The Cancer Genome Atlas and others identified genomic events suggesting that endometrial cancer (EC) should be susceptible to DNA repair inhibition. Data from pre-clinical models suggest poly ...ADP-ribose polymerase (PARP) inhibitors alone or in combination with other targeted agents may be an effective therapeutic strategy in EC. Combinations of angiogenic inhibitors and PARP inhibitors have demonstrated synergistic effects and have been well tolerated in other tumor types. This study compared two experimental arms exploring DNA repair inhibition versus cediranib alone which has previously shown promising activity in GOG 229J.
A 1:1:1 randomized phase II study comparing cediranib (C) versus olaparib (O) or the combination of olaparib and cediranib (OC) for women with recurrent EC. Eligible patients had received at least 1 prior platinum containing chemotherapy but ≤2 prior lines of chemotherapy for recurrent EC. Cediranib was administered 30 mg PO daily, olaparib 300 mg PO BID and in the combination cediranib 20 mg PO daily / olaparib 300 mg PO BID. One cycle in all arms was 28 days. Primary endpoint was progression free survival (PFS) by RECIST1.1. Patients were stratified by histology (serous vs. endometrioid).
120 patients were enrolled. 109 patients were treated: 34 patients C: 39 O and 36 OC. 10 patients withdrew consent prior to treatment. Median age was 66 years (range 41-86); 47 (39.2%) serous, 62 endometrioid (51.7%) and 8 (6.7%) mixed histology. The Kaplan Meir estimated median PFS was 3.8 months for C; 2.0 months O and 5.5 months for OC. The one-sided p value stratified log rank test comparing O vs. C was 0.935: HR 1.45 (95% CI 0.91-2.3) and C vs. OC 0.064; HR 0.7 (95% CI: 0.43-1.14). No new safety signals were reported.
The combination of cediranib and olaparib demonstrated modest efficacy in patients with recurrent, metastatic or persistent EC, but was not significantly different compared to cediranib alone. The combination was safe with no unexpected toxicity. Single agent olaparib demonstrated insufficient efficacy to warrant further investigation as monotherapy in this patient population.
Abstract
STUDY QUESTION
Are live birth rates (LBRs) after artificial cycle frozen-thawed embryo transfer (AC-FET) non-inferior to LBRs after modified natural cycle frozen-thawed embryo transfer ...(mNC-FET)?
SUMMARY ANSWER
AC-FET is non-inferior to mNC-FET with regard to LBRs, clinical and ongoing pregnancy rates (OPRs) but AC-FET does result in higher cancellation rates.
WHAT IS ALREADY KNOWN
Pooling prior retrospective studies of AC-FET and mNC-FET results in comparable pregnancy and LBRs. However, these results have not yet been confirmed by a prospective randomized trial.
STUDY DESIGN, SIZE AND DURATION
In this non-inferiority prospective randomized controlled trial (acronym ‘ANTARCTICA’ trial), conducted from February 2009 to April 2014, 1032 patients were included of which 959 were available for analysis. The primary outcome of the study was live birth. Secondary outcomes were clinical and ongoing pregnancy, cycle cancellation and endometrium thickness. A cost-efficiency analysis was performed.
PARTICIPANT/MATERIALS, SETTING, METHODS
This study was conducted in both secondary and tertiary fertility centres in the Netherlands. Patients included in this study had to be 18–40 years old, had to have a regular menstruation cycle between 26 and 35 days and frozen-thawed embryos to be transferred had to derive from one of the first three IVF or IVF–ICSI treatment cycles. Patients with a uterine anomaly, a contraindication for one of the prescribed medications in this study or patients undergoing a donor gamete procedure were excluded from participation. Patients were randomized based on a 1:1 allocation to either one cycle of mNC-FET or AC-FET. All embryos were cryopreserved using a slow-freeze technique.
MAIN RESULTS AND THE ROLE OF CHANCE
LBR after mNC-FET was 11.5% (57/495) versus 8.8% in AC-FET (41/464) resulting in an absolute difference in LBR of −0.027 in favour of mNC-FET (95% confidence interval (CI) −0.065–0.012; P = 0.171). Clinical pregnancy occurred in 94/495 (19.0%) patients in mNC-FET versus 75/464 (16.0%) patients in AC-FET (odds ratio (OR) 0.8, 95% CI 0.6–1.1, P = 0.25). 57/495 (11.5%) mNC-FET resulted in ongoing pregnancy versus 45/464 (9.6%) AC-FET (OR 0.7, 95% CI 0.5–1.1, P = 0.15). χ2 test confirmed the lack of superiority. Significantly more cycles were cancelled in AC-FET (124/464 versus 101/495, OR 1.4, 95% CI 1.1–1.9, P = 0.02). The costs of each of the endometrial preparation methods were comparable (€617.50 per cycle in NC-FET versus €625.73 per cycle in AC-FET, P = 0.54).
LIMITATIONS, REASONS FOR CAUTION
The minimum of 1150 patients required for adequate statistical power was not achieved. Moreover, LBRs were lower than anticipated in the sample size calculation.
WIDER IMPLICATIONS OF THE FINDINGS
LBRs after AC-FET were not inferior to those achieved by mNC-FET. No significant differences in clinical and OPR were observed. The costs of both treatment approaches were comparable.
STUDY FUNDING/COMPETING INTEREST(S)
An educational grant was received during the conduct of this study. Merck Sharpe Dohme had no influence on the design, execution and analyses of this study. E.R.G. received an education grant by Merck Sharpe Dohme (MSD) during the conduct of the present study. B.J.C. reports grants from MSD during the conduct of the study. A.H. reports grants from MSD and Ferring BV the Netherlands and personal fees from MSD. Grants from ZonMW, the Dutch Organization for Health Research and Development. J.S.E.L. reports grants from Ferring, MSD, Organon, Merck Serono and Schering-Plough during the conduct of the study. F.J.M.B. receives monetary compensation as member of the external advisory board for Merck Serono, consultancy work for Gedeon Richter, educational activities for Ferring BV, research cooperation with Ansh Labs and a strategic cooperation with Roche on automated anti Mullerian hormone assay development. N.S.M. reports receiving monetary compensations for external advisory and speaking work for Ferring BV, MSD, Anecova and Merck Serono during the conduct of the study. All reported competing interests are outside the submitted work. No other relationships or activities that could appear to have influenced the submitted work.
TRIAL REGISTRATION NUMBER
Netherlands trial register, number NTR 1586.
TRIAL REGISTRATION DATE
13 January 2009.
FIRST PATIENT INCLUDED
20 April 2009.
Intervertebral disc (IVD) degeneration is frequently associated with low back and neck pain, which accounts for disability worldwide. Despite the known outcomes of the IVD degeneration cascade, the ...treatment of IVD degeneration is limited in that available conservative and surgical treatments do not reverse the pathology or restore the IVD tissue. Regenerative medicine for IVD degeneration, by injection of IVD cells, chondrocytes or stem cells, has been extensively studied in the past decade in various animal models of induced IVD degeneration, and has progressed to clinical trials in the treatment of various spinal conditions. Despite preliminary results showing positive effects of cell-injection strategies for IVD regeneration, detailed basic research on IVD cells and their niche indicates that transplanted cells are unable to survive and adapt in the avascular niche of the IVD. For this therapeutic strategy to succeed, the indications for its use and the patients who would benefit need to be better defined. To surmount these obstacles, the solution will be identified only by focused research, both in the laboratory and in the clinic.
The behaviour of nearly neutrally-buoyant suspensions has been studied experimentally, using a concentric-cylinder rheometer. The effect on the suspension viscosity of: (i) solid fraction, (ii) ...diameter of the solid, spherical particles, (iii) viscosity of the suspending liquid, and (iv) shear rate has been determined experimentally, where all suspensions have been created using the same particulate and liquid materials. The suspension behaviour can well be described by the Ostwald-deWaele model, i.e. a power-law relation between shear stress and shear rate. For low solid fractions, the behaviour is nearly Newtonian, while for larger solid fractions shear thinning behaviour is observed. The relative viscosity, i.e. the ratio between suspension and liquid viscosities, is a rapidly increasing function of solid fraction. For suspensions based on a liquid with high viscosity, the effect of the particle diameter is small, while for those with a low liquid viscosity, the suspension viscosity decreases weakly with increasing particle diameter. The relative viscosity is higher for systems based on a liquid with low viscosity, in comparison with systems with a high liquid viscosity. The current investigation shows that commonly used relations for the relative viscosity of suspensions, that only include solid fraction and a maximum solid fraction, are not generally valid.
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