Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary ...peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions.
All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade≥3 thrombocytopenia within 30days after the first dose of niraparib and determine cut-off points for chosen variables.
Following dose modification, 200mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade≥3 thrombocytopenia. Patients with a baseline body weight<77kg or a baseline platelet count<150000/µl in effect received an average daily dose ∼200mg (median=207mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100mg was consistent with that of patients who remained at the 300mg starting dose.
The analysis presented suggests that patients with baseline body weight of<77kg or baseline platelets of<150000/µl may benefit from a starting dose of 200mg/day.
NCT01847274.
Guideline recommendations for the treatment of breast cancer with low hormone receptor (HR) expression (1%-9%) are ambiguous and several studies showed more similarities with HR-negative tumors than ...with HR strongly positive tumors (≥10%). We used a population-based 15-year cohort to compare patient characteristics and outcome of HR low positive tumors with HR-negative and HR strongly positive tumors, respectively.
A total of 38 560 women diagnosed with early invasive breast cancer between 2004 and 2018 within the scope of the Munich Cancer Registry with 4.9 million inhabitants were included. Descriptive analyses of prognostic factors, treatment, and outcome analyses using the Kaplan–Meier method; cumulative incidence in consideration of competing risks; and multivariate analyses (Cox regression and Fine–Gray model) were conducted. Endpoints were time to local recurrence (TTLR), time to lymph node recurrence (TTLNR), time to metastasis (TTM), overall survival (OS), and relative survival (RS).
A total of 861 patients (2%) had HR low positive, 4862 (13%) HR-negative, and 32 837 (85%) HR strongly positive tumors. Within the HER2-negative cohort (n = 33 366), survival of HR low positive tumors was significantly worse than that of HR strongly positive tumors OS hazard ratio 0.66 (95% confidence interval 0.55-0.78), whereas between HR low positive and HR-negative tumors no significant survival difference could be detected OS hazard ratio 0.93 (95% confidence interval 0.78-1.11). TTLR, TTLNR, and TTM showed similar results. By contrast, within the HER2-positive cohort (n = 5194), no statistically significant differences between the three HR groups could be detected in multivariate analyses.
Current definitions for HR positivity and its clinical relevance should be reconsidered. Patients with HR low positive/HER2-negative tumors could be regarded and treated similar to patients with triple-negative tumors.
•This study compared HR low positive tumors with HR-negative and HR strongly positive tumors, respectively.•In the HER2-negative cohort outcome of HR low positive tumors was similar to that of HR-negative tumors.•In the HER2-positive cohort no statistically significant differences were observed.•Current definitions for HR positivity and its clinical relevance should be reconsidered.•Patients with HR low pos./HER2-neg. tumors could be regarded and treated similar to patients with triple-negative tumors.
Actin beta-like 2 (ACTBL2) was recently identified as a new mediator of migration in ovarian cancer cells. Yet, its impact on tumor-infiltrating and thus migrating leukocytes (TILs) remains to date ...unknown. This study characterizes the subset of ACTBL2-expressing TILs in epithelial ovarian cancer (EOC) and elucidates their prognostic influence on the overall survival of EOC patients with special regard to different histological subtypes. Comprehensive immunohistochemical analyses of Tissue-Microarrays of 156 ovarian cancer patients revealed, that a tumor infiltration by ACTBL2-positive leukocytes was significantly associated with an improved overall survival (OS) (61.2 vs. 34.4 months; p = 0.006) and was identified as an independent prognostic factor (HR = 0.556; p = 0.038). This significant survival benefit was particularly evident in patients with low-grade serous carcinoma (OS: median not reached vs. 15.6 months, p < 0.001; HR = 0.058, p = 0.018). In the present cohort, ACTBL2-positive TILs were mainly composed of CD44-positive cytotoxic T-cells (CD8+) and macrophages (CD68+), as depicted by double-immunofluorescence and various immunohistochemical serial staining. Our results provide significant evidence of the prognostic impact and cellular composition of ACTBL2-expressing TILs in EOC. Complementary studies are required to analyze the underlying molecular mechanisms of ACTBL2 as a marker for activated migrating leukocytes and to further characterize its immunological impact on ovarian carcinogenesis.
The presence, extent and localization of distant metastases are key prognostic factors in breast cancer patients and play a central role in therapeutic decision making. The aim of this study was to ...compare the diagnostic performance of positron emission tomography using 2-fluorine-18fluoro-2-deoxy-D-glucose (FDG–PET) with that of computed tomography (CT) and conventional imaging including chest radiography, abdominal ultrasound and bone scintigraphy.
A total of 119 consecutive patients with newly diagnosed locally advanced disease (n = 69) or previous history of breast cancer (n = 50) who had clinical suspicion of metastatic disease underwent FDG–PET, CT and conventional imaging procedures. Imaging results were retrospectively compared with histopathology and clinical follow-up which served as a reference standard.
FDG–PET detected distant metastases with a sensitivity of 87% and a specificity of 83%. In contrast, the sensitivity and specificity of combined conventional imaging procedures were 43% and 98%, respectively. CT revealed a sensitivity of 83% and a specificity of 85%.
In breast cancer, FDG–PET is superior to conventional imaging procedures for detection of distant metastases. Although FDG–PET and CT provided similar diagnostic accuracy, the information was often found to be complementary. With increasing availability of FDG–PET/CT, prospective studies are needed to determine whether it could potentially replace the array of conventional imaging procedures used today.
According to current treatment guidelines, comprehensive surgical staging procedures in endometrial cancer confined to the uterus depend on uterine risk factors: a systematic lymph node dissection ...(LND) is recommended in high risk patients and should be omitted in low risk patients. Its role in intermediate and high intermediate risk patients is inconclusive. The aim of this analysis was to review the implementation of this risk-adopted strategy.
Data were provided by the population-based Munich Cancer Registry. Patients with endometrial cancer diagnosed between 1998 and 2016 were included.
Of 5446 eligible patients, 58.5%, 30.1% and 11.4% belonged to the low risk, intermediate/high-intermediate and high risk group, respectively. Lymph node dissection was performed in 20.2%, 53.0% and 63.7% within these groups. Lymph node involvement was diagnosed in 1.7%, 9.6% and 19.3%, respectively. Within these risk groups, there was no significant difference in the time to local recurrence, lymph node recurrence or distant metastases between patients with and without LND. After adjusting for age and comorbidity-status, no significant difference in overall survival was found.
The application of a risk-adopted management of LND in early endometrial cancer in real-life is associated with a high rate of surgical under- and overtreatment. Corresponding survival data do not show a significant benefit of a systematic lymph node dissection. In order to improve the management and outcome of early endometrial cancer in the future, prospective trials, new surgical concepts and prognostic markers will be primary and necessary.
•Although it is recommended, a high proportion of patients had no lymph node surgery.•The incidence of recurrence seems not to be related to lymph node dissection.•The comorbidity status should be considered in analyses of lymph node surgery.•The survival analysis challenges lymph node dissection in endometrial cancer.
Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer ...following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial.
This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017).
Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured.
These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer.
ClinicalTrials.gov identifier: NCT01847274.
•Long-term safety data for patients from the ENGOT-OV16/NOVA trial is reported.•Grade ≥ 3 thrombocytopenia occurred in 28% of patients in month 1, declining to 9% in month 2.•Dose reductions were highest in month 1 (34%), and declined every month thereafter.•These data support dose reductions according to toxicity criteria and the long-term use of niraparib maintenance treatment.
Abstract 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.
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