The impact of comprehensive pelvic and para-aortic lymphadenectomy on survival in patients with stage I or II endometrial cancer with a high risk of recurrence is not reliably documented. The side ...effects of this procedure, including lymphedema and lymph cysts, are evident.
Evaluation of the effect of comprehensive pelvic and para-aortic lymphadenectomy in the absence of bulky nodes on 5 year overall survival of patients with endometrial cancer (International Federation of Gynecology and Obstetrics (FIGO) stages I and II) and a high risk of recurrence.
Comprehensive pelvic and para-aortic lymphadenectomy will increase 5 year overall survival from 75% (no lymphadenectomy) to 83%, corresponding to a hazard ratio of 0.65.
Open label, randomized, controlled trial. In arm A, a total hysterectomy plus bilateral salpingo-oophorectomy is performed. In arm B, in addition, a systematic pelvic and para-aortic lymphadenectomy up to the level of the left renal vein is performed. For all patients, vaginal brachytherapy and adjuvant chemotherapy (carboplatin/paclitaxel) are recommended.
Patients with histologically confirmed endometrial cancer stages pT1b-pT2, all histological subtypes, and pT1a endometrioid G3, serous, clear cell, or carcinosarcomas can be included when bulky nodes are absent. When hysterectomy has already been performed (eg, for presumed low risk endometrial cancer), study participation is also possible.
Patients with pT1a, G1 or 2 of type 1 histology or uterine sarcomas (except for carcinosarcomas), endometrial cancers of FIGO stage III or IV (except for microscopic lymph node metastases) or visual extrauterine disease.
Overall survival calculated from the date of randomization until death.
640 patients will be enrolled in the study.
At present, 252 patients have been recruited. Based on this, accrual should be completed in 2025. Results should be presented in 2031.
NCT03438474.
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.
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.
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.
The combination of carboplatin and pegylated liposomal doxorubicin is feasible and has activity within the investigated study cohort.
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.
With more novel drugs being approved for the treatment of ovarian carcinoma, the question remains to what extent patients benefit from antiangiogenic treatment with bevacizumab, either in combination ...with poly-(ADP-ribose) polymerase inhibitors or as single-agent maintenance. As fibroblast growth factor receptors and their ligands (FGFRs/FGFs) are key players in angiogenic signaling and have been linked to resistance to several drugs, we investigated the prognostic or predictive potential of FGFs/FGFRs signaling in the context of bevacizumab treatment within the prospective phase III AGO-OVAR11/ICON-7 study. FGFR1, FGFR2, FGFR3, FGFR4, FGF1, and FGF19 gene expressions were determined in 380 ovarian carcinoma tumor samples collected from German centers in the multicenter phase III AGO-OVAR11 trial/ICON-7 trial. All patients received carboplatin and paclitaxel, administered every 3 weeks for 6 cycles, and were randomized to bevacizumab. Expressions of FGFR1, FGFR2, FGF1, and FGF19 were associated with progression-free survival in both uni- and multivariate (FGFR1: HR, 1.6, P < .001; FGFR2: HR, 1.6, P = .002; FGF1: HR, 2.3, P < .001; and FGF19: HR, 0.7; P = .007) analysis. A signature built by FGFR1, FGFR4, and FGF19 defined a subgroup (n = 62) of patients that derived the greatest bevacizumab-associated improvement of progression-free survival (HR, 0.3; P = .004). In this exploratory analysis of a prospective randomized phase III trial, we provide evidence that the expression of FGFRs/FGFs might have independent prognostic values. An FGFR/FGF-based gene signature identified in our study appears to predict long-term benefit from bevacizumab. This observation is hypothesis-generating and requires validation on independent cohorts.
In the PAOLA-1/ENGOT-ov25 primary analysis (NCT02477644), adding the PARP inhibitor olaparib to maintenance bevacizumab (bev) after first-line platinum-based chemotherapy with bev led to a ...significant progression-free survival (PFS) benefit vs placebo (pbo) + bev in patients (pts) with advanced high-grade ovarian cancer (HGOC), using modified RECIST v1.1 criteria (HR 0.59; 95% CI 0.49-0.72; P<0.001; median PFS 22.1 vs 16.6 months) (Ray-Coquard et al. NEJM 2019). Limited evidence supports use of serum CA-125, a surrogate biomarker for progression, to detect relapse in pts receiving PARP inhibitor maintenance therapy. We evaluated RECIST/CA-125 progression and CA-125 surveillance in PAOLA-1.
Pts with newly diagnosed, FIGO stage III-IV HGOC in response after platinum-based chemotherapy plus bev received bev (15 mg/kg q3w for 15 months) + olaparib (300 mg bid for 24 months) or pbo. Scans were performed every 24 weeks, or every 12 weeks if there was evidence of clinical or CA-125 progression. CA-125 levels were assessed every 12 weeks. Time to RECIST or CA-125 progression or death was a secondary endpoint; RECIST/CA-125 progression by biomarker status, response to initial therapy and CA-125 level at baseline were explored.
537 pts were randomized to olaparib + bev and 269 to pbo + bev with median follow-up for PFS by RECIST/CA-125 of 24.2 vs 24.7 months (DCO 22 March 2019). In the ITT population, the benefit provided by olaparib + bev vs pbo + bev for PFS by RECIST/CA-125 (HR 0.58; 95% CI 0.48-0.70; P<0.0001; median PFS 22.1 vs 15.4 months) was consistent with the primary analysis of PFS by RECIST. Of 462 pts with RECIST progression (ITT), 39% had RECIST progression alone and 45% had CA-125 progression more than 7 days before RECIST progression, with a median 2.4 months between CA-125 and RECIST progression (Table). In subgroup analyses, 49% of tBRCAm pts and 45% of HRD-positive pts had RECIST progression alone compared with only 37% of HRD-negative pts. 42% of pts with NED or CR had RECIST progression alone compared with 33% of pts with PR. 44% of pts with normal baseline CA-125 levels had RECIST progression alone compared with only 17% of pts with abnormal baseline CA-125 levels (P<0.001). The rate of PFS events by RECIST/CA-125 was higher for pbo + bev vs olaparib + bev (74% vs 53%) (ITT). Of pts with RECIST progression, a similar proportion in each treatment arm had RECIST progression alone, including in subgroup analyses by biomarker status and response to initial therapy. Display omitted
Median PFS and HRs were consistent when progression was assessed by either RECIST or RECIST/CA-125 in PAOLA-1. Scans appear particularly important for detecting progression in HRD-positive pts, tBRCAm pts or pts with normal CA-125 levels at baseline as CA-125 levels did not seem to predict relapse in these pts. Results suggest that CA-125 surveillance alone may be sufficient to detect progression in most pts with abnormal baseline CA-125 levels when starting maintenance therapy.
In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian ...cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status.
Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This
analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status.
Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk.
This
analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.
Purpose
Although thrombocytosis in patients with primary ovarian cancer has been widely investigated, there are only very few data about the role of thrombocytosis in recurrent ovarian cancer. The ...aim of our study was to investigate the impact of pretreatment thrombocytosis prior to chemotherapy on clinical outcome in patients with recurrent platinum eligible ovarian cancer.
Methods
In our retrospective analysis we included 300 patients who were treated by AGO Study Group Centers within three prospective, randomized phase-III-trials. All patients included had been treatment-free for at least 6 months after platinum-based chemotherapy. We excluded patients who underwent secondary cytoreductive surgery before randomization to the trial. Thrombocytosis was defined as a platelet count of ≥ 400⋅10
9
/L.
Results
Pretreatment thrombocytosis was present in 37 out of 300 (12.3%) patients. Patients with thrombocytosis responded statistically significantly less to chemotherapy (overall response rate 35.3% and 41.6%,
P
= 0.046). The median progression-free survival (PFS) for patients with thrombocytosis was 6.36 months compared to 9.00 months for patients without thrombocytosis (hazard ratio HR = 1.19, 95% confidence interval CI = 0.84–1.69,
P
= 0.336). Median overall survival (OS) of patients with thrombocytosis was 16.33 months compared to 23.92 months of patients with a normal platelet count (HR = 1.46, 95% CI = 1.00–2.14,
P
= 0.047).
Conclusions
The present analysis suggests that pretreatment thrombocytosis is associated with unfavorable outcome with regard to response to chemotherapy and overall survival in recurrent ovarian cancer.
Background
Although progress has been made in establishing prognostic factors in breast cancer, there remains an urgent need for better prognostic and predictive scores for patients with early breast ...cancer. The important role of the immune system in controlling cancer progression is widely accepted. Regulatory T cells (T-regs) constitute a specialized T cell subset, which play an essential role in sustaining self-tolerance by negatively regulating immune responses. Increased frequencies of T-regs have been reported in the micromilieu of a variety of malignancies including breast cancer. However, little is known about the role of T-regs in the peripheral blood of cancer patients.
Methods
We analyzed T-reg numbers in the peripheral blood of 292 patients with newly diagnosed early breast cancer by flow cytometry (CD4
+
CD25
+
CD127
low
cells) prior to planned breast surgery.
Results
Absolute T-reg numbers/µl varied from 4 to 212/µl. No difference could be detected in T-reg numbers between nodal negative and nodal positive, well and poorly differentiated or small and locally advanced cancers. However, T-reg numbers of Her-2/neu-positive patients were higher than in samples from patients with hormone receptor positive, Her-2/neu-negative cancers. In contrast, numbers of T-regs were not increased in triple negative patients. In addition, T-reg numbers were higher in patients with invasive ductal carcinomas as compared to invasive lobular cancers.
Conclusions
Increased numbers of circulating T-regs may contribute to the higher metastatic potential of Her-2/neu-positive cells. A potential role as a prognostic or predictive parameter is currently being analyzed in a larger cohort of patients with sufficient follow-up.
