Florian Heitz

Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier occurrence of cerebral metastases

PURPOSE Evaluation of the influence of immunohistochemically defined breast cancer (BC) subtypes and other risk factors on the development of cerebral metastases (CM). METHODS Exploratory analysis of a hospital-based prospective tumour registry including all patients with primary BC treated in our EUSOMA breast unit between 1998 and 2006. RESULTS The study cohort contained 2441 patients, including 284 patients (11.6%) with triple-negative (oestrogen receptor (ER), progesterone receptor (PR) and HER2-negative) and 245 patients (10.1%) with HER2-overexpressing BC subtypes. Overall, 80 patients (3.3%) developed CM within a median follow-up period of 47 months, 19 (23.8%) of them with triple-negative and 19 (23.8%) with HER2-positive tumours. Therefore, 6.7% of all patients with triple-negative and 7.8% of patients with HER2-positive breast cancer developed CM. Multivariate analysis indicated that the highest risk for CM was triple-negative breast cancer. Further independent risk factors were: HER2-overexpression, early onset BC (age<50 years), and large tumour size (pT3/4). Among those patients developing CM, triple-negative BC showed the shortest interval between primary diagnosis and occurrence of CM with a median of 22 months, compared to 30 and 63.5 months in HER2-positive and ER+/HER2- BC, respectively. Survival after occurrence of CM did not differ among the subtypes. CONCLUSION Patients with triple-negative or HER2-positive BC have a higher risk for CM compared with patients bearing the ER+/HER2- phenotype and develop CM earlier in the course of disease. A risk profile for CM might help adjust surveillance in high risk populations and identify patients with a need for new treatment strategies.

Impact of a structured quality management program on surgical outcome in primary advanced ovarian cancer.

OBJECTIVE Surgical outcome in advanced ovarian cancer (AOC) is an important prognostic factor and the only factor amendable to improvement by optimization. Therefore, introduction of quality management programs (QM) regarding the surgical therapy in ovarian cancer may help to improve outcome. METHODS We introduced a specific ovarian cancer quality management program in 2001 in our gynecologic oncology center. Analysis of 396 consecutive patients with primary surgery for advanced ovarian cancer FIGO stages IIB-IV operated before the introduction of the quality management program 1997-2000, or during the introduction years 2001-2003, or after establishing 2004-2008. RESULTS Thirty-three percent had complete debulking to no macroscopic residual disease from 1997 to 2000. This rate increased to 47% in 2001-2003 (n = 86) and 62% in 2004-2008 (n = 259). The utilization of extended surgical procedures increased over time. Patients with complete resection had 5-YSR of 55% compared to 16% in patients with residuals 1-10 mm, and 13% in patients with residuals >1 cm (p < 0.001). The median OS increased from 26 months 1997-2000 to 37 months 2001-2003 and 45 months in 2004-2008 (p < 0.003). CONCLUSIONS Optimizing surgical skills, infrastructure, and introduction of quality management programs may improve both surgical and overall outcome in advanced ovarian cancer.

Neoadjuvant chemotherapy in advanced ovarian cancer: On what do we agree and disagree?

Following the recent publication of the randomized study in stages IIIC and IV ovarian cancer of the European Organisation for Treatment and Research—Gynaecological Cancer Group (EORTC-GCG) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group [1], a lot of controversy on the role of neoadjuvant chemotherapy and primary debulking in advanced ovarian cancer emerged [2–5]. At the recent Gynecologic Cancer InterGroup (GCIG) consensus conference a majority of 21 out of 23 member groups supported the statement: “Delayed primary surgery after neoadjuvant chemotherapy is an option for selected patients with stage IIIC or IV ovarian cancer as included in the EORTC55971” [6]. However, two member groups (the Arbeitsgemeinschaft Gynaekologische Onkologie [AGO] Study Group Germany and the AGO-Austria) voted for the minority statement “Neoadjuvant chemotherapy cannot be regarded as adequate routine therapy of advanced ovarian cancer and should be limited to selected patients with very advanced International Federation ofGynecology andObstetrics stage IIIC or IV disease and contraindications against upfront debulking surgery or tumor dissemination, implying no chance for complete resection.” The latter was also the official statement of the German Society of Gynecologic Oncology [7]. The authors discussed the role of neoadjuvant chemotherapy in advanced ovarian cancer on many conferences. However, the authors believe it is important to summarize in this paper in which groups of patients we agree that primary debulking should be the preferred treatment strategy and in which patients will probably not benefit from upfront surgery and alternative strategies as neoadjuvant chemotherapy followed by interval debulking should be preferred. Furthermore, we summarize in which groups of patients with advanced ovarian cancer we disagree on the preferred treatment policy. The opinions expressed in this paper are solely the opinion of the authors and not of the Cooperative groups or Societies the authors are member of.

Pre-operative serum albumin is associated with post-operative complication rate and overall survival in patients with epithelial ovarian cancer undergoing cytoreductive surgery

OBJECTIVE Hypoalbuminemia has been reported as a risk factor for post-operative complications and unfavorable survival in cancer patients. We aimed to evaluate the predictive value of preoperative serum albumin levels on post-operative complication rate and the impact on overall survival (OS) in patients with epithelial ovarian cancer (EOC) undergoing primary cytoreductive surgery. METHODS The present retrospective study included 604 consecutive patients with EOC who underwent primary cytoreductive surgery at two tertiary cancer centers specialized in gynecologic oncology. Hypoalbuminemia was defined as a pre-operative serum albumin level≤35g/L. Post-operative surgical complications were graded according to the Clavien-Dindo-Classification (CDC). Fisher-test was used to investigate the predictive value of hypoalbuminemia on the rate of severe post-operative complications. Survival analyses were calculated using log-rank test and Cox regression models. RESULTS The incidence of pre-operative hypoalbuminemia in the entire cohort was 16.4%. Hypoalbuminemia was a predictive factor for severe post-operative complications (CDC 3-5) (OR 3.65, (CI95% 1.59--8.39); p=0.002). Furthermore, median overall survival time of patients with hypoalbuminemia was 24 months compared to 83 months in patients with normal albumin (p<0.001), respectively. Hypoalbuminemia was independently associated with shortened overall survival (HR 2.2 (95% CI 1.6-3.0); p<0.001) even after adjusting established prognostic factors such as age, tumor stage, performance status, and post-operative residual disease. CONCLUSION Pre-operative hypoalbuminemia can be used as both an independent predictive factor for severe post-operative complications and as prognostic parameter regarding overall survival in EOC patients. Therefore, albumin levels may be incorporated into future clinical trials as stratification factor.

Systemic therapy in recurrent ovarian cancer: current treatment options and new drugs.

Most patients with ovarian cancer relapse despite aggressive surgery and platinum–taxane-based primary chemotherapy. Further treatment depends on prior response and progression-free interval. Monotherapy is indicated in patients with so-called platinum-resistant or -refractory ovarian cancer. The standard treatment for patients with platinum-sensitive recurrent ovarian cancer is platinum-based combination chemotherapy. Cytoreductive surgery is also a treatment option in such patients. Actual treatment options and strategies in recurrent ovarian cancer will also be discussed. Furthermore, this review focuses on new drugs in the treatment of primary and recurrent ovarian cancer.

Bevacizumab in the Treatment of Ovarian Cancer

IntroductionIn the past decade there have been many attempts to improve systemic treatment and thus the outcome of patients with ovarian cancer. However, neither the sequential addition of non cross-resistant drugs to standard chemotherapy comprising carboplatin and paclitaxel, nor triplet combination therapies with conventional chemotherapeutic drugs have improved outcomes. Instead, such approaches have led to an increase in the incidence of side effects. We are currently experiencing a shift toward the addition of molecularly targeted and biological anticancer therapies to standard treatment. Vascular endothelial growth factor (VEGF), which improves vitally important tumor vasculature, is secreted by a range of tumors, and a high level of VEGF is known to be an independent risk factor for aggressive disease in ovarian cancer. This finding led to the development in the 1990s of bevacizumab, a humanized monoclonal antibody against VEGF.DiscussionSeveral phase II trials and four phase III trials have demonstrated that bevacizumab is active in patients with advanced and recurrent ovarian cancer. Both phase III trials of bevacizumab as first-line therapy in advanced ovarian cancer (ICON 7/AGOOVAR 11 and GOG-0218) have shown that the addition of bevacizumab to chemotherapy and as maintenance therapy improves progressionfree survival (PFS). The phase III trials in platinum-sensitive (OCEANS) and platinumresistant, relapsed disease (AURELIA) have also demonstrated a benefit for bevazicumab with respect to PFS. The administration of bevacizumab to improve survival in patients with ovarian cancer is not without side effects and a broad discussion on the cost-effectiveness of this approach is ongoing.ConclusionThis article presents clinical trial data on bevacizumab in the treatment of ovarian cancer and discusses the indication and pitfalls in the application of bevacizumab in patients with this malignancy.

Poly(ADP-ribosyl)ation polymerases: mechanism and new target of anticancer therapy

Poly(ADP-ribose)polymerase (PARP) is a ubiquitously present nuclear enzyme that is not only involved in many important cellular pathways but also contributes to chromosomal structure and genomic stability. The development of highly selective and potent PARP inhibitors has become of increasing clinical interest because of their promising efficacy in patients with breast or ovarian cancer. Furthermore, recent Phase I and hase II trials have demonstrated that PARP inhibitors have low toxicity rates. In particular patients with either deficiency or dysfunction of BRCA, which is involved in DNA double strand break repair, appear to benefit from PARP inhibition. This article summarizes the present knowledge regarding the physiological function of PARP and ([poly]ADP-ribose) PAR, the functional product of PARP, the development of PARP inhibitors, the recent clinical data of PARP inhibitors in cancer treatment and the selection of patients who may benefit from PARP inhibition.

Prognostic factors for complete debulking in first- and second-line ovarian cancer.

Objectives: Surgery is a mainstay of therapy in ovarian cancer. Are there any actual changes in the definitions and goals of surgery? Methods: Selective review of the actual literature and results in surgery for primary and recurrent ovarian cancer. Results: Actual data strongly suggest changing the surgical aim from the so-called optimal debulking (residual disease <1 cm) to complete resection. The standard in patients in whom complete resection might be possible remains to be primary surgery followed by chemotherapy. There might be a subgroup of patients with a poor prognosis who will have only limited benefit of primary surgery, and interval debulking is also possible. Predictive models for suboptimal debulking at primary diagnosis are discussed. The surgical aim in recurrent ovarian cancer is defined as complete resection. Actual multicenter studies investigated prospectively predictive models for complete resection. Conclusion: Recommendations regarding surgical aim have changed within the recent years. There are still no reliable predictive models for primary surgery of ovarian cancer. The DESKTOP II trial has validated a score of resectability in recurrent ovarian cancer.

Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase

OBJECTIVE Since almost two decades standard 1st-line chemotherapy for advanced ovarian cancer (AOC) has been a platinum/taxane combination. More recently, this general strategy has been challenged because different types of AOC may not benefit homogenously. Low-grade serous ovarian cancer (LGSOC) is one of the candidates in whom efficacy of standard chemotherapy should be revised. METHODS This study is an exploratory case control study of the AGO-metadatabase of 4 randomized phase III trials with first-line platinum combination chemotherapy without any targeted therapy. Patients with advanced FIGO IIIBIV low-grade serous ovarian cancer were included and compared with control cases having high-grade serous AOC. RESULTS Out of 5114 patients in this AGO database 145 (2.8%) had LGSOC and of those thirty-nine (24.1%) had suboptimal debulking with post-operative residual tumor >1cm, thus being eligible for response evaluation. An objective response was observed in only 10 patients and this 23.1% response rate (RR) was significantly lower compared to 90.1% RR in the control cohort of high-grade serous ovarian cancer (HGSOC) (p<0.001). Both, LGSOC and HGSOC patients who underwent complete cytoreduction had significantly better progression free survival (PFS) and overall survival (OS) in comparison to those with residuals after primary surgery, accordingly (p<0.001). CONCLUSIONS Our observation indicates that low-grade serous cancer is not as responsive to platinum-taxane-based chemotherapy as high-grade serous AOC. In contrast, surgical debulking showed a similar impact on outcome in both types of AOC thus indicating different roles for both standard treatment modalities. Systemic treatment of low grade serous AOC urgently warrants further investigations.

Impact of beta blocker medication in patients with platinum sensitive recurrent ovarian cancer-a combined analysis of 2 prospective multicenter trials by the AGO Study Group, NCIC-CTG and EORTC-GCG.

OBJECTIVE Retrospective analyses suggest that the treatment with beta blocker improves survival in patients with breast cancer and melanoma. The aim of this study was to investigate the impact of medication with beta blocker in patients with recurrent ovarian cancer. METHODS Included patients received treatment within two prospective clinical trials: AGO-OVAR 2.4 phase I trial (carboplatin/gemcitabine; N=25, protocol AGO-OVAR 2.4) and AGO led intergroup phase III trial (carboplatin vs carboplatin/gemcitabine; N=356, protocol AGO-OVAR 2.5, EORTC-GCG, NCIC CTG). Concurrent medication was documented after every cycle and thorough monitoring was conducted. RESULTS During the studies 38 patients (9.97%) received a beta blocker as co-medication. Patients treated with beta blockers were significantly older than patients not treated with beta blockers. Response rates to chemotherapy were not different between patients treated with beta blockers and those who were not. After a median follow-up of 17 months, 349 (91.6%) patients had progressive disease and 267 (70.1%) patients had died. No difference in median progression-free survival (7.79 vs 7.62 months (p=0.95)) and overall survival (21.2 vs 17.3 months (p=0.18)) was recorded for patients treated with and without beta blocker. In multivariate analyses including age, platinum free-interval, study treatment and ECOG performance status beta blocker treatment was not associated with a significant impact on progression-free survival (HR: 0.92; 95% CI: 0.65-1.31; p=0.65) and overall survival (HR:0.74; 95%CI: 0.49-1.11; p=0.15). CONCLUSIONS In this series of recurrent platinum-sensitive ovarian cancer patients it could not be confirmed whether beta blocker treatment was associated with better or worse outcome.