Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

Latissimus dorsi flap for breast reconstruction: a large single-institution evaluation of surgical outcome and complications.

PURPOSE: The use of autologous tissues is considered gold standard for patients undergoing breast reconstruction and is the preferred method in the post-radiation setting. Although the latissimus dorsi flap (LDF) has been replaced by abdominal flaps as technique of choice, it remains a valuable option in several specific clinical situations and its use has been regaining popularity in recent years. In this work, we present an 18-year retrospective analysis of a single-institution single-surgeon experience with LDF-based reconstruction with focus on early complications and reconstructive failures. METHODS: Hospital records of all patients undergoing breast surgery for any reason in the Certified Breast Cancer Center, Regio Klinikum Pinneberg, Germany between April, 1st 2005 and October, 31st 2022 were reviewed. 142 consecutive LDF-based reconstructive procedures were identified. Detailed information was gathered on patient characteristics, treatment-related factors, and complications. RESULTS: One hundred forty patients (139 female, 1 male) received 142 LDF-based surgeries. The flap was used mainly for immediate breast reconstruction with or without implant (83% of patients), followed by defect coverage after removal of a large tumor (7%), implant-to-flap conversion with or without placement of a new implant (6%), and delayed post-mastectomy reconstruction (4%). The use of LDF decreased between 2005 and 2020 (2005: 17, 2006: 13, 2007: 14, 2008: 16, 2009: 5, 2010: 9, 2011: 8, 2012: 3, 2013: 10, 2014: 8, 2015: 8, 2016: 7, 2017: 7, 2018: 4, 2019: 4, 2020: 2, 2021: 6, 2022: 4). Surgery was performed for invasive breast cancer in 78%, ductal carcinoma in situ in 20% and other reasons such as genetic mutation in 1% of patients. Ipsilateral radiation therapy was received by 12% of patients prior to LDF surgery and by 37% after the surgery. 25% of patients were smokers. The median duration of surgery, including all procedures conducted simultaneously such as e.g., mastectomy, axillary surgery, or implant placement, was 117 min (range 56-205). Patients stayed in the hospital for a median of 7 days (range 2-23 days). The most common complication was seroma (26%), followed by wound dehiscence (8%), surgical site infection (7%), partial skin and/or nipple necrosis of any size (7%) and hematoma requiring surgical evacuation (2%). 19% of all patients required seroma aspiration or drainage, mostly at the donor site and performed under ultrasound guidance in the ambulatory setting. Flap loss due to necrosis occurred in 2% of patients. CONCLUSIONS: Latissimus dorsi flap is a well-established surgical technique commonly used for immediate breast reconstruction as well as defect coverage in locally advanced breast cancer. To the best of our knowledge, this is one of the largest single-surgeon analyses of early complications in patients receiving LDF. As expected, seroma was the most common complication observed in nearly one third of patients and requiring a therapeutic intervention in every fifth patient. Serious adverse events occurred rarely, and flap loss rate was very low.

Quality of therapy in early ovarian cancer: results of the quality assurance program of the AGO Study Group.

OBJECTIVE: The quality assurance program for ovarian cancer (QS-OVAR) evaluates the implementation of treatment standards and impact on survival for International Federation of Gynecology and Obstetrics (FIGO) stage I ovarian cancer. METHODS: Patients with a first diagnosis of ovarian cancer, diagnosed in the third quarter of 2004, 2008, 2012, and 2016, were documented. Surgical quality was categorized as optimal (maximum one surgical item missing) versus suboptimal (≥2 surgical items missing). Chemotherapy was defined as optimal according to national guidelines. Treatment quality was classified into four categories: surgery and chemotherapy were optimal, optimal surgery and suboptimal chemotherapy, suboptimal surgery and optimal chemotherapy, and surgery and chemotherapy were suboptimal. RESULTS: In total, 19.9% (n=700) of ovarian cancer patients were diagnosed with FIGO stage I. Median age was 60 years (range 18-96), 47.1% had FIGO stage IA and 47.9% had stage IC, with 37.1% high grade serous histology. Optimal surgical quality increased over time from 19.9% to 54.1%. The optimal surgery population increased from 42.2% to 70.9%. Disease free survival improved significantly in the optimal surgery population (84% after 48 months vs 71% in the suboptimal surgery population). Overall survival increased with 91% after 48 months in the optimal surgery population versus 76% in the suboptimal surgery population. In total, 20.7% of patients were undertreated concerning systemic treatment and 1% overtreated. Optimal chemotherapy standard was administered increasingly over time (71.4-80.8%). Disease free survival and overall survival were prolonged with adjuvant chemotherapy. The optimal surgery/chemotherapy subgroup increased from 37.9% to 54.1% with significantly longer disease free survival and overall survival (overall survival at 48 months: optimal surgery and chemotherapy 93%; suboptimal surgery and chemotherapy 68%). CONCLUSION: Although QS-OVAR data showed that the quality of therapy has improved over the years, not all surgical standards were met in nearly 50% of patients. The steady increase in the optimal surgery and chemotherapy collective is an important tool for improvement of prognosis of ovarian cancer patients.

Treatment strategies in patients with gynecological sarcoma: Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA-NOGGO RU1).

OBJECTIVE: Gynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study's objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease. METHODS: The German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021. RESULTS: A total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy. CONCLUSION: Our study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies.

Primary ovarian leiomyoma: a rare ovarian tumour.

After performing laparoscopic unilateral adnexectomy in a 53-year-old woman for a rapidly grown unilateral adnexal mass, pathologists reported a primary ovarian leiomyoma with no genuine ovarian tissue. This rare diagnosis is found in less than 100 reports after systematic literature review, a greater number of asymptomatic ovarian leiomyomas can be expected. Thorough preoperative diagnostic measures are essential as rare cases of malignancy have been described.

Impact of lymphadenectomy on short- and long-term complications in patients with endometrial cancer.

INTRODUCTION: Early endometrial cancer is primarily treated surgically via hysterectomy, adenectomy and, depending on tumor stage and subtype, lymphadenectomy. Systematic lymph node dissection is known to cause surgical complications. The aim of the present study was to investigate morbidity and mortality rates associated with lymphadenectomy in patients with endometrial cancer who underwent surgery in a routine clinical setting. METHODS: We collected data from 232 patients who were operated for endometrial carcinoma between 2006 and 2018 at the University of Lubeck, Germany. Surgical complications were viewed in relation to surgical risk factors. Additionally, a questionnaire concerning long-term lymphatic complications and survival was completed. Survival was compared between patients who underwent lymphadenectomy (group I) and those who did not (group II). RESULTS: Patients in group I needed revision surgery significantly more often due to postoperative complications (such as lymphoceles) compared to those in group II (p = 0.01). The results indicate more serious complications in patients who underwent a systematic lymphadenectomy and in those with lymph node metastases. 15% of patients who underwent a systematic lymphadenectomy had lymph node metastases. Recurrences occurred in 12.5% of cases and were significantly more frequent in patients who had undergone a lymphadenectomy, even if the lymph nodes were negative (p = 0.02). A comparison of survival data during the follow-up period revealed no significant difference. The study highlighted the need for a better preoperative risk stratification and the avoidance of lymphadenectomy for surgical staging alone.

Intraoperative Ultrasound-Guided Excision of Non-Palpable and Palpable Breast Cancer: Systematic Review and Meta-Analysis.

Wire-guided localization (WGL) is the most frequently used localization technique in non-palpable breast cancer (BC). However, low negative margin rates, patient discomfort, and the possibility of wire dislocation have been discussed as potential disadvantages, and re-operation due to positive margins may increase relapse risk. Intraoperative ultrasound (IOUS)-guided excision allows direct visualization of the lesion and the resection volume and reduces positive margins in palpable and non-palpable tumors. We performed a systematic review on IOUS in breast cancer and 2 meta-analyses of randomized clinical trials (RCTs). In non-palpable BC, 3 RCTs have shown higher negative margin rates in the IOUS arm compared to WGL. Meta-analysis confirmed a significant difference between IOUS and WGL in terms of positive margins favoring IOUS (risk ratio 4.34, p < 0.0001, I2 = 0%). 41 cohort studies including 3291 patients were identified, of which most reported higher negative margin and lower re-operation rates if IOUS was used. In palpable BC, IOUS was compared to palpation-guided excision in 3 RCTs. Meta-analysis showed significantly higher rates of positive margins in the palpation arm (risk ratio 2.84, p = 0.0047, I2 = 0%). In 13 cohort studies including 942 patients with palpable BC, negative margin rates were higher if IOUS was used, and tissue volumes were higher in palpation-guided cohorts in most studies. IOUS is a safe noninvasive technique for the localization of sonographically visible tumors that significantly improves margin rates in palpable and non-palpable BC. Surgeons should be encouraged to acquire ultrasound skills and participate in breast ultrasound training.

Robotic surgery in gynecology: is the future already here?

Robotic-assisted surgery has gained widespread acceptance in the surgical community and appears to be the most rapidly developing sector of minimally invasive surgery. However, robotic surgery has been viewed as a development of, or alternative to, laparoscopic surgery and not necessarily as a superior technology. The advantages of MIS over open surgery apply to robotic-assisted surgery as well. Nevertheless, conflicting data have been published about the advantages and disadvantages of robotic-assisted and laparoscopic surgery. In the last few years, robotic-assisted surgery has been used for various gynecological procedures such as hysterectomy, lymphadenectomy, myomectomy, sacrocolpopexy or endometriosis operations. In the present review, we analyze the current use of robotic-assisted surgery and its efficiency in gynecology. Patient-based outcomes, such as quality of life and outcomes in morbidly obese patients are also addressed. The potential benefits of single-port robotic-assisted surgery are discussed. Most of the studies published so far state that robotic-assisted surgery does not essentially improve the surgical outcome compared to conventional laparoscopic surgery. However, randomized studies are scarce. Ongoing technological progress over the next few years may improve robotic-assisted techniques and thus optimize the patient's treatment.

TGFB-induced factor homeobox 1 (TGIF) expression in breast cancer.

BACKGROUND: Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest. METHODS: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue samples from BC patients treated in the GAIN (German Adjuvant Intergroup Node-Positive) study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining. Endpoints were disease-free survival (DFS), overall survival (OS) and time to primary bone metastasis as first site of relapse (TTPBM). RESULTS: We found associations of higher TGIF protein expression with smaller tumor size (p = 0.015), well differentiated phenotype (p < 0.001) and estrogen receptor (ER)-positive BC (p < 0.001). Patients with higher TGIF expression levels showed a significantly longer disease-free (DFS: HR 0.75 [95%CI 0.59-0.95], log-rank p = 0.019) and overall survival (OS: HR 0.69 [95%CI 0.50-0.94], log-rank p = 0.019), but no association with TTPBM (HR 0.77 [95%CI 0.51-1.16]; p = 0.213). Univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: HR 0.68 [95%CI 0.51-0.91]; log-rank p = 0.009, interaction p = 0.130; OS: HR 0.60 [95%CI 0.41-0.88], log-rank p = 0.008, interaction p = 0.107) and in the HER2-negative subgroup (DFS:HR 0.67 [95%CI 0.50-0.88], log-rank p = 0.004, interaction p = 0.034; OS: HR 0.57 [95%CI 0.40-0.81], log-rank p = 0.002, interaction p = 0.015). CONCLUSIONS: Our results suggest that moderate to high TGIF expression is a common feature of breast cancer cells and that this is not associated with bone metastases as first site of relapse. However, a reduced expression is linked to tumor progression, especially in HER2-negative breast cancer. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov ; registration number: NCT00196872 .

Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial.

BACKGROUND: State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin-paclitaxel or carboplatin-gemcitabine) or the most active non-bevacizumab regimen: carboplatin-pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin-pegylated liposomal doxorubicin combined with bevacizumab. METHODS: This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251. FINDINGS: Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin-pegylated liposomal doxorubicin-bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin-gemcitabine-bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3-21·7) in the experimental group and 11·3 months (8·0-18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7-14·2) in the experimental group versus 11·6 months (11·0-12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68-0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage). INTERPRETATION: Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer. FUNDING: F Hoffmann-La Roche.

Association between obesity and vulvar cancer recurrence: an analysis of the AGO-CaRE-1 study.

OBJECTIVE: Obesity is associated with worse survival and an increased risk of relapse in several malignancies. The influence of obesity on vulvar cancer recurrence has not been previously described. The primary objective of this study was to evaluate the association between obesity and tumor recurrence in patients with vulvar cancer. METHODS: This is an analysis of the AGO-CaRE-1 study. Patients diagnosed with squamous cell vulvar cancer (stage IB and higher), treated in 29 cancer centers between January 1998 and December 2008, were registered in a centralized database. The cohort was divided into two gropus depending on the body mass index (BMI) (<30 vs ≥30 kg/m²). Descriptive statistics, survival analyses, and multivariate Cox regression analyses were performed in order to evaluate the association between obesity and progression-free and overall survival. RESULTS: In 849 (52.4%) of 1618 patients in the database, the BMI was documented. Patients were grouped according to their BMI (<30 vs ≥30 kg/m²). There were 621 patients with a BMI <30 kg/m² and 228 patients with a BMI ≥30 kg/m². Besides age, there was no difference in baseline variables (tumor diameter, depth of infiltration, tumor stage, nodal metastasis, tumor grade). Treatment variables (R0 resection, chemotherapy, radiotherapy, continuation of adjuvant therapy) did not differ between groups. However, patients with BMI ≥30 kg/m² underwent radical vulvectomy more often (61.1% vs 51.8%, p=0.04). During follow-up there was a higher recurrence rate in the group with BMI ≥30 kg/m² (43.4% vs 28.3%, p<0.01) due to an increased rate of local recurrences (33.3% vs 18.5%, p<0.01). There was a significantly shorter time to recurrence in obese patients on univariate analysis (BMI ≥30 kg/m² vs <30 kg/m²: 43.8 months (95% CI 23.3 to 64.3) vs 102.3 months (95% CI 72.6 to 131.9), p=0.001) and on multivariate Cox regression analysis (HR 1.94 (95% CI 1.4 to 2.8), p<0.001). CONCLUSIONS: In this study a BMI ≥30 kg/m² was associated with a shorter time to recurrence in patients with vulvar cancer and this was mainly attributed to a higher risk of local recurrence.

Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883).

BACKGROUND: For individuals with ovarian cancer (OC), therapy options mainly depend on BRCA1/2 germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy? METHODS: Paired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (ATM, BRCA1/2, BRIP1, MSH2/6, PALB2, RAD51C/D and TP53) and the PIK3CA and PTEN genes in individuals with OC (AGO-TR1 study, NCT02222883). Results were complemented by BRCA1, PALB2 and RAD51C promoter methylation analyses and stratified by histological subtype; 473 individuals were included. RESULTS: The combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; BRCA1/2: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding TP53 (all: 39/473, 8.2%; BRCA1/2: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; BRCA1: 57/473, 12.1%; RAD51C: 10/473, 2.1%; PALB2: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic PIK3CA and/or PTEN variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles. CONCLUSION: Tumour sequencing of the BRCA1, BRCA2, PIK3CA and PTEN genes along with BRCA1 and RAD51C promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors. TRIAL REGISTRATION NUMBER: NCT02222883.

Predictive factors for lymph node metastases in vulvar cancer. An analysis of the AGO-CaRE-1 multicenter study.

BACKGROUND: Lymph node (LN) metastasis is the most important prognostic factor in primary vulvar cancer. Assessing risk factors for the incidence and extent of LN metastases may help to select the optimal treatment strategy for each individual patient. METHODS: In a subgroup analysis of the large multicenter AGO-CaRE-1 study we included all patients treated with radical groin dissection. Univariate and multivariate regression analyses were performed in order to detect factors associated with the prevalence and extent of nodal involvement. RESULTS: In total, 1162 patients were analyzed. Univariate analyses detected age, ECOG as well as multiple tumor characteristics such as FIGO stage, grading, depth of invasion, tumor diameter, and (lymph)vascular space invasion to be related with the prevalence of LN metastases. Interestingly, only tumor stage, tumor diameter and depth of infiltration were found to be significantly associated with the number of LN metastases. In multivariate analysis, age (OR 1.03), lymphvascular space invasion (OR 4.97), tumor stage (OR 2.22) and depth of infiltration (OR 1.08) showed an association with the prevalence of LN metastases. Regarding the number of metastatic LNs, only tumor stage (OR 2.21) or, if excluded, tumor diameter (OR 1.02) were tested significant. CONCLUSION: This large analysis of the multicenter AGO-CaRE-1-study identified lymphvascular space invasion, tumor stage, and depth of infiltration as factors with the strongest association regarding the prevalence of LN metastasis. Interestingly, tumor stage or, if excluded, tumor diameter were the only factors associated with the prevalence as well as the extent of LN metastases.

Outcome After Sentinel Lymph Node Dissection in Vulvar Cancer: A Subgroup Analysis of the AGO-CaRE-1 Study.

PURPOSE: Analyzing the large patient cohort of the multicenter AGO-CaRE-1 study, we compared isolated sentinel lymph node dissection (SLND) with radical lymph node dissection (LND) of the groin in relation to recurrence rates and survival. METHODS: The AGO-CaRE-1 study retrospectively collected data on treatment patterns and follow-up of vulvar cancer patients [International Federation of Gynecology and Obstetrics (FIGO) stage ≥1B] treated at 29 gynecologic cancer centers between 1998 and 2008. This subgroup analysis evaluated the influence of SLND alone on progression-free survival (PFS) and overall survival (OS). RESULTS: In 487 (63.1%) of 772 included patients with tumors smaller than 4 cm, an LND was performed and no metastatic lymph nodes were detected (LN0). Another 69/772 (8.9%) women underwent SLND alone, showing a negative SLN (SLN0). Tumors in the LN0 group were larger and showed a deeper invasion (LN0 vs. SLN0 tumor diameter: 20.0 vs. 13.0 mm, p < 0.001; depth of invasion: 4.0 vs. 3.0 mm, p = 0.002). After a median follow-up of 33 months (0-156), no significant differences in relation to isolated groin recurrence rates (SLN0 3.0% vs. LN0 3.4%, p = 0.845) were detected. Similarly, univariate 3-year PFS analysis showed no significant differences between both groups (SLN0 82.7% vs. LN0 77.6%, p = 0.230). A multivariate Cox regression analysis, including tumor diameter, depth of invasion, age, grading, and lymphovascular space invasion was performed: PFS [hazard ratio (HR) 0.970, 95% confidence interval (CI) 0.517-1.821] and OS (HR 0.695, 95% CI 0.261-1.849) did not differ significantly between both cohorts. CONCLUSION: This subgroup analysis of the large AGO-CaRE-1 study showed similar results for groin LND and SLND alone with regard to recurrence rates and survival in node-negative patients with tumors <4 cm.

Independent radiologic review of AURELIA, a phase 3 trial of bevacizumab plus chemotherapy for platinum-resistant recurrent ovarian cancer.

OBJECTIVE: The randomized, open-label, phase 3 Avastin® Use in Platinum-Resistant Epithelial Ovarian Cancer (AURELIA) trial achieved its primary efficacy end point of significantly improved progression-free survival (PFS) in patients treated with bevacizumab in combination with chemotherapy (CT) compared with CT alone for platinum-resistant, recurrent ovarian cancer. Primary analyses were conducted via investigator assessment of PFS; to confirm primary results, an independent review committee (IRC) retrospectively assessed radiographic data. METHODS: Per an amendment to the original study protocol, the IRC reviewed radiographic data from 298 (82.5%) patients in a blinded manner using the Response Evaluation Criteria in Solid Tumors (modified version 1.0). IRC-assessed PFS and concordance between the two assessments were evaluated. RESULTS: IRC assessment demonstrated that PFS was significantly prolonged for patients treated with CT+bevacizumab compared with CT alone (median, 8.1 vs. 3.9months; hazard ratio, 0.484; 95% confidence interval, 0.370-0.632; P<0.0001). Results were similar to the primary PFS analysis from investigator assessment (median, 6.8 vs. 3.4months; hazard ratio, 0.384; 95% confidence interval, 0.300-0.491; P<0.0001). Concordance rates for progressive disease status (CT+bevacizumab, 68.2%; CT, 69.9%) and date (CT+bevacizumab, 67.2%; CT, 69.1%) were similar across treatment arms. Among 161 IRC-evaluable patients declared to have progressive disease by investigator and IRC assessment, 68.3% progressed on the same date as determined by both investigator and IRC. CONCLUSIONS: IRC assessment of PFS confirmed the investigator-assessed PFS improvement for patients treated with CT+bevacizumab compared with CT alone in the AURELIA study.

Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8).

OBJECTIVES: To evaluate activity and toxicity of mTOR inhibitor temsirolimus in patients with platinum-refractory/resistant ovarian cancer (OC) or advanced/recurrent endometrial carcinoma (EC). METHODS: Women with epithelial ovarian, fallopian tube or primary peritoneal cancer were eligible, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. Women with advanced/recurrent EC, no longer amenable to curative surgery and/or radiotherapy were eligible when they had no previous or only adjuvant chemotherapy. Preceding endocrine therapy for metastatic/recurrent disease was allowed. Patients received weekly IV infusions of 25mg temsirolimus. Primary endpoint was progression free survival rate after 4 months (OC) or 6 months (EC). A two stage design was applied. RESULTS: Forty-four patients (OC: n=22; EC: n=22) were enrolled and received temsirolimus treatment. Median age was 56 years (OC) or 63 years (EC). After eight weeks of treatment, 10 of 21 evaluable patients in the OC cohort and 8 of 20 evaluable patients in the EC cohort had progressive disease. Thus efficacy did not meet the predefined levels during the first stage of recruitment and the trial was stopped. Some patients in both cohorts had long lasting PFS (>7 months). Toxicity of temsirolimus was mild. CONCLUSIONS: Temsirolimus treatment was well tolerated in our patients, but did not meet the predefined efficacy criteria. In our study as in other trials on rapalogs in OC or EC, a few patients had long lasting disease stabilisations.

Phase II Study Evaluating PegLiposomal Doxorubicin and Carboplatin Combination Chemotherapy in Gynecologic Sarcomas and Mixed Epithelial-Mesenchymal Tumors A Phase II Protocol of the Arbeitsgemeinschaft Gynaekologische Onkologie Study Group (AGO-GYN 7).

BACKGROUND: Gynecologic sarcomas are rare diseases with still undefined optimal treatment. Platinum and anthracyclines were reported as active agents in gynecologic sarcoma and carcinosarcoma. So far, data regarding the combination of carboplatin and pegylated liposomal doxorubicin for this patient population are missing. METHODS: This prospective single-arm multicenter phase II trial evaluated the efficacy of carboplatin AUC 6 in combination with pegylated liposomal doxorubicin 40 mg/m q28 in 40 patients with newly diagnosed or recurrent gynecologic sarcoma or carcinosarcoma. RESULTS: Twenty patients with carcinosarcoma and 20 patients with leiomyosarcoma or endometrial stromal sarcoma were included. The percentage of patients with grade 3/4 neutropenia was 50%, but we did not observe any febrile neutropenia. The rates of grade 1 and 2 palmo-plantar erythema were moderate with 25% and 10%, respectively. Response rate was 33.3%. The 12-month progression-free and overall survival times were 32.5% and 77.0%, respectively. CONCLUSIONS: The combination of carboplatin and pegylated liposomal doxorubicin is feasible and has activity within the investigated study cohort.

The prognostic impact of age in different molecular subtypes of breast cancer.

Breast cancer is a heterogeneous entity composed of distinct molecular subgroups with different molecular and clinical features. We analyzed the association between molecular breast cancer subgroups, age at diagnosis, and prognosis in a compilation of publicly available gene expression datasets. Affymetrix gene expression data (U133A or U133Plus2.0 arrays) of 4467 breast cancers from 40 datasets were compiled and homogenized. Breast cancer subgroups were defined based on expression of ESR1, PR, HER2, and Ki67. Event-free survival was calculated as recurrence-free survival or distant metastasis-free survival if recurrence-free survival was not available. Young age at diagnosis is associated with higher frequency of triple negative and HER2 subtypes and lower frequency of luminal A breast cancers. The 5-year event-free survival rates of patients aged less than 40, between 40 and 50, and >50 years were 54.3 ± 3.5, 68.5 ± 1.9, and 70.4 ± 1.3 %, respectively. When controlling for breast cancer subtype, we found that age <40 years remained significantly associated with poor prognosis in triple negative breast cancer. The effect was modest in luminal tumors and not found in HER2 subtype. Both subtypes and age retained their significances in multivariate analysis. Association of age at diagnosis with molecular breast cancer subtype contributes to its important role as prognostic factor among patients with breast cancer. Still, within the group of triple negative breast cancer, young age <40 years has a significant prognostic value which was retained in multivariate analysis.

The Value of Serum CA125 in the Diagnosis of Borderline Tumors of the Ovary: A Subanalysis of the Prospective Multicenter ROBOT Study.

OBJECTIVE: The value of the serum tumor marker CA125 in borderline tumors of the ovary (BOTs) is not well defined, with unclear benefit in both diagnosis and follow-up. The aim of the present project was to identify the predictive value of CA125 for stage and relapse. METHODS: CA125 data were extracted from the ROBOT multicenter study of patients with BOT treated between 1998 and 2008 in 24 German centers. While patients' data were retrieved retrospectively from hospital records and clinical tumor registries, follow-up and independent central pathology review were performed prospectively. RESULTS: We identified 127 patients from the ROBOT database fulfilling the eligibility criterion of available CA125 at initial diagnosis. Eighty-three (65.3%) patients had increased CA125 levels (>35 U/L). Of the patients, 85.0% presented with serous and 13.4% with mucinous BOT histology, whereas 29.9% had stage I disease. Fifteen (11.8%) patients experienced a relapse. Multivariate analysis identified raised CA125, young age, and serous histology as independent predictors of peritoneal implants of any type at initial presentation. Raised CA125 at initial diagnosis was, however, not an independent predictor of future relapse. DISCUSSION: Elevated CA125 seems to be associated with the presence of peritoneal implants of any type at initial diagnosis of serous BOT, but failed to have any independent predictive value on future relapse. Prospective multicenter studies are warranted to evaluate CA125 measurements in the follow-up management of BOT.