Klaus Pietzner

Prognostic role of platinum sensitivity in patients with brain metastases from ovarian cancer: results of a German multicenter study

BACKGROUND Ovarian cancer is the leading cause of death in women with gynecological malignancies. Brain metastases are considered an uncommon metastatic site. Only few data exist on prognostic factors for this patient collective. PATIENTS AND METHODS A multicenter retrospective chart review was carried out including all patients with histologically confirmed ovarian cancer from six different German hospitals from 1981 to 2008. Overall, 4277 cases of patients with ovarian cancer were screened and patients with brain metastasis were identified and analyzed regarding various clinical variables and survival. RESULTS A total of 74 women with brain metastases were identified, resulting in an incidence of 1.73%. In multivariate analysis, the following clinical parameters had a significant impact on overall survival: multiple lesions [hazard ratio (HR) 4.4, 95% confidence interval (CI) 2.0-9.7] and low grading (HR 3.1, 95% CI 1.7-5.8) were associated with a negative impact. Platinum sensitivity (HR 0.23, 95% CI 0.12-0.48) was significantly associated with a favorable outcome. Good performance status (60%-80% HR 0.48, 95% CI 0.23-0.99 and 90%-100% HR 0.21, 95% CI 0.08-0.53) also had a positive impact on overall survival. CONCLUSIONS Platinum sensitivity is the most important prognostic factor in patients with ovarian cancer metastatic to the brain. This novel finding should be considered in the strategy of multimodal therapy for brain metastases in ovarian cancer.

Expression of epithelial cell adhesion molecule in paired tumor samples of patients with primary and recurrent serous ovarian cancer.

Objective Ovarian cancer (OC) recurrence constitutes a therapeutic dilemma with various novel targeted agents emerging that offer alternative treatment options. The aim of the present study was to evaluate and compare epithelial cell adhesion molecule (EpCAM) expression profiles in paired tumor samples of patients with OC relapse. Methods EpCAM expression was analyzed by immunohistochemistry using the avidin-biotin-complex method on paraffin-embedded OC tissues obtained at primary surgery as well as on corresponding tumor samples of the same patients at relapse. The EpCAM overexpression was defined as 76% to 100% of tumor cells positively stained for EpCAM. Clinical data were collected within the Tumorbank Ovarian Cancer Network. Results Nineteen patients with serous OC histology were included in the study (median age at primary diagnosis, 50 years; range, 40–74 years). The majority of the patients (95%) presented with International Federation of Gynecology and Obstetrics stage III/IV, and 68.4% of the tumors were poorly differentiated. A complete macroscopic tumor resection could be achieved in 15 patients (78.9%) at diagnosis. Epithelial cell adhesion molecule overexpression was detected in 17 (89%) of the primary and 16 (84%) of the recurrent tumors (P = 1.0); hence, no significant change of the EpCAM expression profile could be identified over time. Conclusions Epithelial cell adhesion molecule expression profile appears to remain stable during the course from the primary throughout the relapse of serous OC. The results indicate that EpCAM might be an interesting therapeutic target structure in serous OC.

Salvage surgery due to bowel obstruction in advanced or relapsed ovarian cancer resulting in short bowel syndrome and long-life total parenteral nutrition: surgical and clinical outcome.

Objective Salvage surgery for patients with highly advanced or relapsed epithelial ovarian cancer (EOC) complicated by bowel obstruction and resulting in short bowel syndrome (SBS) constitutes a therapeutic dilemma. Our aim was to evaluate surgical and clinical outcome in these highly palliative situations. Methods We evaluated all patients with EOC who underwent salvage extraperitoneal en bloc intestinal resection with terminal ileostomy or jejunostomy resulting in SBS and total parenteral nutrition owing to bowel obstruction between May 2003 and January 2012 in our institution. Results Thirty-seven patients were identified (median age, 58 years; range, 22–71 years), 3 (8.1%) with primary and 34 (91.6%) with relapsed EOC. Five patients (13.5%) were platinum sensitive. Median residual intestinal length was 70 cm (range, 10–180 cm); 21 patients (56.8%) had a residual intestinal length less than 1 m. Operative 30-day mortality and major morbidity rates were 10% and 51%, respectively. Median overall survival was 5.6 months (range, 0.1–49 months). One-year and 2-year overall survival rates were 18.3% (95% confidence interval, 5.1%–31.5%) and 8.1% (95% confidence interval, 0%–18.0)%, respectively. Within a median follow-up period of 5 months (range, 0.2–49 months), 4 patients (10.8%) are still alive. No significant differences in survival were seen between patients with or without major complications, tumor residuals, or residual intestinal length of less than 1 m versus greater than 1 m. Conclusions Salvage palliative surgery in EOC due to bowel obstruction resulting in SBS and in need of long-life total parenteral nutrition is associated with high morbidity rates and low overall survival. These surgeries should ideally be performed only in a multidisciplinary setting with adequate infrastructure and possibility of home care support. Conservative management should be the route of action in the absence of acute abdomen or intestinal perforation.

Clinical experience of young patients with small cell ovarian carcinoma of the hypercalcemic type (OSCCHT)

OBJECTIVE Small cell ovarian cancer of the hypercalcemic type (OSCCHT) is a very rare and highly aggressive disease which mainly affects young women, while optimal treatment guidelines have not yet been defined. The objective of this work is to present our experience with four OSCCHT patients. STUDY DESIGN We evaluated the surgical course and clinical outcome of all OSCCHT patients treated in the European Competence Center for Ovarian Cancer, Charité, University Medicine of Berlin. Pathology was reviewed by specialized gynecological pathologists of our center. RESULTS Four OSCCHT patients were identified between 2008 and 2011 (median age: 24.5 years; range: 18-29) out of 845 ovarian cancer patients being operated on within this timeframe. Two patients were diagnosed at a very early tumor stage (FIGO Ia), one in FIGO IIb, and one patient presented with advanced stage disease FIGO IIIc. Treatment of choice was surgery followed by adjuvant platinum-based chemotherapy. In all patients the uterus was preserved and also the contralateral ovary in three out of the four patients. Within a median follow-up time of 22 months (range: 8-47) only the FIGO IIIC-patient relapsed twice and died 15 months after initial diagnosis. The other three patients are all alive and with no signs of relapse at 8, 29 and 47 months after initial diagnosis. CONCLUSION OSCCHT is a rare tumor entity which usually affects young women with hopes of childbearing. The clinical course varies widely and although it is associated with an overall dismal prognosis, fertility-sparing surgery followed by platinum-based adjuvant chemotherapy may be considered in early stages of the disease.

Prognostic role of early versus late onset of bone metastasis in patients with carcinoma of the ovary, peritoneum and fallopian tube

BACKGROUND Bone metastases are a rare manifestation in the management of ovarian cancer and thought to be associated with a poor prognosis as sign of distant spread. Only few data exist on this rare condition. The present study aimed to more information on this very distinct patient collective. PATIENTS AND METHODS A retrospective chart review was carried out including all patients who had been treated from 1994 to 2009 for histologically confirmed ovarian, peritoneal and fallopian tube cancer. Overall, 1717 cases were detected and screened. Patients with bone metastasis were identified and analyzed regarding survival as well as various clinical variables. RESULTS A total of 26 women who had been diagnosed with bone metastases ante mortem could be identified, resulting in an incidence of 1.50%. The majority of patients presented multiple bone lesions (80.8%) and bone spread was symptomatic in 62.5% of the cases. Mean overall survival from primary diagnosis of EOC was 50.5 months (range: 2.5-142.5 months). Median overall survival after diagnosis of bone metastases was 7.2 months. When divided into two subsets depending on timepoint diagnosis of bone metastases, there was a significant difference in overall survival. The mean overall survival from primary diagnosis of EOC in the early-onset group (n = 8), defined as occurence of bone manifestation within 12 months, was 11.2 months. The mean overall survival in the late-onset group (n = 15) was 78.4 months (P = 0.000001). CONCLUSIONS The time interval from diagnosis to appearance of bone metastases is a prognostic factor in ovarian cancer. While early onset bone spread has a strong negative prognostic impact, late-onset bone diagnosis of bone metastases hardly influences the prognosis at all. This finding should be considered in the management of patients with bone metastases from ovarian cancer.

Impact of ascites on the perioperative course of patients with advanced ovarian cancer undergoing extensive cytoreduction: results of a study on 119 patients.

Objective Cytoreductive surgery for epithelial ovarian cancer (EOC) is the cornerstone of multimodal therapy and considered as a high-risk surgery because of extensive multivisceral procedures. In most patients, ascites is present, but its impact on the surgical and clinical outcomes is unclear. Methods One hundred nineteen patients undergoing surgical cytoreduction because of EOC between 2005 and 2008 were included. All surgical data and the individual tumor pattern were collected systematically based on a validated documentation tool (intraoperative mapping of ovarian cancer) during primary surgery. The amount of ascites was determined at the time of surgery, and 3 groups were classified (no ascites [NOA, n = 56], low amount of ascites [< 500 mL, n = 42], and high amount of ascites [HAS > 500 mL, n = 21]). Results Group NOA compared with HAS showed less transfusions of packed red blood cells (median [quartiles], 0 [0–2] vs 0 [0–2] vs 3 [1–4] U; P < 0.001) and fresh frozen plasma (median [quartiles], 0 [0–2] vs 0 [0–4] vs 2 [2–6] U; P < 0.001). In addition, in patients with ascites, noradrenaline was administered more frequently and in higher doses. The postoperative length of stay in the intensive care unit was significantly shorter in the NOA versus the group with low amount of ascites and HAS (median [quartiles], 1 [0–1] vs 1 [0–2] vs 2 [1–5] days; P < 0.001). The hospital length of stay is extended in HAS compared with that in NOA (median [quartiles], 16 [13–20] vs 17 [14–22] vs 21 [17–41] days; P = 0.004). Postoperative complications were increased in patients with ascites at the time of surgery (P = 0.007). Conclusions The presence of a high amount of ascites at cytoreductive surgery because of EOC is associated with higher amounts of blood transfusions, whereas the length of hospital stay and the postoperative intensive care unit treatment are significantly prolonged compared with those of patients without ascites.

Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

BACKGROUND Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. METHODS We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1-5) plus either oral sorafenib 400 mg or placebo twice daily on days 6-15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01047891. FINDINGS Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43-0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8-7·6) with sorafenib versus 4·4 months (3·7-5·0) with placebo. The most common grade 3-4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]). INTERPRETATION Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies. FUNDING Bayer, Amgen, and GlaxoSmithKline.

Hemodynamic Consequences of Malignant Ascites in Epithelial Ovarian Cancer Surgery*: A Prospective Substudy of a Randomized Controlled Trial.

AbstractMalignant ascites (MA) is most commonly observed in patients scheduled for epithelial ovarian cancer (EOC) surgery and is supposed as a major risk factor promoting perioperative hemodynamic deterioration. We aimed to assess the hemodynamic consequences of MA on systemic circulation in patients undergoing cytoreductive EOC surgery.This study is a predefined post-hoc analysis of a randomized controlled pilot trial comparing intravenous solutions within a goal-directed algorithm to optimize hemodynamic therapy in patients undergoing cytoreductive EOC surgery. Ascites was used to stratify the EOC patients prior to randomization in the main study. We analyzed 2 groups according to the amount of ascites (NLAS: none or low ascites [<500 mL] vs HAS: high ascites group [>500 mL]). Differences in hemodynamic variables with respect to time were analyzed using nonparametric analysis for longitudinal data and multivariate generalized estimating equation adjusting the analysis for the randomized study groups of the main study.A total of 31 patients in the NLAS and 16 patients in the HAS group were analyzed. Although cardiac output was not different between groups suggesting a similar circulatory blood flow, the HAS group revealed higher heart rates and lower stroke volumes during surgery. There were no differences in pressure-based hemodynamic variables. In the HAS group, fluid demands, reflected by the time to reindication of a fluid challenge after preload optimization, increased steadily, whereas stroke volume could not be maintained at baseline resulting in hemodynamic instability after 1.5 h of surgery. In contrast, in the NLAS group fluid demands were stable and stroke volume could be maintained during surgery. Clinically relevant associations of the type of fluid replacement with hemodynamic consequences were particularly observed in the HAS group, in which transfusion of fresh frozen plasma (FFP) was associated to an improved circulatory flow and reduced vasopressor and fluid demands, whereas the administration of artificial infusion solutions was related to opposite effects.Malignant ascites >500 mL implies increased fluid demands and substantial alterations in circulatory blood flow during cancer surgery. Fresh frozen plasma transfusion promotes recovering hemodynamic stability in patients with malignant ascites >500 mL, in whom artificial infusion solutions could not prevent from hemodynamic deterioration.

Checkpoint-inhibition in ovarian cancer: rising star or just a dream?

The introduction of checkpoint inhibitors revolutionized immuno-oncology. The efficacy of traditional immunotherapeutics, like vaccines and immunostimulants was very limited due to persistent immune-escape strategies of cancer cells. Checkpoint inhibitors target these escape mechanisms and re-direct the immune system to anti-tumor toxicity. Phenomenal results have been reported in entities like melanoma, where no other therapy was able to demonstrate survival benefit, before the introduction of immunotherapeutics. The first experience in ovarian cancer (OC) was reported for nivolumab, a fully human anti-programmed cell death protein 1 (PD1) antibody, in 2015. While the data are extraordinary for a mono-immunotherapeutic agent and very promising, they do not match up to the revolutionary results in entities like melanoma. The key to exceptional treatment response in OC, could be the identification of the most immunogenic patients. We hypothyse that BRCA mutation could be a predictor of improved response in OC. The underlying DNA-repair-deficiancy should result in increased immunogenicity because of higher mutational load and more neoantigen presentation. This hypothesis was not tested to date and should be subject to future trials. The present article gives an overview of the immunologic background of checkpoint inhibition (CI). It presents current data on nivolumab and other checkpoint-inhibitors in solid tumors and OC specifically and depicts important topics in the management of this novel substance group, such as side effect control, diagnostic PD-1/programmed cell death-ligand 1 (PD-L1) expression assessment and management of pseudoprogression.

Aktuelle Therapiestrategien bei malignem Aszites

ZusammenfassungMaligner Aszites beeinträchtigt die Lebensqualität von Krebspatienten gravierend. Aufgrund der oft palliativen Situation der Patienten ist eine kurative Therapie nicht immer möglich. Es gibt aber effektive Behandlungsmethoden, die auf neuen Forschungsergebnissen zur Pathophysiologie des malignen Aszites basieren.