Barbara Schmalfeldt

The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial

Malignant ascites is a common manifestation of advanced cancers, and treatment options are limited. The trifunctional antibody catumaxomab (anti‐epithelial cell‐adhesion molecule x anti‐CD3) represents a targeted immunotherapy for the intraperitoneal (i.p.) treatment of malignant ascites secondary to epithelial cancers. In this phase II/III trial (EudraCT 2004‐000723‐15; NCT00836654), cancer patients (n = 258) with recurrent symptomatic malignant ascites resistant to conventional chemotherapy were randomized to paracentesis plus catumaxomab (catumaxomab) or paracentesis alone (control) and stratified by cancer type (129 ovarian and 129 nonovarian). Catumaxomab was administered as an i.p. infusion on Days 0, 3, 7 and 10 at doses of 10, 20, 50 and 150 μg, respectively. The primary efficacy endpoint was puncture‐free survival. Secondary efficacy parameters included time to next paracentesis, ascites signs and symptoms and overall survival (OS). Puncture‐free survival was significantly longer in the catumaxomab group (median 46 days) than the control group (median 11 days) (hazard ratio = 0.254: p < 0.0001) as was median time to next paracentesis (77 versus 13 days; p < 0.0001). In addition, catumaxomab patients had fewer signs and symptoms of ascites than control patients. OS showed a positive trend for the catumaxomab group and, in a prospectively planned analysis, was significantly prolonged in patients with gastric cancer (n = 66; 71 versus 44 days; p = 0.0313). Although adverse events associated with catumaxomab were frequent, they were manageable, generally reversible and mainly related to its immunologic mode of action. Catumaxomab showed a clear clinical benefit in patients with malignant ascites secondary to epithelial cancers, especially gastric cancer, with an acceptable safety profile.

Surgery in Recurrent Ovarian Cancer: The Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR Trial

BackgroundThe role of cytoreductive surgery in relapsed ovarian cancer is not clearly defined. Therefore, patient selection remains arbitrary and depends on the center’s preference rather than on established selection criteria. The Descriptive Evaluation of preoperative Selection KriTeria for OPerability in recurrent OVARian cancer (DESKTOP OVAR) trial was undertaken to form a hypothesis for a panel of criteria for selecting patients who might benefit from surgery in relapsed ovarian cancer.MethodsThe DESKTOP trial was an exploratory study based on data from a retrospective analysis of hospital records. Twenty-five member institutions of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Committee (AGO OC) and AGO-OVAR boards collected data on their patients with cytoreductive surgery for relapsed invasive epithelial ovarian cancer performed in 2000–2003.ResultsTwo hundred and sixty-seven patients were included. Complete resection was associated with significantly longer survival compared with surgery leaving any postoperative residuals [median 45.2 vs. 19.7 months; hazard ratio (HR) 3.71; 95% confidence interval (CI) 2.27–6.05; P < .0001]. Variables associated with complete resection were performance status (PS) [Eastern Cooperative Oncology Group (ECOG) 0 vs. > 0; P < .001], International Federation of Gynecology and Obstetrics (FIGO) stage at initial diagnosis (FIGO I/II vs. III/IV, P = .036), residual tumor after primary surgery (none vs. present, P <.001), and absence of ascites > 500 ml (P < .001). A combination of PS, early FIGO stage initially or no residual tumor after first surgery, and absence of ascites could predict complete resection in 79% of patients.ConclusionsOnly complete resection was associated with prolonged survival in recurrent ovarian cancer. The identified criteria panel will be verified in a prospective trial (AGO-DESKTOP II) evaluating whether it will render a useful tool for selecting the right patients for cytoreductive surgery in recurrent ovarian cancer.

Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial.

BACKGROUND The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. METHODS In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1-10 of each 21-day cycle) plus paclitaxel (175 mg/m(2), administered intravenously on day 1) and carboplatin (area under the curve [AUC] 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m(2) on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov, number NCT01081951, and has been completed. FINDINGS Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12.2 months [95% CI 9.7-15.0]) than in the chemotherapy alone group (median 9.6 months [95% CI 9.1-9.7) (HR 0.51 [95% CI 0.34-0.77]; p=0.0012), especially in patients with BRCA mutations (HR 0.21 [0.08-0.55]; p=0.0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 [74%] of 81 vs 44 [59%] of 75), nausea (56 [69%] vs 43 [57%]), neutropenia (40 [49%] vs 29 [39%]), diarrhoea (34 [42%] vs 20 [27%]), headache (27 [33%] vs seven [9%]), peripheral neuropathy (25 [31%] vs 14 [19%]), and dyspepsia (21 [26%] vs 9 [12%]); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 [43%] of 81 patients in the olaparib plus chemotherapy group vs 26 [35%] of 75 in the chemotherapy alone group) and anaemia (seven [9%] vs five [7%]). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group. INTERPRETATION Olaparib plus paclitaxel and carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA-mutated patients, and had an acceptable and manageable tolerability profile. FUNDING AstraZeneca.

Prediction of Response to Neoadjuvant Chemotherapy by Sequential F-18-Fluorodeoxyglucose Positron Emission Tomography in Patients With Advanced-Stage Ovarian Cancer

PURPOSE The aim of this study was to evaluate sequential F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) to predict patient outcome after the first and third cycle of neoadjuvant chemotherapy in advanced-stage (International Federation of Gynecology and Obstetrics stages IIIC and IV) ovarian cancer. PATIENTS AND METHODS Thirty-three patients received three cycles of carboplatin-based chemotherapy, followed by cytoreductive surgery. Quantitative FDG-PET of the abdomen and pelvis was acquired before treatment and after the first and third cycle of chemotherapy. Changes in tumoral FDG uptake, expressed as standardized uptake values (SUV), were compared with clinical and histopathologic response; overall survival served as a reference. RESULTS A significant correlation was observed between FDG-PET metabolic response after the first (P = .008) and third (P = .005) cycle of chemotherapy and overall survival. By using a threshold for decrease in SUV from baseline of 20% after the first cycle, median overall survival was 38.3 months in metabolic responders compared with 23.1 months in metabolic nonresponders. At a threshold of 55% decrease in SUV after the third cycle median overall survival was 38.9 months in metabolic responders compared with 19.7 months in nonresponders. There was no correlation between clinical response criteria (P = .7) or CA125 response criteria (P = .5) and overall survival. There was only a weak correlation (P = .09) between histopathologic response criteria and overall survival. CONCLUSION Sequential FDG-PET predicted patient outcome as early as after the first cycle of neoadjuvant chemotherapy and was more accurate than clinical or histopathologic response criteria including changes in tumor marker CA125. FDG-PET appears to be a promising tool for early prediction of response to chemotherapy.

Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM x anti-CD3 antibody: a phase I/II study.

Purpose: Malignant ascites in ovarian carcinoma patients is associated with poor prognosis and reduced quality of life. The trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3) enhances the antitumor activity by redirecting T cells and Fcγ receptor I/III–positive accessory cells to the tumor. This multicenter phase I/II dose-escalating study investigated tolerability and efficacy of i.p. catumaxomab application in ovarian cancer patients with malignant ascites containing epithelial cell adhesion molecule (EpCAM)–positive tumor cells. Experimental Design: Twenty-three women with recurrent ascites due to pretreated refractory ovarian cancer were treated with four to five i.p. infusions of catumaxomab in doses of 5 to 200 μg within 9 to 13 days. Results: The maximum tolerated dose was defined at 10, 20, 50, 200, and 200 μg for the first through fifth doses. Side effects included transient fever (83%), nausea (61%), and vomiting (57%), mostly CTCAE (Common Terminology Criteria for Adverse Events) grade 1 or 2. A total of 39 grade 3 and 2 grade 4 treatment-related adverse events (AE), 9 of them after the highest dose level (200 μg), were observed in 16 patients. Most AEs were reversible without sequelae. Treatment with catumaxomab resulted in significant and sustained reduction of ascites flow rate. A total of 22/23 patients did not require paracentesis between the last infusion and the end of study at day 37. Tumor cell monitoring revealed a reduction of EpCAM-positive malignant cells in ascites by up to 5 log. Conclusion: I.p. immunotherapy with catumaxomab prevented the accumulation of ascites and efficiently eliminated tumor cells with an acceptable safety profile. This suggests that catumaxomab is a promising treatment option in ovarian cancer patients with malignant ascites.

Prospective validation study of a predictive score for operability of recurrent ovarian cancer: The multicenter intergroup study DESKTOP II. A project of the AGO kommission OVAR, AGO study group, NOGGO, AGO-Austria, and MITO

Purpose: The DESKTOP I trial proposed a score for the prediction of complete cytoreduction in recurrent ovarian cancer. Resectability was assumed if 3 factors were present: (1) complete resection at first surgery, (2) good performance status, and (3) absence of ascites. The DESKTOP II trial was planned to verify this hypothesis prospectively in a multicenter setting. Methods: Participating centers prospectively enrolled all consecutive patients with platinum-sensitive first or second relapse. The score was applied to all patients, but centers were free to decide on therapy. All further therapies were documented, and the outcome of patients was analyzed. A 75% complete resection rate in 110 prospectively classified patients had to be achieved to confirm a positive predictive value of 2 or higher of 3 with 95% probability. Results: A total of 516 patients were screened within 19 months; of these, 261 patients (51%) were classified as score positive, and 129 patients with a positive score and first relapse were operated on. The rate of complete resection was 76%, thus confirming the validity of this score regarding positive prediction of complete resectability in 2 or more of 3 patients. Complication rates were moderate including second operations in 11% and perioperative mortality in 0.8%. Conclusions: This score is the first prospectively validated instrument to positively predict surgical outcome in recurrent ovarian cancer. It can aid in the selection of patients who might benefit from secondary cytoreductive surgery and will be enrolled in the recently started randomized prospective DESKTOP III trial investigating the role of surgery in recurrent platinum-sensitive ovarian cancer.

Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIc

SummaryStrong evidence has accumulated on the prognostic value of tumour-associated proteolytic factors in patients afflicted with solid malignant tumours, including advanced ovarian cancer. We evaluated the prognostic impact of the protease urokinase plasminogen activator (uPA) and its inhibitor PAI-1 on overall survival in patients with advanced ovarian cancer stage FIGO IIIc in order to select patients at risk. uPA and PAI-1 antigen were determined by ELISA in primary tumour tissue extracts of 86 ovarian cancer patients FIGO stage IIIc enrolled in a prospective study. Univariate and multivariate analyses were performed using the Cox proportional hazard model. The time-varying coefficient model of Gray was used to assess the time-dependent strength of prognostic factors tumour mass, uPA and PAI-1 on overall survival. In all patients, uPA and PAI-1 (optimized cut-offs of 2.0 and 27.5 ng mg-1 protein respectively), in addition to the traditional prognostic parameters of residual tumour mass, nodal status, grading and ascites volume, were of prognostic significance in univariate analysis for overall survival. Even in patients with residual tumour mass (n = 43), the statistically independent prognostic impact of PAI-1 persisted, allowing further discrimination between low- and high-risk patients. In multivariate analysis, residual tumour mass (P < 0.001, relative risk (RR) 4.5), PAI-1 (P < 0.001; RR 3.1) and nodal status (P = 0.022, RR 2.6) turned out to be strong, statistically independent prognostic parameters. Evaluation of the time-dependent prognostic impact of residual tumour mass and PAI-1 on overall survival (n = 86, 50 months) revealed that the prognostic power of these factors increased with time. In patients with advanced ovarian cancer, both residual tumour mass and PAI-1 are statistically independent strong prognostic factors. Even within patient subgroups with or without residual tumour mass, PAI-1 allowed selection of patients at risk who might benefit from individualized therapy protocols.

The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients

Epithelial ovarian cancer is the leading cause of death among female genital malignancies. Reduced expression of the cell adhesion molecule E-cadherin was previously shown to be associated with adverse prognostic features. The role of the E-cadherin repressor Snail in ovarian cancer progression remains to be elucidated. We analysed formalin-fixed and paraffin-embedded specimens of 48 primary ovarian tumours and corresponding metastases for expression of E-cadherin and Snail by immunohistochemistry. We found a significant correlation between E-cadherin expression in primary cancers and their corresponding metastases (P<0.001). This correlation was found for Snail expression as well (P<0.001). There was a significant (P=0.008) association of reduced E-cadherin expression in primary ovarian cancer with shorter overall survival. Similarly, Snail expression in corresponding metastases (P=0.047) was associated with reduced overall survival of the patients. Additionally, the group of patients showing reduced E-cadherin and increased Snail immunoreactivity in primary tumours and corresponding metastases, respectively, had a significantly higher risk of death (P=0.002 and 0.022, respectively) when compared to the patient group with the reference expression profile E-cadherin positive and Snail negative. Taken together, the results of our study show that the E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients.

Subcutaneous Mastectomy With Conservation of the Nipple-Areola Skin: Broadening the Indications

Background:Numerous authors take multiple predictive factors into account to decide whether or not the nipple-areola complex (NAC) can be conserved during mastectomy. These factors include the tumor-nipple distance, tumor size, axillary lymph node status, and lymphovascular invasion. Thus only a very limited percentage of patients can keep their NAC. If the breast gland tissue and all milk ducts can be separated completely from the nipple-areola skin (NA-skin) during subcutaneous mastectomy (SCM), conservation of the NA-skin is feasible even in the case of large, central, and retroareolar tumors. Patients and Methods:From July 2003 to May 2006, we performed 109 SCMs on 96 patients. Total mastectomy was indicated in 94 of these breasts, in 16 because of extensive ductal carcinoma in situ, and 78 breasts with invasive carcinoma required additional axillary dissection resulting in indication for modified radical mastectomy. At least 33 of the breasts had malignancy underneath the skin within the areolar margin (centrally located tumors). After dissection of all the breast tissue, the skin envelope with the areola is turned inside out and all milk ducts and any tissue beneath the areola are precisely dissected under the surgeon’s visual control. Frozen sections and HE histopathologic examination of this retroareolar tissue next to the skin are requested to decide whether the NA-skin can be preserved or not. This study was registered on the www.clinicaltrials.com website and has the following identification number ID: NCT00641628. Results:We found it necessary to dissect the NA-skin in 13 of 109 breasts (12%), altering the procedure to a skin sparing mastectomy. Necrosis of the NA-skin requiring surgical intervention occurred in only 1 of the conserved 96 breasts. After follow-up of 20 to 54 months (median: 34 months), no recurrence within the nipple-areola region was observed. One local recurrence on the chest wall and 1 axillary recurrence were detected. Of 96 patients, 2 developed distant metastases. One death was recorded. Occasionally, partial necrosis of the nipple occurred, with residual depigmentation of the skin but a good or excellent cosmetic result was maintained in most cases. Conclusion:SCM with NAC-skin conservation may be performed according to total mastectomy indications if an intraoperative frozen section (and the corresponding HE histopathology) of the tissue next to the nipple-areola skin is free of tumor. The remaining contraindications for SCM are: extensive tumor involvement of the skin, inflammatory breast cancer, and a clinically suspicious nipple.

Immunomonitoring results of a Phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3)

Patients with malignant ascites secondary to primary carcinomas benefit from intraperitoneal therapy with the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3). Here, we report the analysis of peritoneal fluid samples from 258 patients with malignant ascites randomized to catumaxomab or control groups to investigate the molecular effects of catumaxomab treatment. In the catumaxomab group, tumor cell numbers and peritoneal levels of VEGF decreased, whereas the activation status of CD4(+) and CD8(+) T-cell populations increased more than two-fold after treatment. Notably, CD133(+)/EpCAM(+) cancer stem cells vanished from the catumaxomab samples but not from the control samples. In vitro investigations indicated that catumaxomab eliminated tumor cells in a manner associated with release of proinflammatory Th1 cytokines. Together, our findings show that catumaxomab therapy activates peritoneal T cells and eliminates EpCAM(+) tumor cells, establishing a molecular and cellular basis to understand in vivo efficacy within the immunosuppressed malignant ascites tissue microenvironment.