Felix Hilpert

Bevacizumab Combined With Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer: The AURELIA Open-Label Randomized Phase III Trial

PURPOSE In platinum-resistant ovarian cancer (OC), single-agent chemotherapy is standard. Bevacizumab is active alone and in combination. AURELIA is the first randomized phase III trial to our knowledge combining bevacizumab with chemotherapy in platinum-resistant OC. PATIENTS AND METHODS Eligible patients had measurable/assessable OC that had progressed < 6 months after completing platinum-based therapy. Patients with refractory disease, history of bowel obstruction, or > two prior anticancer regimens were ineligible. After investigators selected chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan), patients were randomly assigned to single-agent chemotherapy alone or with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) until progression, unacceptable toxicity, or consent withdrawal. Crossover to single-agent bevacizumab was permitted after progression with chemotherapy alone. The primary end point was progression-free survival (PFS) by RECIST. Secondary end points included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes. RESULTS The PFS hazard ratio (HR) after PFS events in 301 of 361 patients was 0.48 (95% CI, 0.38 to 0.60; unstratified log-rank P < .001). Median PFS was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-containing therapy. RECIST ORR was 11.8% versus 27.3%, respectively (P = .001). The OS HR was 0.85 (95% CI, 0.66 to 1.08; P < .174; median OS, 13.3 v 16.6 months, respectively). Grade ≥ 2 hypertension and proteinuria were more common with bevacizumab. GI perforation occurred in 2.2% of bevacizumab-treated patients. CONCLUSION Adding bevacizumab to chemotherapy statistically significantly improved PFS and ORR; the OS trend was not significant. No new safety signals were observed.

Molecular and prognostic distinction between serous ovarian carcinomas of varying grade and malignant potential

Profiles of gene transcription have begun to delineate the molecular basis of ovarian cancer, including distinctions between carcinomas of differing histology, tumor progression and patient outcome. However, the similarities and differences among the most commonly diagnosed noninvasive borderline (low malignant potential, LMP) lesions and invasive serous carcinomas of varying grade (G1, G2 and G3) have not yet been explored. Here, we used oligonucleotide arrays to profile the expression of 12 500 genes in a series of 57 predominantly stage III serous ovarian adenocarcinomas from 52 patients, eight with borderline tumors and 44 with adenocarcinomas of varying grade. Unsupervised and supervised analyses showed that LMP lesions were distinct from high-grade serous adenocarcinomas, as might be expected; however, well-differentiated (G1) invasive adenocarcinomas showed a strikingly similar profile to LMP tumors as compared to cancers with moderate (G2) or poor (G3) cellular differentiation, which were also highly similar. Comparative genomic hybridization of an independent cohort of five LMP and 63 invasive carcinomas of varying grade demonstrated LMP and G1 were again similar, exhibiting significantly less chromosomal aberration than G2/G3 carcinomas. A majority of LMP and G1 tumors were characterized by high levels of p21/WAF1, with concomitant expression of cell growth suppressors, gadd34 and BTG-2. In contrast, G2/G3 cancers were characterized by the expression of genes associated with the cell cycle and by STAT-1-, STAT-3/JAK-1/2-induced gene expression. The distinction between the LMP-G1 and G2–G3 groups of tumors was highly correlated to patient outcome (χ2 for equivalence of death rates=7.681189; P=0.0056, log-rank test). Our results are consistent with the recent demonstration of a poor differentiation molecular ‘meta-signature’ in human cancer, and underscore a number of cell-cycle- and STAT-associated targets that may prove useful as points of therapeutic intervention for those patients with aggressive disease.

AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC).

LBA5002^ Background: In three phase III trials in OC (2 front line, 1 PT-sensitive recurrent), BEV + CT → BEV significantly improved progression-free survival (PFS) vs CT alone. AURELIA is the first randomized trial of BEV in PT-resistant OC. METHODS Eligible patients (pts) had OC (measurable by RECIST 1.0 or assessable) that had progressed ≤6 mo after ≥4 cycles of PT-based therapy. Pts with refractory OC, history of bowel obstruction, or >2 prior anticancer regimens were ineligible. After CT selection by the investigator (pegylated liposomal doxorubicin [PLD], topotecan [TOP], or weekly paclitaxel [PAC]), pts were randomized to CT either alone or with BEV (10 mg/kg q2w or 15 mg/kg q3w depending on CT) until progression (PD), unacceptable toxicity, or withdrawal of consent. Pts in the CT-alone arm could cross over to BEV monotherapy at PD. The primary endpoint was PFS by RECIST. Secondary endpoints included objective response rate (ORR), overall survival, safety, and quality of life. The design provided 80% power to detect a PFS hazard ratio (HR) of 0.7 with 2-sided log-rank test and α=0.05 after 247 events, assuming median PFS of 4.0 mo with CT and 5.7 mo with CT + BEV. RESULTS Between Oct 2009 and Apr 2011, 361 pts were randomized to receive selected CT (PLD: 126; PAC: 115; TOP: 120) alone or with BEV. Median follow-up after 301 PFS events was 13.5 mo. CONCLUSIONS In PT-resistant OC, BEV + CT provides statistically significant and clinically meaningful improvement in PFS and ORR vs CT alone. Strict inclusion criteria minimized the incidence of BEV AEs. This is the first phase III trial in PT-resistant OC to show benefit with a targeted therapy and improved outcome with a combination vs monotherapy. [Table: see text].

Patient-Reported Outcome Results From the Open-Label Phase III AURELIA Trial Evaluating Bevacizumab-Containing Therapy for Platinum-Resistant Ovarian Cancer

PURPOSE To determine the effects of bevacizumab on patient-reported outcomes (PROs; secondary end point) in the AURELIA trial. PATIENTS AND METHODS Patients with platinum-resistant ovarian cancer were randomly assigned to chemotherapy alone (CT) or with bevacizumab (BEV-CT). PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Ovarian Cancer Module 28 (EORTC QLQ-OV28) and Functional Assessment of Cancer Therapy-Ovarian Cancer symptom index (FOSI) at baseline and every two or three cycles (8/9 weeks) until disease progression. The primary PRO hypothesis was that more patients receiving BEV-CT than CT would achieve at least a 15% (≥ 15-point) absolute improvement on the QLQ-OV28 abdominal/GI symptom subscale (items 31-36) at week 8/9. Patients with missing week 8/9 questionnaires were included as unimproved. Questionnaires from all assessments until disease progression were analyzed using mixed-model repeated-measures (MMRM) analysis. Sensitivity analyses were used to determine the effects of differing assumptions and methods for missing data. RESULTS Baseline questionnaires were available from 89% of 361 randomly assigned patients. More BEV-CT than CT patients achieved a ≥ 15% improvement in abdominal/GI symptoms at week 8/9 (primary PRO end point, 21.9% v 9.3%; difference, 12.7%; 95% CI, 4.4 to 20.9; P = .002). MMRM analysis covering all time points also favored BEV-CT (difference, 6.4 points; 95% CI, 1.3 to 11.6; P = .015). More BEV-CT than CT patients achieved ≥ 15% improvement in FOSI at week 8/9 (12.2% v 3.1%; difference, 9.0%; 95% CI, 2.9% to 15.2%; P = .003). Sensitivity analyses gave similar results and conclusions. CONCLUSION Bevacizumab increased the proportion of patients achieving a 15% improvement in patient-reported abdominal/GI symptoms during chemotherapy for platinum-resistant ovarian cancer.

Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial

Summary Background In the Gynecologic Cancer Intergroup International Collaboration on Ovarian Neoplasms 7 (ICON7) trial, bevacizumab improved progression-free survival in patients with ovarian cancer when used in combination with first-line chemotherapy and as a single-drug continuation treatment for 18 cycles. In a preliminary analysis of a high-risk subset of patients, there was also an improvement in overall survival. This study aims to describe the health-related quality-of-life (QoL) outcomes from ICON7. Methods ICON7 is a randomised, multicentre, open-label phase 3 trial. Between Dec 18, 2006, and Feb 16, 2009, after a surgical procedure aiming to debulk the disease, women with International Federation of Gynecology and Obstetrics (FIGO) high-risk stage I–IV epithelial ovarian cancer were randomly allocated (1:1) by computer program and block randomisation to receive either six cycles of standard chemotherapy (total 18 weeks) with carboplatin (area under the curve 5 or 6) and paclitaxel (175 mg/m2) alone or with bevacizumab (7·5 mg/kg) given intravenously with chemotherapy and continued as a single drug thereafter (total 54 weeks). The primary QoL endpoint was global QoL from the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire–core 30 at week 54, analysed by ANOVA and adjusted for baseline score. Analyses were by intention to treat. The ICON7 trial has completed recruitment and remains in follow-up. This study is registered, number ISRCTN91273375. Findings 764 women were randomly assigned to the standard chemotherapy group and 764 to the bevacizumab group. At baseline, 684 (90%) of women in the standard chemotherapy group and 691 (90%) of those in the bevacizumab group had completed QoL questionnaires. At week 54, 502 (66%) women in the bevacizumab group and 388 (51%) women in the standard chemotherapy group provided QoL data. Overall, the mean global QoL score improved during chemotherapy by 7·2 points (SD 24·4) when analysed for all women with data at baseline and week 18. The mean global QoL score at 54 weeks was higher in the standard chemotherapy group than in the bevacizumab group (76·1 [SD 18·2] vs 69·7 [19·1] points; difference 6·4 points, 95% CI 3·7–9·0, p<0·0001). Interpretation Bevacizumab continuation treatment seems to be associated with a small but clinically significant decrement in QoL compared with standard treatment for women with ovarian cancer. The trade-off between the prolongation of progression-free survival and the quality of that period of time needs to be considered in clinical practice when making treatment decisions. Funding Roche and the National Institute for Health Research through the UK National Cancer Research Network.

Randomized Study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group Comparing Quality of Life in Patients With Ovarian Cancer Treated With Cisplatin/Paclitaxel Versus Carboplatin/Paclitaxel

PURPOSE The objective of this study was to compare the quality of life (QoL) of ovarian cancer patients treated with paclitaxel/carboplatin (TC) versus paclitaxel/cisplatin (PT) and to determine the impact of treatment toxicity on the various QoL domains. PATIENTS AND METHODS In this phase III trial, 798 patients with ovarian cancer stages IIB-IV were randomly assigned to receive TC or PT. The primary end point was progression-free survival; secondary end points included toxicity, QoL, and response to treatment. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 before treatment, within 3 days before the second and the fourth chemotherapy cycle, and 3 weeks after completion of chemotherapy. RESULTS Previously reported data showed that patients undergoing TC or PT did not differ in progression-free survival and overall survival. However, the TC arm was superior, indicating a better overall QoL compared with the PT arm. Controlling for toxicity and age, a significant treatment by assessment time interaction was found for four QoL functioning scales and three symptoms scales. Patients in the TC arm showed better means scores after treatment on overall QoL (P = .012), physical functioning (P = .012), role functioning (P = .005), and cognitive functioning (P = .024), compared with the PT arm. Concerning symptom experience, patients undergoing TC showed less nausea and vomiting (P < .001), less appetite loss (P < .001), and less fatigue (P = .033) after completion of treatment compared with patients undergoing PT. CONCLUSION The TC regimen achieved better QoL outcomes compared with the PT regimen. Thus, clinicians may consider replacing cisplatin with carboplatin when treating ovarian cancer patients with chemotherapy.

Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. METHODS In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. FINDINGS Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). INTERPRETATION Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. FUNDING Boehringer Ingelheim.

Adjuvant Therapy in Lymph Node–Positive Vulvar Cancer: The AGO-CaRE-1 Study

Background: Women with node-positive vulvar cancer have a high risk for disease recurrence. Indication criteria for adjuvant radiotherapy are controversial. This study was designed to further understand the role of adjuvant therapy in node-positive disease. Methods: Patients with primary squamous-cell vulvar cancer treated at 29 gynecologic cancer centers in Germany from 1998 through 2008 were included in this retrospective exploratory multicenter cohort study. Of 1618 documented patients, 1249 had surgical groin staging and known lymph node status and were further analyzed. All statistical tests were two-sided. Results: Four hundred forty-seven of 1249 patients (35.8%) had lymph node metastases (N+). The majority of N+ patients had one (172 [38.5%]) or two (102 [22.8%]) positive nodes. The three-year progression-free survival (PFS) rate of N+ patients was 35.2%, and the overall survival (OS) rate 56.2% compared with 75.2% and 90.2% in node-negative patients (N-). Two hundred forty-four (54.6%) N+ patients had adjuvant therapy, of which 183 (40.9%) had radiotherapy directed at the groins (+/-other fields). Three-year PFS and OS rates in these patients were better compared with N+ patients without adjuvant treatment (PFS: 39.6% vs 25.9%, hazard ratio [HR] = 0.67, 95% confidence interval [CI[= 0.51 to 0.88, P = .004; OS: 57.7% vs 51.4%, HR = 0.79, 95% CI = 0.56 to 1.11, P = .17). This effect was statistically significant in multivariable analysis adjusted for age, Eastern Cooperative Oncology Group, Union internationale contre le cancer stage, grade, invasion depth, and number of positive nodes (PFS: HR = 0.58, 95% CI = 0.43 to 0.78, P < .001; OS: HR = 0.63, 95% CI = 0.43 to 0.91, P = .01). Conclusion: This large multicenter study in vulvar cancer observed that adjuvant radiotherapy was associated with improved prognosis in node-positive patients and will hopefully help to overcome concerns regarding adjuvant treatment. However, outcome after adjuvant radiotherapy remains poor compared with node-negative patients. Adjuvant chemoradiation could be a possible strategy to improve therapy because it is superior to radiotherapy alone in other squamous cell carcinomas.

A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy

BACKGROUND Recurrent platinum-resistant ovarian cancer usually has a poor outcome with conventional chemotherapeutic therapy and new treatment modalities are warranted. This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting. MATERIAL AND METHODS The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously). RESULTS Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to the continuous treatment arm (arm 2). The mean age was 58.8 and 58.5 years, respectively. We observed six responders (complete response+partial response) in arm 1 (16.7%) and 2 responders in arm 2 (5.4%). The median progression-free survival (arm 1: 4.8 [2.9-8.1] months; arm 2: 2.9 [2.9-5.1] months) and the median overall survival (arm 1: 13.6 [7.0-23.2] months; arm 2: 13.7 [8.4-25.6] months) revealed no significant difference. Adverse events included fatigue as well as cardiovascular, gastrointestinal and abdominal symptoms, hematologic and hepatic laboratory abnormalities. Pattern and frequency of adverse events revealed no substantial differences between both treatment groups. CONCLUSIONS Sunitinib treatment is feasible and moderately active in relapsed platinum-resistant ovarian cancer. The noncontinuous treatment schedule should be chosen for further studies in ovarian cancer.BACKGROUND Recurrent platinum-resistant ovarian cancer usually has a poor outcome with conventional chemotherapeutic therapy and new treatment modalities are warranted. This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting. MATERIAL AND METHODS The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously). RESULTS Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to the continuous treatment arm (arm 2). The mean age was 58.8 and 58.5 years, respectively. We observed six responders (complete response + partial response) in arm 1 (16.7%) and 2 responders in arm 2 (5.4%). The median progression-free survival (arm 1: 4.8 [2.9-8.1] months; arm 2: 2.9 [2.9-5.1] months) and the median overall survival (arm 1: 13.6 [7.0-23.2] months; arm 2: 13.7 [8.4-25.6] months) revealed no significant difference. Adverse events included fatigue as well as cardiovascular, gastrointestinal and abdominal symptoms, hematologic and hepatic laboratory abnormalities. Pattern and frequency of adverse events revealed no substantial differences between both treatment groups. CONCLUSIONS Sunitinib treatment is feasible and moderately active in relapsed platinum-resistant ovarian cancer. The noncontinuous treatment schedule should be chosen for further studies in ovarian cancer.

An Integrated Clinical-Genomics Approach Identifies a Candidate Multi-Analyte Blood Test for Serous Ovarian Carcinoma

Purpose: Cancer of the ovary confers the worst prognosis among women with gynecologic malignancies, underscoring the need to develop new biomarkers for detection of early disease, particularly those that can be readily monitored in the blood. Experimental Design: We developed an algorithm to identify secreted proteins encoded among ∼22,500 genes on commercial oligonucleotide arrays and applied it to gene expression profiles of 67 stage I to IV serous papillary carcinomas and 9 crudely enriched normal ovarian tissues, to identify putative diagnostic markers. ELISAs were used to validate increased levels of secreted proteins in patient sera encoded by genes with differentially high expression. Results: We identified 275 genes predicted to encode secreted proteins with increased/decreased expression in ovarian cancers (<0.5- or >2-fold, P < 0.001). The serum levels of four of these proteins (matrix metalloproteinase-7, osteopontin, secretory leukoprotease inhibitor, and kallikrein 10) were significantly elevated in a series of 67 independent patients with serous ovarian carcinomas compared with 67 healthy controls (P < 0.001, Wilcoxon rank sum test). Optimized support vector machine classifiers with as few as two of these markers (osteopontin or kallikrein 10/matrix metalloproteinase-7) in combination with CA-125 yielded sensitivity and specificity values ranging from 96% to 98.7% and 99.7% to 100%, respectively, with the ability to discern early-stage disease from normal, healthy controls. Conclusions: Our data suggest that this assay combination warrants further investigation as a multi-analyte diagnostic test for serous ovarian adenocarcinoma.