Preoperative HE4 expression in plasma predicts surgical outcome in primary ovarian cancer patients: Results from the OVCAD study

ObjectivesEpithelial ovarian cancer (EOC) is the major cause of death due to gynecological malignancies. The most important prognostic factors are residual tumor mass after surgery and platinum-response. No predictive biomarkers are available to identify patients who will benefit from standard treatment. The aim of our study was to analyze the role of HE4 in predicting surgical and clinical outcome in primary EOC.MethodsIn the European multicentric project “OVCAD”, 275 consecutive patients with primary EOC were enrolled. Patients were eligible if radical cytoreductive surgery was performed and platinum-based chemotherapy was applied. Plasma and ascites samples were collected before or during surgery. The concentrations of HE4 and CA125 was determined using ELISA and Luminex technique, respectively.ResultsMedian age at first diagnosis was 58 years (range 18–85 years). Most patients presented with advanced stage disease, FIGO III or IV (94.6%), grades II–III (96%) and serous histology (86.2%). In most cases a complete cytoreduction to no residual tumor mass was achieved (68.4%). Higher plasma HE4 levels correlated with poor surgery outcome in terms of macroscopically residual tumor mass (p < 0.001) and platinum-resistance (p = 0.009). Plasma CA125 and the risk index (HE4 and CA125) were independent predictive factors for surgical outcome (p = 0.001, OR = 3.37, 95% CI = 1.61–7.06 and p < 0.001, OR = 6,041, 95% CI = 2.33–15.65, respectively). FIGO stage III was an independent predictive factor for platinum response (p = 0.039, OR = 0.436, 95% CI = 0.198–0.960).ConclusionsThe presented data are showing that the combination of HE4 and CA125 expression in plasma might predict the surgical outcome in EOC and by this may have a prognostic impact on PFS and OS.     

Adjuvante Therapiekonzepte beim Ovarialkarzinom

Background

The overall survival of patients with advanced ovarian cancer after optimal cytoreductive surgery and adjuvant chemotherapy could be improved over the last four decades but is still limited with 35–45?%. Thus ovarian cancer is still the deadliest of all genital cancers. There is a great need for optimization in efficacy of the current adjuvant treatment standard of carboplatin and paclitaxel and a reduction of acute and long-term side effects.

Objective

This article presents an evidence-based review of the current state of the art therapy as well as new developments

Material and methods

A systematic literature search was carried out and relevant publications, congress reports as well as current clinical trials are summarized.

Results

Management of early stage ovarian cancer requires an adequate intraoperative staging. For all patients other than FIGO stage Ia, G1 chemotherapy should be recommended following the individual risk situation. Inhibition of angiogenesis is a new and highly effective treatment strategy for treatment of advanced ovarian cancer. Bevacizumab has been approved since 2011 for the adjuvant therapy of advanced stage disease FIGO stages IIIb-IV in combination with carboplatin and paclitaxel.

Conclusion

The long-term focus of management of ovarian cancer aims at the implementation of targeted strategies to reduce toxicity and optimize the therapeutic index. Currently running clinical trials are focusing on additional inhibitors of angiogenesis. The great challenge for clinicians is to identify subgroups of patients who may benefit of different targeted treatment strategies.     

Möglichkeiten und Grenzen der Diagnostik beim Ovarialkarzinom

Background

Ovarian cancer is the gynecological malignancy with the highest mortality. This is mainly due to the absence of an efficient screening and diagnostic test; thus, most ovarian cancer patients are diagnosed in late stages when the survival rates are significantly worse.

Methods

A literature search of PubMed, Medline, and a manual internet search was performed. The most relevant studies regarding biomarkers, ultrasound and mini-invasive tests for early diagnosis are summarized. Due to the fact that CA-125 is considered the gold standard for ovarian cancer and that HE4 seems to be the most promising serum biomarker, these two proteins are the focus of this article.

Results

HE4 seems have more reliable results in premenopausal patients compared to CA-125, mainly due to not being increased in endometriosis cases. Standardized ultrasound examination seems to be suitable for discriminating patients with pelvic tumors. The opinion of IOTA (International Ovarian Tumor Analysis) experts seems to have the highest sensitivity and specificity; nevertheless, ultrasound is a very subjective examination and depends on the experience of the examiner.

Conclusion

Ultrasound and biomarkers failed to significantly increase sensitivity and specificity of early diagnostic tests for ovarian cancer. The combination of both ultrasound and biomarker improves early diagnosis. New techniques such as uterine lavage and detection of genetic changes might also lead to improvement in early diagnosis.     

A randomised,double-blind,phase II study of two doses of pemetrexed in the treatment of platinum-resistant,epithelial ovarian or primary peritoneal cancer

PurposeWe conducted a randomised phase II study to assess the safety and efficacy of standard versus high-dose pemetrexed in platinum-resistant epithelial ovarian cancer (PR-EOC). The expression of ten genes was also examined as potential biomarkers of pemetrexed/platinum activity.Patients and methodsPatients received pemetrexed 500 mg/m² (Pem500) or 900 mg/m² (Pem900) on day 1 of each 21-d cycle. Responses were defined per RECIST for measurable disease or by Gynaecologic Cancer Intergroup (GCIG) CA-125 criteria for non-measurable disease.ResultsOf 102 patients randomised, 98 were evaluable for toxicity (47 Pem500, 51 Pem900) and 91 were evaluable for efficacy (43 Pem500, 48 Pem900) of whom 68 had measurable disease and 23 had CA-125-defined disease. The overall RR was 9.3% (95% CI: 2.6–22.1%) on Pem500 and 10.4% (95% CI: 3.5–22.7%) on Pem900. The median progression-free survival (PFS) was 2.8 months on both arms, and the median survival was 11.9 and 10.3 months, respectively. Lower mRNA expression of excision repair cross-complementation group 1 (ERCC1) and reduced folate carrier 1 (RFC1) were associated with longer PFS and time to treatment failure, respectively. Grade 3/4 toxicities, including fatigue, nausea and vomiting, were numerically greater on Pem900. Pemetrexed-related SAEs occurred in 17% and 28% of Pem500 and Pem900 patients, respectively.ConclusionsPemetrexed has activity in PR-EOC equivalent to other agents in platinum-resistant disease; however, Pem500 has the preferable toxicity profile. ERCC1 and RFC1 may merit examination as predictive biomarkers in PR-EOC.     

Pegylated liposomal doxorubicin (CAELYX®) in patients with advanced ovarian cancer: results of a German multicenter observational study

Purpose

Pegylated liposomal doxorubicin (PLD, CAELYX^®) has demonstrated activity in several phase-III trials and has been approved for the therapy of relapsed ovarian cancer after platinum treatment. Aim of this observational study was to analyze the efficacy and toxicity profile of PLD under routine clinical conditions and without the general restrictions of defined inclusion and exclusion criteria of clinical trials.

Methods

Between 2003 and 2005, a total of 190 patients with relapsed ovarian cancer were enrolled. 183 patients were available for evaluation; dose-intensity, modifications, treatment duration, toxicities and response were systematically analyzed.

Results

The median patient age was 62 years (range 23–86 years). 45.4% of the patients received PLD as second-line therapy and a median of four courses per patient were administered. The median dose of PLD was 40 mg/m², most frequently used every 4 weeks (68.8%). Grade 3 Leucopenia (1.6%) and grade 3 and 4 thrombocytopenia (0.5%) were the most frequent hematological toxicities. The most frequent non-hematological toxicities were skin toxicity, pain and nausea, which were observed in 38.8, 41 and 45.9% of the patients, respectively. Twenty-seven percent of the patients showed a response to therapy with 6.9% achieving complete remission and 20.1% achieving partial remission. 37.7% achieved a stable disease. The median duration of response for all patients was 4.8 months (range 0–51.8 months). Median progression-free interval and overall survival were 5.8 months (95% CI 5.1–6.6 months) and 16.6 months (95% CI 13.9–22.6 months), respectively.

Conclusions

PLD is safe and effective in patients with relapsed ovarian cancer, even after numerous previous treatment regimens. A dose of 40 mg/m² every 28 days seems to be an effective and well-tolerated therapeutic option in advanced ovarian cancer with a low incidence of hematological toxicities and acceptable non-hematological toxicities.     

Pegylated liposomal doxorubicin-associated hand-foot syndrome: recommendations of an international panel of experts

BackgroundHand–foot syndrome (HFS) is dose-limiting and the most common cumulative toxicity associated with pegylated liposomal doxorubicin (PLD). It can cause considerable discomfort and lead to therapy interruption. Numerous approaches to HFS management have been reported, but there is no consensus.MethodsPublished literature (identified via Medline and internet search) and expert experience regarding HFS and its pathogenesis, incidence, risk factors, prevention and treatment in patients undergoing treatment with PLD were collected and reviewed by a panel of experts. A consensus technique was used to develop recommendations.FindingsThe pathogenesis of PLD-associated HFS has been recently elucidated. Systems used to grade, prevent and treat HFS in individuals treated with PLD vary widely. A randomised clinical study demonstrated that PLD dose intensity reduction can prevent HFS. While there is limited literature support, patient education and supportive measures were endorsed by the expert panel as effective strategies for HFS prevention and treatment. An easy to use HFS grading and management algorithm was developed, early signs and symptoms of HFS outlined and specific recommendations for supportive care developed.InterpretationThe paucity of data on the management of PLD-associated HFS led the expert panel to develop consensus-based recommendations. Patient education and supportive measures are important elements in the management of HFS and dose intensity reduction has documented efficacy in prevention. At a PLD dose intensity not exceeding 10 mg/m² weekly, HFS can be easily managed. Phase III research to support the efficacy other interventions is lacking.     

Can Fried Frailty Score predict postoperative morbidity and mortality in gynecologic cancer surgery? Results of a prospective study

BackgroundAim of this study is to evaluate the predictive ability of Fried Frailty Score for surgical outcomes in patients undergoing gynecologic cancer surgery.MethodsThis is a prospective cohort study at an academic gynecological cancer center from Oct 2015 through Jan 2017. We applied systematically numerous screening tools, geriatric questionnaires and single measurements which may provide predictions for surgical outcomes. We classified frailty according to the Fried definition and surgical complications were graded according Clavien-Dindo criteria. Using logistic regression analysis, we identified predictive clinical variables for postoperative complications (POC).ResultsOverall 226 patients were enrolled (median age 59 years, range 18–87 years). The prevalence of frailty based on the presence of three or more frailty criteria was 14.2%, the presence of one or two frailty criteria was classified as prefrail with 59.4% and without any presence as robust with 26.5%. Within 30 days of surgery, nine (3.8%) patients have died and 40 (18.3%) experienced a grade ≥ IIIb complication. In the regression analysis obesity (OR: 5.37, 95% CI 1.99–14.49, p = 0.001) as well as ECOG >1 (OR: 4.32, 95% CI 1.28–1.55, p = 0.018) and Albumin<3.6 g/dl (OR: 3.88, 95% CI 1.37–10.98, p = 0.011) emerged as significant predictors of postoperative complications (POC). Fried Frailty Score (OR: 2.41, 95% CI 0.91–6.41, p = 0.077) showed no significant additional predictive value.ConclusionFried Frailty Score could help the surgeon to estimate the risk for POC among patients undergoing gynecologic cancer surgery. But preoperatively determined ECOG, BMI and Albumin can predict severe POC in patients undergoing gynecologic surgery more precisely and should be assessed routinely.     

Zytostatikaextravasate

Extravasation of systemic chemotherapy agents is a much-feared adverse event in oncology patients. Extravasation into the soft tissues can lead to severe ulceration and functional impairment of the extremities. The incidence of extravasation reported in the literature is 0.1–6%. The proper maintenance of intravenous lines, immediate discontinuation of the infusion, application of local cooling or warming for specific extravasations, and the use of antidotes to some, to prevent the local toxic effects of the extravasated agents, are the basis of adequate management. This review focuses on the etiology, pathomechanism, and prevention of the extravasation of systemically administered chemotherapy agents and its conservative and surgical management, all with reference to the current literature available.