INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after last platinum line.

BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.

Surgery due to mechanical bowel obstruction in relapsed ovarian cancer: clinical and surgical results of a bicentric analysis of 87 patients.

INTRODUCTION: Mechanical bowel obstruction is a frequent acute and life-threatening event in relapsed ovarian cancer. Salvage surgery after failure of all conservative approaches, resulting in short bowel syndrome (SBS) constitutes a therapeutic dilemma. Our aim was to evaluate patients' surgical and clinical outcome in these highly palliative situations. Previous, limited, data reported a high morbidity and mortality. However, recent surgical and therapeutical improvements in relapsed ovarian cancer (ROC) offer better identification of patients who might benefit from surgery in an effort to extend the window of opportunity to subsequently offer these patients novel systemic therapeutic approaches. MATERIAL AND METHODS: All subsequent ROC patients between 2012 and 2017 with acute mechanical bowel obstruction who underwent salvage extraperitoneal en bloc intestinal resection were retrospectively identified. Data were collected from two ESGO certified Ovarian Cancer Centers of Excellence (Charité Berlin and Imperial College London) and systematically evaluated regarding surgical and clinical outcomes. RESULTS: Overall, 87 ROC patients were included in the analysis (median age 56 years, range 24-88), 47% were platinum resistant. High grade serous was the most common histology (76%) while most of the patients (67%) had at least two previous lines of treatment. Mean observed OS was 7.8 months. After salvage surgery, 46% of the patients had a residual small bowel length < 180 cm and 18% > 180 cm resulting in 41% in need of total parental nutrition. In 80% of the patients a permanent stoma was necessary. 30d morbidity and mortality was 74% and 10%, respectively. More than half of the patients were able to receive further courses of chemotherapy after surgery. DISCUSSION: Salvage surgery for bowel obstruction in ROC patients needs careful consideration and identification of optimal surgical candidates to have the maximal therapeutic benefit. Despite the challenging morbidity profile, most patients managed to proceed to subsequent novel and conventional systemic treatment and so have their window of therapeutic opportunity extended.

Influence of migrant background on patient preference and expectations in breast and gynecological malignancies (NOGGO-expression V study): results of a prospective multicentre study in 606 patients in Germany.

BACKGROUND: An effective cross-cultural doctor-patient communication is vital for health literacy and patient compliance. Building a good relationship with medical staff is also relevant for the treatment decision-making process for cancer patients. Studies about the role of a specific migrant background regarding patient preferences and expectations are lacking. We therefore conducted a multicentre prospective survey to explore the needs and preferences of patients with a migrant background (PMB) suffering from gynecological malignancies and breast cancer to evaluate the quality of doctor-patient communication and cancer management compared to non-migrants (NM). METHODS: This multicentre survey recruited patients with primary or recurrence of breast, ovarian, peritoneal, or fallopian tube cancer. The patients either filled out a paper form, participated via an online survey, or were interviewed by trained staff. A 58-item questionnaire was primarily developed in German and then translated into three different languages to reach non-German-speaking patients. RESULTS: A total of 606 patients were included in the study: 54.1% (328) were interviewed directly, 9.1% (55) participated via an online survey, and 36.8% (223) used the paper print version. More than one quarter, 27.4% (166) of the participants, had a migrant background. The majority of migrants and NM were highly satisfied with the communication with their doctors. First-generation migrants (FGM) and patients with breast cancer were less often informed about participation in clinical trials (p < 0.05) and 24.5% of them suggested the help of an interpreter to improve the medical consultation. Second and third-generation migrants (SGM and TGM) experienced more fatigue and nausea than expected. CONCLUSIONS: Our results allow the hypothesis that training medical staff in intercultural competence and using disease-related patient information in different languages can improve best supportive care management and quality of life in cancer patients with migrant status.

Prognostic role of chemotherapy-induced nausea and vomiting in recurrent ovarian cancer patients: results of an individual participant data meta-analysis in 1213.

BACKGROUND: The aim of this study was to analyze the potential impact of chemotherapy-induced nausea and vomiting (CINV) on dose reductions, discontinuation of chemotherapy, and survival. PATIENTS AND METHODS: This study was designed as individual participant data meta-analysis with the original study data of three phase II/III trials that were conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) including 1213 patients with recurrent ovarian cancer. Logistic and Cox regression analyses were used to estimate odds and hazard ratios after adjusting for age, ECOG, amount of delivered cycles, amount of recurrences, and amount of comedications and study. RESULTS: The majority of patients developed nausea (58.1%) and almost one third experienced vomiting (31.0%). CINV was not associated with FIGO stage, grading, histology, and number of recurrences. The necessity of dose reduction and discontinuation of chemotherapy did not correlate to nausea and vomiting (p = 0.88, p = 0.39 and p = 0.25, p = 0.54 respectively). Progression-free survival was shorter in patients with grade III/IV nausea and vomiting (p = 0.02; hazard ratio (HR) for grade III/IV nausea 1.58, 95% CI 1.14-2.20, and p = 0.02; HR for grade III/IV vomiting 1.67, 95% CI 1.15-2.42 respectively). CINV grade III/IV was also associated with poorer overall survival (p < 0.001; HR for grade III/IV nausea 2.35, 95% CI 1.64-3.37, and p < 0.001; HR for grade III/IV vomiting 1.67, 95% CI 1.15-2.42 respectively). CONCLUSION: CINV is significantly associated with poorer prognosis in recurrent ovarian cancer patients while there was no correlation found with the necessity of dose reduction and prior discontinuation of treatment. This study underlines the importance of prevention and treatment of CINV as part of early best supportive care.

The prognostic and predictive role of pain before systemic chemotherapy in recurrent ovarian cancer: an individual participant data meta-analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO) of 1226 patients.

BACKGROUND: Aim of this study was to analyze the impact of pain on quality of life and survival in recurrent OC patients. METHODS: Raw data including the QLQ-C30 questionnaire from three phase II/III trials ("Topotecan phase III," "Hector," and "TRIAS") conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) were synthesized and analyzed using logistic and Cox regression analyses. RESULTS: Data on pain was available for 952 patients out of 1226. Moderate to severe pain, which was defined as pain ≥ 50 in the QLQ-C30 symptom scale, was experienced by more than one-third of patients (36.6%). A total of 31% were taking non-opioid pain medication and 16% opioids. Median age at randomization was 61 years (range 25-84). Most patients (84.7%) were diagnosed in FIGO III/IV. Pain was independent from age, FIGO stage, grading, amount of recurrences, and chemotherapy-free interval. ECOG was significantly worse in patients with pain (p < 0.001). Fatigue, nausea/vomiting, sleeping disorders, and abdominal symptoms such as loss of appetite, diarrhea, and constipation were more frequently found in patients with pain (all p < 0.001). Quality of life was significantly diminished (p < 0.001). Pain was also an independent marker for overall survival (OS). Median OS was 18.2 months in patients with pain compared with 22.0 months in patients without pain (p = 0.013, HR 1.25, 95% confidence interval 1.05-1.48). OS was shorter in patients with pain and without pain medication compared with those on sufficient pain medication, whereas OS was mostly decreased in patients having pain despite pain medication (18.5, 19.6, and 15.0 months respectively; p = 0.026). Progression-free survival and prior treatment discontinuation were not associated with pain. CONCLUSION: Best supportive care including sufficient pain medication should be delivered as early as possible because effective pain management is crucial for both quality of life and overall survival in patients with recurrent ovarian cancer.

Survival and prognostic factors in patients with recurrent low-grade epithelial ovarian cancer: An analysis of five prospective phase II/III trials of NOGGO metadata base.

OBJECTIVE: Low-grade epithelial ovarian cancers (EOC), constitute the minority among all epithelial cancers. Our study objective was to focus on low-grade recurrent EOC and compare the survival with high-grade disease, as well as in regard to "platinum-sensitive" and "-resistant" recurrences according to platinum-free interval. METHODS: This is an exploratory analysis within the North-Eastern German Society of Gynecological Oncology (NOGGO) database including five randomized phase II/III trials comparing different chemotherapy regimens in recurrent EOC. We conducted survival analyses and cox-proportional regression models. RESULTS: Out of 1050 patients having the first recurrence, 42 (4%) patients had low-grade and 1008 (96%) patients had high-grade disease. In the subgroup of platinum-sensitive recurrences, progression-free survival (PFS) (8.7 m vs 9.7 m, p = 0.7) and overall survival (OS) (23.9 m vs 24.8 m, p = 0.9) did not differ between low-grade and high-grade diseases. In platinum-resistant recurrences, patients with low-grade ovarian cancer had significantly better PFS (7.6 m vs 3.6 m, p = 0.03) and OS (41.9 m vs 9.5 m p = 0.002) in comparison to those with high-grade cancer. At low-grade EOC, there were no significant PFS (p = 0.91) and OS (p = 0.25) differences between platinum-sensitive and -resistant recurrences. Patients with low-grade non-serous histology had lower PFS with compared to those with low-grade serous histology (p = 0.004). At cox regression analysis presence of ascites and residual disease after secondary cytoreductive surgery were independently associated with poor PFS within low-grade recurrent EOC. CONCLUSION: Our study indicates, platinum-free interval does not have any prognostic significance at recurrent low-grade EOC and non-serous histology is associated with poorer outcome in recurrence. Secondary surgical cytoreduction to no-gross residual disease and ascites are independently associated with disease progression.

Expression III: patients' expectations and preferences regarding physician-patient relationship and clinical management-results of the international NOGGO/ENGOT-ov4-GCIG study in 1830 ovarian cancer patients from European countries.

Backround: The primary aim of this study was to investigate information needs and treatment preferences of patients with ovarian cancer, focusing especially on physician-patient relationship and treatment. Patients and methods: A questionnaire was developed based on the experiences of the national German survey 'Expression II', and was provided to patients with ovarian cancer either at initial diagnosis or with recurrent disease via Internet (online-version) or as print-out-version. Results: From December 2009 to October 2012, a total of 1830 patients with ovarian cancer from eight European countries (Austria, Belgium, France, Germany, Italy, Poland, Romania, Spain) participated, 902 (49.3%) after initial diagnosis and 731 (39.9%) with recurrent ovarian cancer. The median age was 58 years (range 17-89). Nearly all patients (96.2%) had experienced upfront surgery followed by first-line chemotherapy (91.8%). The majority of patients were satisfied with the completeness and comprehensibility of the explanation about the diagnosis and treatment options. The three most important aspects, identified by patients to improve the treatment for ovarian cancer included: 'the therapy should not induce alopecia' (42%), 'there must be more done to counter fatigue' (34.5%) and 'the therapy should be more effective' (29.7%). Out of 659 (36%) patients, who were offered participation in a clinical trial, 476 (26%) were included. Conclusion: This study underlines the high need of patients with ovarian cancer for all details concerning treatment options irrespective of their cultural background, the stage of disease and the patient's age. Increased information requirements regarding potential side effects and treatment alternatives were recorded. Besides the need for more effective therapy, alopecia and fatigue are the most important side effects of concern to patients.

Prevention of palmoplantar erythrodysesthesia in patients treated with pegylated liposomal doxorubicin (Caelyx®).

PURPOSE: Palmoplantar erythrodysesthesia (PPE) is one of the most frequent side effects during systemic treatment with pegylated liposomal doxorubicin (PLD, Caelyx®). PPE lesions show a range of symptoms, from numbness to painful erosions, and can have a major impact on the quality of life in affected patients. Previously, a possible pathomechanism of PPE was found in doxorubicin-treated patients based on radical formation in the skin. Here, a preventive strategy using a topically applied ointment with a high radical protection factor was investigated. METHODS: In this randomized placebo-controlled double-blind study the antioxidant-containing ointment was compared with a placebo ointment regarding PPE grade III occurrence, overall PPE grade I-III occurrence and PPE severity in PLD patients. The verum or placebo cream was topically applied for a period of 16 weeks, starting 3 days prior to the first cycle of chemotherapy. Clinical evaluations were carried out by a dermatologist prior to the first cycle of chemotherapy and every 4 weeks for the duration of 16 weeks. RESULTS: Thirty-two patients were enrolled in total, of which 17 (66%) completed the study. No PPE grade III was found in the verum group, while five out of seven patients (71%) had to be unblinded in the placebo arm due to PPE grade III (p = 0.003). General PPE occurrence of all grades was 60% under verum and 86% under placebo treatment. CONCLUSIONS: The preventive application of an antioxidant-containing ointment was shown to be significantly more effective in the prevention of PPE grade III compared to placebo treatment.

Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR).

BACKGROUND: Randomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC). PATIENTS AND METHODS: Patients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m2/ days 1-3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes [(PC) paclitaxel plus carboplatin; (GC) gemcitabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin] which could be chosen by individual preference but before randomization. The primary end point was progression-free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points. RESULTS: A total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a median follow-up of 20 months, the median PFS was 10 months [95% confidence interval (CI) 9.4-10.6] and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4-27.6 resp. 26.0-36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia. CONCLUSION: The combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens.

Elderly ovarian cancer patients: An individual participant data meta-analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO).

BACKGROUND: Barriers for optimal treatment and enrolment in clinical trials are the physicians' perceptions towards age, comorbidities and fear of toxicity as well as the eligibility criteria of clinical trials. There is a high need to gain more knowledge about this patient group in order to optimize treatment. We aimed to evaluate the influence of age above 65 years on comorbidities, comedication, grade III/IV toxicity, prior discontinuation of chemotherapy and survival. PATIENTS AND METHODS: An individual participant data meta-analysis of three phase II/III studies ('Tower', 'Topotecan phase III' and 'Hector') of the North-Eastern German Society of Gynecological Oncology including 1213 patients with recurrent ovarian cancer was conducted using logistic regression and Cox regression analysis. RESULTS: Median age at diagnosis was 59 years. The patient group ≥65 years included 349 versus 864 patients younger than 65 years. Cardiovascular disease and diabetes were more frequent in the older age group (p < 0.001 and p = 0.001). Haematological and cardiovascular grade III/IV toxicities were more often seen in patients above 65 years, while non-haematological toxicity was not (p = 0.03, odds ratio [OR] 1.35; p = 0.04, OR 1.83; and p = 0.90, OR 0.98, respectively). There was no difference in prior discontinuation of treatment in multivariate analysis. Cox regression showed a trend towards poorer progression-free survival (p = 0.053, hazard ratio 1.143) in the older age group. CONCLUSION: Haematological and cardiovascular toxicities are more frequent in elderly patients. However, this did not influence prior discontinuation of therapy. Elderly patients should not be deprived of adequate chemotherapy or excluded from clinical studies just because of their age. Thorough geriatric assessment and monitoring is mandatory.

PARP Inhibitors for Recurrent Ovarian Carcinoma: Current Treatment Options and Future Perspectives.

More than simply a promising management option, PARP inhibitors can be regarded as a milestone in the development of personalised treatment of recurrent ovarian carcinoma. Their mechanism of action, known as "synthetic lethality", is dependent on functional differences of the DNA repair mechanisms of healthy cells and tumour cells; cells that repair DNA damage less efficiently are particularly sensitive to PARP inhibitors. Olaparib, licensed for use this year, is the best-studied PARP inhibitor used for treatment of high-grade serous ovarian carcinoma (HGSC). The efficacy of PARP inhibitors appears to be increased when used in combination with other treatments.

The influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and overall survival in ovarian cancer.

BACKGROUND: Ovarian cancer is mostly diagnosed in the elderly woman who is likely to have comorbid disease and to take several comedications on a regular basis. Aim of this study was to evaluate the influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and survival. PATIENTS AND METHODS: In this individual participant data meta-analysis the original data of three phase II/III studies of the North-Eastern German Society of Gynecological Oncology (NOGGO) were analyzed using multivariate logistic and Cox regression. RESULTS: Overall, 1213 patients with recurrent ovarian cancer were included in these analyses. An increasing amount of medication was associated with overall grade III/IV toxicity (p<0.001; OR 1.120), and hematological (p<0.001; OR 1.056) and non-hematological (p<0.001; OR 1.134) toxicities. Prior discontinuation of chemotherapy was not influenced by an increasing amount of medication (p=0.196). There was no association of polypharmacy with overall survival (p=0.068). CONCLUSION: As polypharmacy does not influence survival ovarian cancer patients taking several comedications may be included in clinical trials and should not be deprived of adequate cancer treatment. However, a thorough monitoring is mandatory due to the increased risk of toxicities.

The influence of comorbidity and comedication on grade III/IV toxicity and prior discontinuation of chemotherapy in recurrent ovarian cancer patients: An individual participant data meta-analysis of the North-Eastern German Society of Gynecological Oncology (NOGGO).

BACKGROUND: Ovarian cancer is usually a cancer of the older age group. Comorbidities and comedications increase with rising age. Aim of this study was to evaluate association of comorbidity and comedication with grade III/IV toxicities and prior cessation of chemotherapy in ovarian cancer patients. PATIENTS AND METHODS: As an individual participant data meta-analysis this study analyzes the original data of three phase II/III chemotherapy studies of the North-Eastern German Society of Gynecological Oncology (NOGGO). Risk scores for certain combinations of risk factors were calculated based on stepwise regression analyses. RESULTS: Altogether, 1213 patients were included in the study. Cardiovascular disease was the most frequent comorbidity (47.5%). In multivariate analyses it was associated with hematological, non-hematological, pulmonary and renal grade III/IV toxicities (p=0.002; p<0.001; p=0.005; p<0.001). Renal toxicity was more frequent when using diuretics and ACE-inhibitors (p<0.001; p=0.002). Prior cessation of therapy was e.g. associated with use of diuretics, insulin and digitalis (p=0.001; p=0.04; p=0.03). The risk for renal grade III/IV toxicities was more than 16 times higher when using both a diuretic and an ACE-inhibitor. CONCLUSIONS: Regimens of ovarian cancer treatment should not be restricted to direct cancer therapy but rather include additional individualized treatment of comorbidities. Comedications such as diuretics increase grade III/IV toxicities and patients at risk should be closely monitored.

Intra- and postoperative catumaxomab in patients with epithelial ovarian cancer: safety and two-year efficacy results from a multicentre, single-arm, phase II study.

BACKGROUND: This is the first study investigating the safety and efficacy of the trifunctional antibody catumaxomab administered i.p. at the end of cytoreductive surgery and postoperatively prior to standard chemotherapy in patients with primary epithelial ovarian cancer (EOC). METHODS: Patients received i.p. catumaxomab 10 µg intraoperatively and 10, 20, 50 and 150 µg on days 7, 10, 13 and 16, respectively, postoperatively. After the study, patients received standard chemotherapy and were followed for 23 months. The primary endpoint was the rate of postoperative complications. RESULTS: Forty-one patients entered the study and were evaluable for safety and 34 were alive at 24 months. Complete tumour resection rate was 68%. Postoperative complications were observed in 51%, the most common anastomotic leakage (7%) and wound infections (5%). The most common catumaxomab-related adverse events were abdominal pain, nausea, vomiting and pyrexia. Thirty-nine percent discontinued catumaxomab therapy, and 98% received chemotherapy post study. Kaplan-Meier estimates of disease-free and overall survival after 24 months were 56% and 85%, respectively. CONCLUSIONS: Intra- and close postoperative catumaxomab seems feasible, but efficacy and safety were limited by postsurgical complications. In the future prospective trials are needed to investigate the best schedule of integration of catumaxomab into current treatment strategies for EOC.

The time interval from surgery to start of chemotherapy significantly impacts prognosis in patients with advanced serous ovarian carcinoma - analysis of patient data in the prospective OVCAD study.

OBJECTIVE: Cytoreductive surgery and platinum-based systemic therapy constitute the standard treatment of patients with advanced ovarian cancer. The aim of the present study was to evaluate whether the time interval from surgery to start of chemotherapy has an impact on clinical outcome. METHODS: Data of 191 patients with advanced serous (FIGO III-IV) ovarian cancer from the prospective multicenter study OVCAD (OVarian CAncer Diagnosis) were analyzed. All patients underwent primary surgery followed by platinum-based chemotherapy. RESULTS: The 25%, 50%, and 75% quartiles of intervals from surgery to start of chemotherapy were 22, 28, and 38 days, respectively (range, 4-158 days). Preoperative performance status (P<0.001), extent of surgery (P<0.001), and perioperative complications (P<0.001) correlated with intervals from surgery to initiation of chemotherapy. Timing of cytotoxic treatment [≤ 28 days versus >28 days; hazard ratio (HR) 1.73 (95% confidence interval 1.08-2.78), P=0.022], residual disease [HR 2.95 (95% confidence interval 1.87-4.67), P<0.001], and FIGO stage [HR 2.26 (95% confidence interval 1.41-3.64), P=0.001] were significant prognostic factors for overall survival in multivariate analysis. While the interval from surgery to start of chemotherapy did not possess prognostic significance in patients without postoperative residual disease (n=121), it significantly correlated with overall survival in patients with postoperative residual disease [n=70, HR 2.24 (95% confidence interval 1.08-4.66), P=0.031]. CONCLUSION: Our findings suggest that delayed initiation of chemotherapy might compromise overall survival in patients with advanced serous ovarian cancer, especially when suboptimally debulked.

Role of serum concentration of VEGFR1 and TIMP2 on clinical outcome in primary cervical cancer: results of a companion protocol of the randomized, NOGGO-AGO phase III adjuvant trial of simultaneous cisplatin-based radiochemotherapy vs. carboplatin and paclitaxel containing sequential radiotherapy.

OBJECTIVE: Aim of the present study was to analyze the expression-profile of IGF1, IGFBP3, sICAM1, sVCAM1, MMP2, MMP9, TIMP2, VEGFA, VEGFD, VEGFC and VEGFR1 in patients with high-risk FIGO-stage Ib-IIb cervical cancer. METHODS: Serum from 68 cervical cancer patients treated within a phase-III-trial with either simultaneous cisplatin radiochemotherapy or sequential systemic carboplatin and paclitaxel followed by percutaneous irradiation was analyzed by ELISA. Both target expression and correlation with important clinicopathological factors were analyzed following standard statistic procedures. RESULTS: All 68 patients underwent a primary radical hysterectomy with pelvic and/or paraaortic lymphadenectomy. 85.3% of the extirpated tumors had clear surgical margins (R0). Increased levels of VEGFR1, TIMP2 and MMP2 were significantly associated with positive surgical margins (p=0.004, p=0.018 and p=0.004, respectively). High concentration of MMP2 and TIMP2 correlated additionally with an advanced age at time of diagnosis (p=0.001 and p=0.007, respectively). For the cut-off value of 100 pg/ml, an increased VEGFR1 was significantly associated with poor overall (OS) and progression-free (PFS) survival (p=0.017 and p=0.015, respectively). A TIMP2 concentration of lower than 90 ng/ml was significantly associated with poorer OS and PFS (p=0.009 and p=0.043, respectively). In the multivariate analysis, TIMP2 expression in serum was the only independent prognostic factor for OS (p=0.032, HR=6.51, 95% CI=1.17-36.01). CONCLUSIONS: Expression-profile of specific biomarkers associated with tumor invasion, cell migration and angiogenesis seems to be of prognostic value for both OS and PFS in patients undergoing surgery due to primary cervical cancer. Further analyses are warranted to allow an implementation of such markers into clinical practice.

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

OBJECTIVES: Epithelial 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. METHODS: In 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. RESULTS: Median 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). CONCLUSIONS: The 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.

First evaluation of the Joint Clinical Registries of the Coordinating Tumor Center of Berlin.

In the present study, we report the first analysis of the clinical management [corrected] of patients with primary ovarian cancer following the summarized data of the Joint Clinical Registries of the Coordinating Tumor Center of Berlin (Dachverband Tumorzentrum Berlin e.V.). All data were summarized for the period of 2005 to 2008 regarding age, histopathology, time of surgical intervention, follow-up and survival, based on 1124 provided data sets of patients with suspected ovarian tumours. We identified 946 patients with a diagnosis of primary ovarian cancer, mostly of advanced T3 tumour stage (63.7%), FIGO III and IV stage (40.6%) or grade II and III (91%) histology. The median age at time of diagnosis was 61 years (range 15 to 94 years). Most patients (n=414, 69.8%) underwent cytoreductive surgery within one month of diagnosis. The median follow-up period was 26 months; 241 patients died in the analyzed period. The calculated 3-year survival rate was 63.3%, although the median overall survival has not yet been reached. We detected positive correlation of tumour stage (p<0.001) and of FIGO stage (p<0.001) with survival, and these were evaluated as being prognostically significant. The implementation of institutional based clinical registries as part of the modern clinical management of patients with ovarian cancer is feasible and well accepted inside the gynaecological departments of Berlin.

Optimizing the clinical management of gynecological and breast cancer via online tumor conferences.

BACKGROUND: The therapy of gynecological malignancies and breast cancer requires a multimodal therapy approach based on current individualized and risk adapted state of the art therapy concepts. The aim of this online tumor conference project is to reach a broad interdisciplinary and cross-sectoral participation of specialists in order to develop high-quality therapy recommendations for complex casuistics. PATIENTS AND METHODS: The concept of the interdisciplinary online tumor conference was established in 2004 at the Department of Gynecology, Charité Campus Virchow, University Hospital of Berlin to conduct online tumor board meetings of specialists in the field of gynecological cancer from different hospitals and gynecological and oncological practitioners from the outpatient sector. Following a systematic approach, patient data, relevant external clinical evidence and therapy preference are presented to the participants. An individual therapy recommendation for each patient is reached by consensus discussion. RESULTS: By July 2009, 131 online tumor conferences had been performed with a total of 275 participants were developed. Per session, a median of 14 participants logged in online. Additionally 398 second opinion recommendations were performed. In an anonymous survey, carried out at the beginning of 2009, 95% of the participating physicians reported being satisfied with the information content and 50% were stimulated to seek more second opinions by the possibility of the online tumor conference. All contributors attested to a high comprehension of the developed therapy recommendations; 70% confirmed further that the conference presents an optimal possibility for fast and detailed exchange of information between disciplines and care sectors (in- and out-patient) and improves advanced educational training (81%). CONCLUSION: The online tumor conference provides a time saving and high quality possibility for receiving a treatment recommendation based on the best available clinical and scientific evidence and contributes to continuously advanced training for therapists in the field of gynecological cancer.