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.
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.
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.
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.).
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.
Zusammenfassung
Die lymphogene Metastasierung ist bei genitalen Karzinomen ein wichtiger diagnostischer und prognostischer Parameter. Zunehmend wird aber die therapeutische Bedeutung der operativen ...Resektion von Lymphknoten diskutiert. Systematische Lymphonodektomien bergen darüber hinaus ein erhebliches Morbiditätsrisiko, weshalb die Indikation jeweils kritisch geprüft werden muss. Zunehmende Bedeutung gewinnt die Sentinel-Node-Biopsie (SNB), die ein Lymphknotenstaging bei geringem Komplikationsrisiko ermöglichen kann. Bei fortgeschrittenen Ovarialkarzinomen und beim Endometriumkarzinom zeigt sich nach aktuellem Kenntnisstand kein Überlebensvorteil nach systematischer Lymphonodektomie und auch die pelvine Lymphonodektomie beim Vulvakarzinom wird kontrovers diskutiert. Die SNB beim Vulva- und Endometriumkarzinom wurde in einer größeren Anzahl von Studien evaluiert und sollte bei entsprechender Indikation in der Klinik eingesetzt werden. Die SNB kann u. U. zudem bei frühen Zervixkarzinomen eingesetzt werden. Beim frühen Ovarialkarzinom werden in den nächsten Jahren Daten zur SNB aus der SELLY-Studie erwartet. Die diagnostische Bedeutung der systematischen Lymphonodektomie beim Zervixkarzinom bleibt derzeit hoch. So erfolgt bei pelvinen Lymphknotenmetastasen anstelle einer radikalen Hysterektomie in der Regel eine primäre Radiochemotherapie. Im folgenden Artikel werden aktuelle Erkenntnisse in Bezug auf Lymphonodektomien bei genitalen Karzinomen dargestellt.
Abstract 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. 3.9 months; 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. 3.4 months; 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.
To compare standard versus extended duration of bevacizumab treatment in combination with front-line chemotherapy in women with newly diagnosed stage IIB-IV ovarian cancer.
In this multicenter, ...open-label, randomized phase III trial (ClinicalTrials.gov identifier: NCT01462890), patients with newly diagnosed International Federation of Gynecology and Obstetrics stage IIB-IV epithelial ovarian, fallopian tube, or peritoneal cancer underwent primary cytoreductive surgery followed by six cycles of chemotherapy (paclitaxel 175 mg/m
plus carboplatin area under the curve 5 once every 3 weeks) and bevacizumab (15 mg/kg once every 3 weeks). Patients were randomly assigned 1:1 to receive bevacizumab for either 15 or 30 months, stratified by International Federation of Gynecology and Obstetrics stage/residual tumor. The primary end point was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary end points included overall survival (OS), safety, and tolerability.
Between November 11, 2011, and August 6, 2013, 927 women were randomly assigned. There was no difference in PFS between treatment arms (hazard ratio, 0.99; 95% CI, 0.85 to 1.15; unstratified log-rank
= .90). Median PFS was 24.2 versus 26.0 months with standard versus extended duration of bevacizumab, respectively; restricted mean PFS was 39.5 versus 39.3 months, respectively. There was no OS difference between treatment arms (hazard ratio, 1.04; 95% CI, 0.87 to 1.23;
= .68). Serious/nonserious adverse events of special interest occurred in 29% versus 34% of patients in the standard versus experimental arms, respectively, and were consistent with the known safety profile of standard bevacizumab.
Longer treatment duration with bevacizumab for up to 30 months did not improve PFS or OS in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer. A bevacizumab treatment duration of 15 months remains the standard of care.
This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were ...progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile.
Current treatment of
using doxycycline and azithromycin introduces detrimental side effects on the host's microbiota. As a potential alternative treatment, the myxobacterial natural product ...sorangicin A (SorA) blocks the bacterial RNA polymerase. In this study we analyzed the effectiveness of SorA against
in cell culture, and explanted fallopian tubes and systemic and local treatment in mice, providing also pharmacokinetic data on SorA. Potential side effects of SorA on the vaginal and gut microbiome were assessed in mice and against human-derived
species. SorA showed minimal inhibitory concentrations of 80 ng/mL (normoxia) to 120 ng/mL (hypoxia) against
in vitro and was eradicating
at a concentration of 1 µg/mL from fallopian tubes. In vivo, SorA reduced chlamydial shedding by more than 100-fold within the first days of infection by topical application corresponding with vaginal detection of SorA only upon topical treatment, but not after systemic application. SorA changed gut microbial composition during intraperitoneal application only and did neither alter the vaginal microbiota in mice nor affect growth of human-derived lactobacilli. Additional dose escalations and/or pharmaceutical modifications will be needed to optimize application of SorA and to reach sufficient anti-chlamydial activity in vivo.
Totally implanted venous access devices (TIVAD) are increasingly used in the treatment of cancer patients. The aim of this study was to assess the incidence of early and late complications resulting ...from subcutaneous TIVADs in patients with breast cancer.
Between 2004 and 2009, we reviewed patients with breast cancer who had a TIVAD placed. Early and late complications, as well as risk factors for TIVAD-associated thrombosis were retrospectively assessed.
A total of 281 patients were included. Complications occurred in 26% of patients, the majority of which were late complications (21.4%.) The development of TIVAD associated thrombosis was the most frequent late complication (16.4%). In the univariate analysis followed by a multivariate model, risk factors for TIVAD associated thrombosis were not identified. Only within the subgroup of metastatic breast cancer patients an increased risk of TIVAD-associated thrombosis of left compared to right venous access was detected (p=0.015).
TIVAD implantation done in a gynecological outpatient setting is feasible and safe.
Acid ceramidase (ASAH1) is a key player in sphingolipid metabolism and signaling. It has prognostic value for several cancers, but histotype-specific analyses of ovarian cancer are not yet available. ...We used three retrospective TMA cohorts encompassing a total of 1106 ovarian cancers with follow-up data for immunohistochemical analysis of acid ceramidase (ASAH1) expression. Patients with sub-optimal debulking and persistent residual tumor after surgery introduced bias in the prognostic analysis and were excluded from further studies. Overall, we detected an association of ASAH1 expression with better prognosis in ovarian cancer patients. ASAH1 expression differed between histological ovarian cancer histotypes with most frequent expression in endometrioid and clear cell ovarian cancer, which are both associated with good prognosis. Stratified subgroup analyses within these histotypes did not reveal significant survival differences, but the power of the analysis may be limited by smaller sample sizes. In contrast to breast cancer, we found only a modest concordance between estrogen receptor status and ASAH1 expression within the endometrioid ovarian cancer histotype. In an exploratory analysis of estrogen receptor negative endometrioid ovarian cancer, ASAH1 expression was associated with significantly better overall survival (
P
= 0.007). Acid ceramidase is most frequently expressed in endometrioid and clear cell histotypes and could add independent prognostic value to estrogen receptor in endometrioid ovarian cancer. Modulating sphingolipid metabolism may lead to novel therapeutic intervention strategies for this disease.
Fascin-1 (FSCN1) plays an important role in cancer development and is associated with invasion and metastasis. Therefore, we explored the expression and localization of FSCN1 in epithelial ovarian ...cancer (EOC).
Expression analysis was performed by immunohistochemistry of paraffin-embedded tumor samples from 89 patients with EOC. Staining intensity and the percentage of positively stained tumor cells were used to calculate an immunoreactive score of 0-12 (IRS). These results were correlated to clinical and pathological characteristics as well as to patient survival.
Negative (IRS=0), weak (IRS=0-2) and strong (IRS>2) expression of FSCN1 in EOC was found in 5 (5.6%), 30 (33.7%) and 54 (60.7%) tumor samples, respectively. There was a strong correlation of residual postoperative tumor of >1 cm with higher immunoexpression of FSCN1 (p=0.04). Lower FSCN1 expression was associated with significantly poorer overall survival (p=0.02).
FSCN1 is frequently expressed in primary EOC. Its prognostic impact and function remains inconclusive and should be further examined in larger trials.
PDF
