There is limited information regarding the impact of radical surgery including pelvic and para-aortic lymphadenectomy (LNE) and subsequent chemotherapy on sexuality in patients (pts...

5550Background: Complete resection (CR) at primary debulking surgery is the single most important prognostic factor in AOC. It has been demonstrated, that suboptimal debulking (residual disease > 1...

5518Background: AGO-OVAR 16 study investigated PZ, an oral multi-kinase inhibitor of VEGFR-1, -2, -3, PDGFR-α and -β and c-Kit. This study was designed to test efficacy, safety and tolerability of ...

Second-line treatment with paclitaxel and carboplatin enhances survival of women with platinum-sensitive recurrent ovarian cancer (ROC). However, because of its cumulative neurotoxicity, there is a strong demand for platinum-combinations with better therapeutic index. Because of its pharmacological properties, topotecan is a good adjunct to carboplatin in this setting, but its safety and efficacy remains to be defined.Patients with platinum-sensitive ROC were eligible in this multicenter phase I/II study, stratified according to treatment-free interval (TFI). Dose level 0 consisted of topotecan 1 mg/m(2)/d1-3/q21d plus carboplatin AUC5/d3/q21d. DLT was defined as gradeor =3 neutropenia or thrombocytopenia or gradeor =3 non-hematological toxicity excluding alopecia, nausea and vomiting, accompanied by a treatment delay1 week.From June 2004 to August 2005, 26 patients were enrolled, receiving a total of 145 cycles of chemotherapy. MTD was reached at topotecan 0.75 mg/m(2) and carboplatin AUC5. We observed a single grade 4 leucopenia. There were 3 (12%), 15 (58%) and 8 (31%) events of grade 3/4 hematological anaemia, leucopenia, and thrombocytopenia. Response rate was 67% (95% CI 43-85), median progression-free survival 9.5 months (95% CI 7.3-12.0), median overall survival 19.4 months (95% CI 12.3-26.9). None of the toxicity or efficacy endpoints were associated with TFI.Topotecan and carboplatin is a well tolerated novel doublet option for women with platinum sensitive ROC. We encourage further studies on this approach, but to limit the doses of topotecan to 0.75 mg/m(2)/d1-3 and carboplatin AUC 5/d3.

Background: Abagovomab is a murine anti-idiotypic antibody against the antigen CA-125 which has been shown to elicit humoral and cellular immune responses against ovarian cancer (oc). Patients and methods: This phase I trial included 36 patients with recurrent oc comparing two subcutaneous (s.c.) vaccination schedules: nine (group L) versus six injections (group S), 18 patients in each group. Four injections of 2.0 mg abagovomab were administered every 2 weeks and then two or five additional doses monthly. Primary endpoint was drop-out rate due to toxicity, and the secondary endpoint was analysis of immunological response. Results: Treatment was completed in eight (44%) and 16 (89%) patients in groups L and S, respectively. Premature termination occurred due to patient withdrawal or disease progression. No treatment-limiting toxicities occurred in either group. The most common toxicity related to the vaccine was grade 1/2 local injection site reaction. Induction of Ab3 was observed in all evaluable patients. There were no differences between the groups with regard to induction of human anti-mouse antibody (P = 0.1006). IFNγ-expressing CA125-specific CD8+ T-cells were significantly more frequent in group L, while there was no significant difference between CD4+ T-cells in the two groups. Conclusions: Abagovomab s.c. vaccination is safe and well tolerated. The long vaccination schedule tended to be more effective with regard to AB3-induction and cellular cytotoxicity.

Various diagnostic tests are available to rule out metastases. However, not all of these tests provide significant information. Based on data collected at our institution, we have analyzed the significance of various imaging methods.In 337 patients with fully staged endometrial carcinoma, the results of chest X-rays, bone scintigraphy, computed tomography (CT), magnetic resonance imaging (MRI) and ultrasonography of the liver, kidneys and abdomen were analyzed.In the 7 patients who showed metastases, the liver was the most frequently affected organ. Hepatic CT is associated with a likelihood ratio (LR) of 9.0, hence representing a valuable technique. In cases with a pretest probability of 1.19% (independent of the disease stage), CT results in a post-test probability of 9.78%, putting into question the usefulness of the method for confirming metastases. With all other analyzed diagnostic modalities, even less information is gained.The routine use of the above diagnostic methods, indiscriminate of the disease stage, is not justified. LRs provide an estimate of the information gained by a diagnostic procedure.

Background: Mucin-1 (MUC1) is a promising antigen for the development of tumor vaccines. We evaluated the frequency of MUC1 expression and its impact on therapy response and survival after neoadjuvant chemotherapy for breast cancer. Patients and methods: Pre-treatment core biopsies of patients from the GeparTrio neoadjuvant trial (NCT 00544765) were evaluated for MUC1 by immunohistochemistry (IHC; N = 691) and quantitative RT-PCR (qRT-PCR; N = 286) from formalin-fixed paraffin-embedded (FFPE) samples. Results: MUC1 protein and mRNA was detectable in the majority of cases and was associated with hormone-receptor-positive status (P < 0.001). High MUC1 protein and mRNA expression were associated with lower probability of pathologic complete response (P = 0.017 and P < 0.001) and with longer patient survival (P = 0.03 and P < 0.001). In multivariable analysis, MUC1 protein and mRNA expression were independently predictive (P = 0.001 and P < 0.001). MUC1 protein and mRNA expression were independently prognostic for overall survival (P = 0.029 and P = 0.015). Conclusions: MUC1 is frequently expressed in breast cancer and detectable on mRNA and protein level from FFPE tissue. It provides independent predictive information for therapy response and survival after neoadjuvant chemotherapy. In clinical immunotherapy trials, MUC1 expression may serve as a predictive marker.

5522Background: Sorafenib (S), a multi TK-inhibitor in combination with topotecan (T), a topoisomerase inhibitor showed preclinical synergistic effects in ovarian cancer but critical toxicity. To a...

Background Patients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. Patients and methods The nomogram was developed using data from the CAELYX in Platinum-Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). Results The nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65–0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO-OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). Conclusions This nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients.

Objectives This study evaluates whether a molecular targeted therapy with the farnesyltransferase inhibitor lonafarnib added to standard chemotherapy in first-line treatment of advanced ovarian cancer (OC) could improve progression-free (PFS) and overall survival (OS). Patients and Methods We performed a prospective randomized phase II study to compare standard therapy carboplatin (C; AUC 5) and paclitaxel (T; 175mg/m 2 ) in primary advanced OC with or without lonafarnib (L). Lonafarnib was given in a dose of 100mg orally twice a day during chemotherapy and was increased afterwards to 200mg up to six months as a maintenance therapy. Results 105 patients were recruited (53 patients were randomized to receive LTC, 52 to TC). Hematologic toxicity was similar in both arms. Grade 3 and 4 non-hematological toxicity, occurred significantly more often with LTC (23% versus 4%, p=0.005) and was associated with a higher dropout rate. PFS and OS were not significantly different among both arms. The LTC arm showed inferiority in the stratum with residual tumor of more than 1cm: median PFS was 11.5months (95% CI: 7.4–14.2) compared with 16.4 (95% CI: 10.3–40.4) for TC (p=0.0141; HR=0.36 (95% CI: 0.15–0.84)) with median OS 20.6months (95% CI: 13.1–31.0) and 43.4months (95% CI: 15.7–) for the TC arm (p=0.012; HR=0.32 (95% CI: 0.13–0.8)). Conclusion The addition of lonafarnib did not improve PFS or OS. Patients with a residual tumor of more than 1cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended.

Simultaneous adjuvant platinum-based radiochemotherapy in high-risk cervical cancer (CC) is an established treatment strategy. Sequential paclitaxel (Taxol) and platinum followed by radiotherapy may offer further advantages regarding toxicity.An open-labeled randomized phase III trial was conducted to compare paclitaxel (175 mg/m(2)) plus carboplatin (AUC5) followed by radiation (50.4 Gy) (experimental arm-A) versus simultaneous radiochemotherapy with cisplatin (40 mg/m(2)/week) (arm-B) in patients with stage IB-IIB CC after surgery. Primary objective was progression-free survival (PFS).Overall, 271 patients were randomized and 263 were eligible for evaluation; 132 in arm-A and 131 in arm-B appropriately balanced. The estimated 2-year PFS was 81.8% [95% confidence interval (CI) 74.4-89.1] in arm-B versus 87.2% (95% CI 81.2-93.3) in arm-A (P = 0.235) and the corresponding 5-year survival rates were 85.8% in arm-A and 78.9% in arm-B (P = 0.25). Hematological grade 3/4 toxicity was higher in arm-B. Alopecia (87.9% versus 4.1%; P0.001) and neurotoxicity (65.9% versus 15.6%; P0.001) were significantly higher in arm-A. Early treatment termination was significantly more frequent in arm-B than in arm-A (32.1% versus 12.9%; P = 0.001).Sequential chemotherapy and radiation in high-risk CC could not show any significant survival benefit; however, a different toxicity profile appeared. This sequential regime may constitute an alternative option when contraindications for immediate postoperative radiation are present.

Purpose Weekly administration of topotecan (Tw) is less toxic and widely considered a better treatment option than conventional 5-day therapy (Tc) in women with platinum-resistant recurrent ovarian cancer. We conducted a randomized phase II trial (TOWER [Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer]) to better define the ratio between benefits and risks with either treatment approach. Patients and Methods Patients were randomly assigned to two independent two-stage protocols of Tw (4 mg/m2/wk administered on days 1, 8, and 15) or Tc (1.25 mg/m2/d on days 1 to 5). We evaluated risk ratios (RRs) for the primary end point of clinical benefit (complete response, partial response, and stable disease), the duration of progression-free survival (PFS) and overall survival (OS), associated hazard ratios (HRs), and RRs of toxicity with 95% CIs. Results In total, 194 patients were randomly assigned at 54 centers to Tw (n = 97) or Tc (n = 97). Clinical benefit was observed in 36 of 76 (47%; 95% CI, 36% to 59%) Tw and 46 of 80 (58%; 95% CI, 46% to 68%) Tc patients (RR, 1.21; 95% CI, 0.90 to 1.64; P = .205). Patients in the Tw group had a slightly shorter PFS (HR, 1.29; 95% CI, 0.96 to 1.76) but similar OS (HR, 1.04; 95% CI, 0.74 to 1.45) compared with Tc. Tw was associated with significantly lower risks of anemia (RR, 0.35; 95% CI, 0.16 to 0.79), neutropenia (RR, 0.38; 95% CI, 0.23 to 0.65), and thrombocytopenia (RR, 0.23; 95% CI, 0.09 to 0.57). Conclusion With regard to effectiveness in terms of response and PFS, Tc remains the standard of care in patients with platinum-resistant recurrent ovarian cancer. However, comparable OS rates and a favorable toxicity profile make Tw another viable treatment option in this setting.

International audience; In order to explore the effect of neoadjuvant chemotherapy (NACT) on clinical mid-course and pathological complete response (pCR) at surgery in different biological breast cancer subtypes. The GeparTrio study included 2,072 patients with operable or locally advanced breast cancer. After two cycles with docetaxel, doxorubicin and cyclophosphamide (TAC) patients were randomized according to their clinical response. Clinical and biological factors were assessed for predicting clinically mid-course response and pCR at surgery. The overall pCR rate, defined as no invasive residuals in breast and axilla, was 20.5%. The highest pCR rate of 57% was observed in patients below 40 years of age with triple negative or grade 3 tumors. Independent factors for mid-course response and pCR were: young age, non-T4 tumors, high grade, and hormone receptor status, the strongest single predictive factor. Within the biological subtypes, grading was an independent factor to predict pCR for luminal tumors, clinical tumor stage for the HER2 like tumors and age for the triple negative ones. Grading gave independent information for mid-course response within the triple negative group. No factor predicted mid-course response within the other groups. Grading and age can identify subgroups within the luminal and triple negative patients who have an increased benefit from NACT.

Purpose A multicenter, nonrandomized, phase II study was initiated to evaluate the tolerability, toxicity, and activity of paclitaxel, carboplatin, and gemcitabine combination in previously untreated ovarian cancer. Patients and methods Chemonaive patients who had radical debulking surgery for primary epithelial ovarian cancer International Federation of Gynecology and Obstetrics (FIGO) IC–IV received sequentially paclitaxel 175 mg/m 2 , carboplatin AUC 5, and gemcitabine 800 mg/m 2 on day 1 and gemcitabine 800 mg/m 2 on day 8, every 3 weeks. Results From October 2001 to July 2002, 55 patients were treated and evaluated. Main toxicities were hematological with NCI-CTC grade 3/4 anemia 12.7%, leukopenia 70.9%, neutropenia 76.3%, and thrombocytopenia 45.5. However, febrile neutropenia occurred only in 1.8%. Grade 3/4 nonhematological toxicities were rare and occurred in less than 10% of patients. Toxicity-induced treatment delays occurred in 3.1% of cycles and resulted in early treatment cessation in four patients. Dose intensity reached 90.8% for carboplatin and paclitaxel, and 73.3% for gemcitabine. Objective response was observed in 10 of 14 patients with measurable disease. Conclusions The triplet combination of paclitaxel–carboplatin–gemcitabine is feasible and active, with manageable hematological toxicity and no unexpected nonhematological toxicity. This regimen has proceeded to phase III evaluation.

Paclitaxel-carboplatin-gemcitabine (TCG) as first-line treatment of ovarian cancer: a prospective multicenter phase II study (AGO-OVAR 8) followed by a prospectively randomized phase III GCIG intergroup study (AGO-OVAR 9, GINECO-TCG, NSGO-OC-0102) comparing TCG with standard TC

624 Background: Combinations of trastuzumab and anthracyclines in HER2-positive breast cancer are highly active but associated with a high incidence of cardiotoxicity. The risk of cardiac damage can be significantly reduced through liposomal encapsulation of anthracyclines. This phase I/II study was initiated to evaluate the combination of non-pegylated liposomal doxorubicin (NPLD), paclitaxel and lapatinib as primary treatment for patients with early stage, HER2-positive primary breast cancer. Methods: Patients with newly diagnosed HER2-positive (IHC 3+ or FISH+) early stage (T1c N1-2 or T2 N0-2) breast cancer were treated with NPLD (60mg/m2; day 1), paclitaxel (175mg/m2, day 1) and lapatinib (750-1500 mg orally daily) in 3-week intervals for up to 6 cycles. The primary endpoints were dose-limiting toxicities (DLT) and pathological complete response (pCR). Secondary endpoints include safety, incidence of cardiac events, and clinical response. Exploratory endpoints include molecular markers for sensitivity or resistance to chemotherapy and/or lapatinib evaluated. Results: A total of 84 patients have been included to date.No DLTs were observed and the maximum tolerated doses were NPLD 60mg/m2, paclitaxel 175mg/m2 and lapatinib 1500mg. Recommended phase 2 doses (P2D) were NPLD 60mg/m2, paclitaxel 175mg/m2 and lapatinib 1250mg. The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents. No cardiac event has been observed to date. Preliminary efficacy data confirm a pCR breast rate of 41.7% and pCR rate in breast and lymph nodes of 37.5%, in 24 evaluable patients treated at ≥P2D. Conclusions: The combination of NPLD, paclitaxel and lapatinib is well tolerated and has high antitumour activity in patients with HER2-positive primary breast cancer. The phase II part of the study is ongoing and updated results will be presented.

522 Background: Mucin-1 (MUC1) is expressed in normal epithelial cells and in breast cancer. Immunotherapeutic agents targeting MUC1 are currently tested in clinical trials. Methods: We evaluated the frequency of MUC1 expression by immunohistochemistry (IHC; n = 691) and quantitative RT-PCR (qRT-PCR; n = 286) in formalin-fixed paraffin-embedded (FFPE) pre-treatment biopsies from patients of the GeparTrio trial (NCT 00544765). mRNA levels were analyzed as a continuous variable, a distribution-based cut-off was chosen for IHC data. The predictive value for therapy response and survival after neoadjuvant anthracycline/taxane-based chemotherapy (CTX) was evaluated. Results: MUC1 was detectable by IHC in 95%. qRT-PCR covered a dynamic range of 3 orders of magnitude. IHC and mRNA data were correlated (p < 0.001). MUC1 was detected in higher quantities in HR+ tumors (p < 0.001), the lowest levels were found in HR-/HER2- tumors (p < 0.001). High MUC1 protein and mRNA expression were associated with lower probability of pathologic complete response (pCR) in the overall population (p < 0.001) and in HR+ (p = 0.004 and < 0.001), HER2- (p < 0.001) and HR+/HER2- tumors (p < 0.001). In multivariable logistic regression, MUC1 was independently predictive (high MUC1 protein: odds ratio (OR) 0.464, 95% CI 0.300 – 0.719, p = 0.001; MUC1 mRNA (per 20-dCT unit): OR 0.673, CI 0.546 – 0.829, p < 0.001). MUC1 protein and mRNA expression were associated with longer patient survival in the overall population (p = 0.03 and < 0.001) and in HER2- tumors (p = 0.005 and < 0.001). MUC1 mRNA was also prognostic in HR+ (p < 0.001) and HR+/HER2- tumors (p = 0.001). In multivariable analysis, protein and mRNA expression were independently prognostic (high MUC1 protein: hazard ratio (HR) 0.388, CI 0.166 – 0.907, p = 0.029; MUC1 mRNA per 20-dCT unit: HR 0.763, CI 0.595 – 0.909, p = 0.005). Conclusions: MUC1 is frequently expressed in breast cancer and detectable by IHC and qRT-PCR from FFPE tissue. Despite its association with HR+ status, it provides independent predictive information for therapy response and survival after neoadjuvant CTX. In clinical immunotherapy trials, MUC1 expression may serve as a predictive marker.

5031 Background: We present the efficacy data from a phase III study of topotecan (T) plus carboplatin (C) versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or carboplatin plus pegylated doxorubicin (PLDC). Methods: From 02/07 to 12/09, 590 pts were screened and 550 pts were randomized to either T (0.75mg/m²/d1-3/q21d) + C (AUC 5/d1/q21d) or to standard therapy with CP or GC or PLDC based on patient preference. Progression free survival at 1 year was defined as primary endpoint. Results: Median number of cycles was 6 (range 0-9) in both arms. Most patients preferred GC (78%) in the standard therapy arm.. Best Response (CR+PR) was 73.1% (95%CI) and 75.1% (95%CI) for the CA. Median follow-up was 18 (0-52) months for TC and 20 (0-48) months for standard therapy. TC failed to show any advantage regarding 1-yr.-PFS or OAS. Conclusions: The combination of topotecan plus carboplatin failed to improve PFS or OAS in platinum sensitive relapsed ovarian cancer. In addition, carboplatin plus gemcitabine was well tolerated with lower rates of severe and long-lasting (neuropathy) toxicities compared to paclitaxel-carboplatin. [Table: see text]

Mucin-1 (MUC1) is expressed in normal breast epithelium and invasive breast cancer. It has pleiotropic effects on tumour biology, e.g. regulation of cell polarity, crosstalk with cellular signalling and regulation of immune response. Tumor vaccines targeting MUC1 are currently tested in clinical trials. The aim of this study was to evaluate the frequency of MUC1 expression and its predictive value for response and survival after neoadjuvant anhracycline/taxane-based chemotherapy. We investigated MUC1 protein (n = 691) and mRNA (n = 268) expression in pre-treatment core biopsies from participants of the GeparTrio trial by immunohistochemistry and quantitative RT-PCR from formalin-fixed paraffin-embedded (FFPE) samples. MUC1 protein expression was detectable in 656 (95%) cases; mRNA levels covered a range of 103 copy numbers. Protein and mRNA expression were correlated (p High MUC1 protein and mRNA expression were more frequently in HR+ (hormone-receptor positive) tumors (p Low MUC1 protein and mRNA expression were predictive for pCR (pathologic complete response) in the overall population (p MUC1 protein expression was a positive prognostic marker for survival in the overall population (p = 0.03) and in HER2- (p = 0.005) tumors. MUC1 mRNA was prognostic in the overall population (p MUC1 is frequently expressed in a large cohort of breast cancer, especially in HR+ tumors. Evaluation is feasible by immunohistochemistry and quantitative RT-PCR from FFPE tissue and provides information on therapy response and survival following neoadjuvant chemotherapy. MUC1 expression may serve as a predictive marker in clinical immunotherapy trials. Disclosure All authors have declared no conflicts of interest.

5109 Background: To determine the toxicity, tolerability and quality of life (QoL) of adjuvant CT with sequential RT in patients (pts) with high-risk endometrial cancer (hrec). Methods: Pts with hr...

5038 Background: To determine the response rate and toxicity of primary concomitant radio-chemotherapy (cRCH) consisting of ifosfamide and carboplatin plus external beam radiotherapy with curative ...

5005 Background: Adjuvant platinum based radiochemotherapy in high-risk cervical cancer is an established treatment strategy to improve overall survival. Based on several trials for primary and rec...

5526 Background: Optimizing the therapeutic index (that is, maintaining drug effectiveness while reducing toxicity) is a major goal in chemotherapy for platinum-resistant ovarian cancer. Early phase-I/II studies suggest that weekly topotecan (T) might be effective and apparently better tolerated than the established 5-day regimen. As yet, no randomized comparison of both regimes was attempted. To prove the hypothesis of an improved therapeutic index with weekly T, we conducted a randomized, multicenter, two-stage phase-II trial, and herein present the data of the planned interim analysis. Methods: Pts with platinresistent ovarian and fallopian tube cancers or primary peritoneal carcinoma, measurable or assessable disease (GCIG-CA-125 response criteria), were eligible. Pts were randomized to receive either weekly T (d1,8,15/q28d, 4 mg/m2) or T from d1–5/q21d at a dose of 1.25 mg/m2. According to Gehan’s two-stage-design, both arms were handled as independent studies. Overall response rate (CR + PR) was defined as primary study endpoint, secondary endpoints of the interim analysis were toxicity and safety. Results: 28 pts in the weekly and 21 pts in the conventional group, enrolled at 38 centers form the basis of this report. 230 cycles of chemotherapy were evaluated for toxicity analyses. Median age was 61 years (range, 36 - 82 years). Demographic baseline characteristics, including tumor stage and grade were well balanced between treatment arms. There were 2/28 and 5/21 responses in weekly and the conventional arm, respectively (Risk Ratio [RR] 0.30, 95% confidence interval [CI] 0.06 - 1.40, p=0.122). The risk of early treatment termination due to tumor progression (RR 1.39, 95%CI 0.75 - 2.56), haematological (RR 0.20, 95% CI 0.01 - 3.97) or non- hematological toxicities (RR 1.96, 95% CI 0.18 - 20.83) did not differ significantly between groups. The only three events of neutropenic fever occurred in the conventional arm (RR 1.70, 95% CI 0.99 - 1.16). Conclusions: Weekly T is well tolerated and potentially active. The second stage of this study will require additional 46 patients each arm. Complete enrolment is expected to be accomplished in May 2007. No significant financial relationships to disclose.

16074 Background: Isolated adjuvant radio- or chemotherapy (CHT) only reduces local or distant relapses in HREC without impact on overall-survival. Therefore a multicenter feasibility study on adjuvant sequential chemo- and radiotherapy of HREC was initiated in order to evaluate safety and toxicity. Planned number of patients was 40, if after 17 pts. no termination of therapy because of toxicity was necessary, study can be closed and a phase III-study can be initiated. The data on toxicity are presented. Methods: Eligibility criteria: adenocarcinomas G1/G2 stage IC or G3 stage IA-IC or all stages II and IIIA (histological), all tumours with more than 2 cm diameter in size or non endometrioid cancers stage IA-C, II and IIIA and all cases with vessel invasion. Surgery: abdominal hysterectomy with bilateral adnexectomy without lymphadenectomy or with pelvic and para-aortic lymphadenectomy and positive lymph nodes. Further: Karnofsky-Index > 70, normal bone marrow, kidney, and liver function with laboratory tests not higher than 1.5 times of the normal local reference values. CHT: 175 mg/m2 paclitaxel plus carboplatin AUC 5, q 3 weeks for 4 cycles beginning latest 6 weeks after surgery. Within 6 further weeks after CHT an external beam irradiation (total dose 50.4 Gy, 28 fractions with 1.8 GY/d) plus 3 intracavitary HDR-iridium-192- brachytherapy courses with 3 x 5 GY were performed. Results: To date 17 pts (mean 64.1 years) completed 68 cycles CHT and following radiotherapy. There was no termination of therapy. Grade III leucopenia was observed in 9 % with 2 pts. requiring prolongation of treatment interval. There were 3 and 1 % grade II anemia and thrombocytopenia respectively. Further grade II toxicity: alopecia 38, fatigue 12, nausea/emesis 3, sensory neuropathy 12 %. Administration of G-CSF (pegfilgrastim) and epoitin (darbepoetin) was necessary in 2 and 6 % of cycles. Conclusions: Adjuvant sequential chemo- and radiotherapy of HREC is feasible by safety and toxicity and a phase III study can be initiated. No significant financial relationships to disclose.

5556 Background: The trifunctional antibody catumaxomab specifically binds EpCAM+ tumor cells, CD3+ T lymphocytes and accessory cells via the Fcγ RI/III thereby inducing a tumor specific cell mediated cytotoxicity in vitro and in vivo. This study was conducted to evaluate efficacy and safety of two different regimens of catumaxomab. Methods: Women with platinum-refractory (progressing during or ≤ 6 mos. after the last platinum containing regimen) epithelial ovarian cancer and measurable recurrent disease were randomized to receive either 10 -10 -10 - 10 μg or 10–20–50–100 μg of catumaxomab over 6h i.p on days 0, 3, 7 and 10. Results: 45 pts. were entered (22 high dose (HD)-arm, 23 low dose (LD)-arm). Both groups were well balanced concerning ECOG-perfomance score, with a median age of 65.6y in the HD- and 57.6y in the LD-arm and with a median diameter of measurable lesions of 90mm in the HD- and 104mm in the LD-arm. Based on the AEs, changes in laboratory parameters and other safety variables observed in the safety population in the course of this study, the accumulated safety experience is consistent with the key features of the mode of action of catumaxomab. Their intensity on median level was mostly mild to moderate. A clinical benefit was detectable in 27.3% of pts. for the HD- (1PR/5SD) and 8.7% of pts. for the LD-arm (2SD). After a median follow-up of 4.96 months, the median overall survival time was 182 d for the HD- and 114 d for the LD-arm. Conclusion: The results demonstrate that catumaxomab is safe with acceptable toxicity when administered as a sequence of 4 IP infusions at 10, 20, 50 and 100 μg. A modest dose effect is observed for the higher doses of catumaxomab. No significant financial relationships to disclose.

5081 Background: Retrospective analysis suggested that participation in clinical trials is associated with better outcome. However, it is not clear to what extent selection bias contributes to this...