Regimen Of Letrozole Research Articles

P-631 Extended letrozole regimen versus routine letrozole regimen in women with polycystic ovary syndrome undergoing their first ovulation induction cycle

Abstract Study question Whether an extended letrozole regimen could result in a higher ovulatory rate than a routine regimen in PCOS women undergoing their first ovulation induction cycle. Summary answer PCOS women using the extended letrozole regimen failed to obtain a statistically higher rate of ovulation in comparison with the routine letrozole regimen. What is known already Letrozole has become the first-line agent for ovulation induction, however, nonresponsive cycles occurred in 10-58.8% of PCOS women during their ovulation induction therapy with letrozole alone. The extended letrozole regimen has been demonstrated to be a feasible method for inducing ovulation in those nonresponders. However, whether it could be applied to all the PCOS women as a first choice in the induction of ovulation remains to be explored. Study design, size, duration This is a prospective randomized controlled trial including 148 women with PCOS undergoing their first ovulation induction cycle with letrozole from January 2021 to October 2022. Participants/materials, setting, methods Participants were randomly assigned to receive an extended letrozole regimen (5 mg letrozole daily for 7 days) or a routine regimen(5 mg letrozole daily for 5 days) for one treatment cycle. Ovulation rate was the primary outcome. Secondary outcomes included the clinical pregnancy rate, the number of preovulatory follicles, the rate of multiple pregnancies. Main results and the role of chance The ovulation rate among women receiving a 7-day regimen was slightly higher than the rate with a 5-day regimen, but it did not reach a statistical significance in both the intention-to-treat analysis (90.54%[67/74]vs. 82.43%[59/74], P = 0.065) and per-protocol analysis (90.54%[67/74]vs. 84.29%[59/70], P = 0.257). The number of preovulatory follicles was nearly identical in the two groups (1.39±0.62 vs.1.37±0.59, P = 0.956), and no cases of ovarian hyperstimulation syndrome were observed. In the per-protocol analysis, the rates of clinical pregnancy (20.27%[15/74]vs.16.95%[10/70], P = 0.343) and live birth (13.51%[10/74]vs.11.43%[8/70], P = 0.976) did not differ significantly between treatment groups. Moreover, all the conceptions were singletons without neonatal defects. Limitations, reasons for caution The major concern of the current research is its single-centre and open label nature. Additionally, the limited number of lean PCOS women with a mean body mass index of 23-25 kg/m2 enrolled in our trial also restrict the generalizability of our findings. Wider implications of the findings Letrozole 5-day regimen remains to be the first choice for PCOS women undergoing ovulation induction therapy. Additional prospective trials with a larger sample size and different subgroups of PCOS are needed to assess the ovulatory effects of different letrozole treatment duration. Trial registration number ChiCTR2100042082

Comparing the effectiveness of letrozole versus methotrexate for treatment of ectopic pregnancy: A randomized controlled trial

ObjectiveTo evaluate the efficacy of two different regimens of Letrozole, an aromatase inhibitor, in the management of ectopic pregnancy compared to methotrexate. Study DesignThis randomized controlled trial was conducted on 88 women diagnosed with ectopic pregnancy with a baseline level of serum beta-human chorionic gonadotropin under 3000 mIU/mL between June 30, 2023, and December 30, 2023, at the Department of Obstetrics and Gynecology of the Vali-e-Asr Hospital affiliated with Tehran University of Medical Sciences. Participants were allocated into either methotrexate (n = 43), 5-day course Letrozole (n = 24), or 10-day course Letrozole (n = 21) treatments. The methotrexate group received a single dose of 50 mg/m2 dosage intramuscular methotrexate. The 5-day Letrozole group received a 2.5 mg Letrozole tablet three times daily for 5 days, whereas the 10-day Letrozole group received a 2.5 mg Letrozole tablet twice daily for 10 days. The primary outcome was the treatment response, defined as the achievement of a negative serum beta-human chorionic level without the need for additional methotrexate treatment or surgery. The secondary outcomes were the need for additional methotrexate dose or laparoscopic surgery intervention. The trial protocol was prospectively registered in ClinicalTrials.gov with code NCT05918718. ResultsThe treatment response rates in methotrexate, 5-day Letrozole, and 10-day Letrozole groups were 76.7 %, 75.0 %, and 90.5 %, respectively, with no significant differences between the groups (P-value = 0.358). A total of 10 (23.3 %) patients from the methotrexate group, 3 (12.5 %) from the 5-day Letrozole group, and 2 (9.5 %) from the 10-day Letrozole group required an additional methotrexate dose, with no significant differences between the groups (P-value = 0.307). Furthermore, only 3 (12.5 %) patients, all from the 5-day Letrozole group, were suspected of tubal rupture and underwent surgery (P-value = 0.016). ConclusionOur findings suggest Letrozole as a safe alternative to methotrexate in treating stable ectopic pregnancies, with a favorable treatment response rate. However, there is still a need for future larger studies to determine the applicability of Letrozole in the EP management. Also, the non-significant higher effectiveness of the 10-day Letrozole regimen than the 5-day Letrozole group underscores the need for future research to determine the optimal Letrozole regimen for the management of ectopic pregnancy.

Extended versus conventional letrozole regimen in patients with polycystic ovary syndrome undergoing their first ovulation induction cycle: a prospective randomized controlled trial.

Can an extended letrozole (LE) regimen result in a higher ovulatory rate than a conventional regimen in patients with polycystic ovary syndrome (PCOS) undergoing their first ovulation induction cycle? There was no statistical difference in ovulation rate between patients with PCOS using the extended LE regimen and those using the conventional LE regimen. LE has become the first-line agent for ovulation induction. However, there is still a proportion of non-responsive cycles in patients with PCOS undergoing ovulation induction therapy with LE alone, and the extended LE regimen has been demonstrated to be a feasible method for inducing ovulation in these non-responders. Nevertheless, whether the extended regimen could be applied to all patients with PCOS as a first choice for the induction of ovulation remains to be explored. This was a prospective randomized controlled trial that included 148 female patients with PCOS who underwent their first ovulation induction cycle with LE from January 2021 to October 2022. Participants were randomly assigned to receive an extended (5 mg LE daily for 7 days) or conventional regimen (5 mg LE daily for 5 days) for one treatment cycle. The ovulation rate was the primary outcome. Secondary outcomes included the clinical pregnancy rate, the number of preovulatory follicles, and the rate of multiple pregnancies. The ovulation rate among patients receiving an extended LE regimen was slightly higher than the rate with a conventional LE regimen, but the difference did not reach statistical significance in either the intention-to-treat analysis (90.54% [67/74] vs 79.73% [59/74], P = 0.065; relative risk [95% CI]: 0.881 [0.768-1.009]) or the per-protocol analysis (90.54% [67/74] vs 84.29% [59/70], P = 0.257; relative risk [95% CI]: 0.931 [0.821-1.055]). The number of preovulatory follicles was nearly identical in the two groups (1.39 ± 0.62 vs 1.37 ± 0.59, P = 0.956), and no cases of ovarian hyperstimulation syndrome were observed. With regards to the endometrial parameters, the mean endometrium thickness was slightly thicker with the conventional LE regimen compared to that with the extended LE regimen, though with no statistical difference (9.27 ± 1.72 mm vs 9.57 ± 2.28 mm, P = 0.792). In the per-protocol analysis, the rates of clinical pregnancy (20.27% [15/74] vs 14.29% [10/70], P = 0.343; relative risk [95% CI]: 0.705 [0.34-1.463]) and live birth (13.51% [10/74] vs 11.43% [8/70], P = 0.705; relative risk [95% CI]: 0.846 [0.354-2.019]) did not differ significantly between treatment groups. Moreover, all conceptions were singletons without neonatal defects. The major concerns regarding this study are its single-center and open-label nature. Additionally, the limited number of lean patients with PCOS with a mean body mass index of 23-25 kg/m2 enrolled in our trial also restricted the generalizability of our findings. A change from the standard strategy of ovulation induction in patients with PCOS is not advisable, because a statistically superior effect of the extended LE regimen over a conventional regimen was not detected. The extended LE regimen could be applied with caution in a specific population who failed to respond to a conventional regimen rather than all the patients with PCOS during ovulation induction. Additional prospective trials with larger sample sizes and different PCOS subgroups are needed to assess the ovulatory effects of various LE treatment durations. This study was funded by the Shanghai First Maternity and Infant Hospital, affiliated with Tongji University School of Medicine (grant numbers: 2023B03 to Y.F., 2023B18 to X.Z., and 2020RC02 to Y.F.). The authors report no conflicts of interest. Chinese Clinical Trial Registry (ChiCTR2100042082). 13 January 2021. 21 January 2021.

A comparison of letrozole regimens for ovulation induction in women with polycystic ovary syndrome

To determine the optimal letrozole regimen for ovulation induction (OI) in women with polycystic ovary syndrome (PCOS). Retrospective cohort study. Single academic fertility clinic from 2015-2022. A total of 189 OI cycles in 52 patients with PCOS. Patients were prescribed 1 of 4 letrozole regimens (group 1: 2.5 mg for 5 days, group 2: 2.5 mg for 10 days, group 3: 5 mg for 5 days, and group 4: 5 mg for 10 days). The primary outcome was ovulation, and secondary outcomes included multifollicular development, and clinical pregnancy rate, which were analyzed with binary logistic regression. Kaplan-Meier cumulative response curves and a Cox proportional hazard regression model were used for time-dependent analyses. Mean age was 30.9 years (standard deviation [SD], 3.6) and body mass index was 32.1 kg/m2 (SD, 4.0). Group 2 (odds ratio [OR], 9.12; 95% confidence interval [CI], 1.92-43.25), group 3 (OR, 3.40; 95% CI, 1.57-7.37), and group 4 (OR, 5.94; 95% CI, 2.48-14.23) had improved ovulation rates after the starting regimen as compared with group 1. Cumulative ovulation rates exceeded 84% in all groups, yet those who received 5 mg and/or 10 days achieved ovulation significantly sooner. Multifollicular development was not increased in groups 2-4 as compared with group 1. Groups 2-4 also demonstrated improved time to pregnancy. Ovulation rates are improved when starting with letrozole at 5 mg and/or a 10-day extended course as compared with the frequently-used 2.5 mg for 5 days. This may shorten time to ovulation and pregnancy.

Induction of abortion in the first trimester of pregnancy using letrozole and misoprostol combination versus misoprostol alone - A comparative observational study

Background: Medical abortion is safer than surgical abortion. Several studies have shown that combination of antiprogesterone drug mifepristone and prostaglandin misoprostol can increase complete abortion rate in medical management of first-trimester miscarriage compared to misoprostol alone. Letrozole, an aromatase inhibitor, has emerged as an alternative to mifepristone for induction of medical abortion as mifepristone is expensive and not registered in many countries. Aims and Objectives: The aim of the present study was to evaluate the safety and efficacy of combined regimen of letrozole and misoprostol in first-trimester medical abortion compared to misoprostol alone. Materials and Methods: It was a comparative observational study conducted at R. G. Kar Medical College, a tertiary care hospital in West Bengal, India. The study population was the antenatal mothers booked at antenatal clinic willing for termination of pregnancy at <12 weeks of gestational age. Participants were allocated, 39 in each group in a non-randomized manner. Patients in one group (Group A) were posted for medical abortion with combination regimen of tablet letrozole (10 mg) once daily for 3 days followed by application of tablet misoprostol 800 mcg sublingually on day 4. In other group (Group B), patients were on misoprostol-only regimen with the application of tablet misoprostol 800 mcg sublingually. Results: Induction-abortion time was significantly less in the letrozole group (11±0.79 h) than the misoprostol group (13.23±0.81 h), P=0.0001. Complete abortion rate was significantly higher in the letrozole group compared to misoprostol group (84.62% and 64.10%, respectively, P=0.03). 15.38% patients in the letrozole group and 35.90% patients in the misoprostol group had excessive vaginal bleeding and the difference was statistically significant, P=0.03. The duration of vaginal bleeding was also significantly less in the letrozole group (2.45±0.29 days) than the misoprostol group (2.82±0.37 days), P<0.0001. Incidence of side-effects was comparable and the severity of side-effects was not significantly different between the groups. Conclusion: Letrozole and misoprostol combination regimen leads to significant increase in complete abortion rate and also significant reduction of the duration of vaginal bleeding, induction-abortion time, and need for surgical intervention when compared to misoprostol regimen.

Letrozole plus misoprostol versus misoprostol alone in the induction of anembryonic missed abortion: a randomized controlled trial conducted in Upper Egypt

BackgroundA missed abortion is a spontaneous abortion in which the embryo or fetus has already died but has remained in the uterus for days or weeks with a closed cervical ostium. Termination of pregnancy could be achieved either by surgical evacuation or medical or expectant management. Letrozole is a third-generation aromatase inhibitor. According to many recent studies, letrozole given for three days before the administration of misoprostol was more effective than misoprostol alone at inducing abortion. Our study compared the efficacy of various letrozole regimens (10 mg/d for three days and a single dose of 20 mg) combined with misoprostol vs. misoprostol alone in inducing abortion. To find the most efficient regimen of letrozole administered before misoprostol to induce an abortion.MethodologyThis prospective, parallel, three-arm, single-blinded, allocation-concealed randomized controlled trial was conducted in Sohag Teaching Hospital in Upper Egypt. We randomly divided 105 patients with anembryonic missed abortion (up to 63 days gestation) with no history of medical disorders or a history of allergies to misoprostol or letrozole into three equal groups (a single-dose letrozole group, a multiple-dose letrozole group, and a misoprostol-only group). The complete abortion rate, incomplete abortion rate, failure to abort rate, and induction-to-abortion interval were all collected. All statistical calculations were performed using the computer program SPSS (Statistical Package for the Social Science, SPSS Inc., Chicago, IL, USA).ResultsThe complete abortion rate was significantly higher in the single-dose letrozole and multiple-dose letrozole groups than in the misoprostol group (p values = 0.0455 and 0.001, respectively). On the other hand, there was no significant difference in the complete abortion rate between the single-dose group and the multiple-dose letrozole group (p-value = 0.1713). The time to complete abortion was significantly shorter in the single-dose and multiple-dose letrozole groups than in the misoprostol group (p values = 0.0036 and 0.0049, respectively). On the other hand, there was no significant difference in the time to complete abortion between the single-dose letrozole group and the multiple-dose letrozole group (P = 0.532).ConclusionSingle- and multiple-dose letrozole regimens followed by misoprostol had a higher rate and a shorter time to complete abortion than misoprostol alone.Trial registrationThe trial is registered at gov with the name “letrozole and abortion” and the identifier “NCT05198050”. The date of registration was April 1, 2022, registered prospectively. URL: https://register.clinicaltrials.gov/prs/app/action/ViewOrUnrelease?uid=U0004GED&ts=25&sid=S000BPDQ&cx=43mobl.

P-496 The effect of adding letrozole to the combined treatment of caesarean scar pregnancy with methotrexate followed by hysteroscopic evacuation of products of conception

Abstract Study question Does adding letrozole to combined cesarean scar pregnancy (CSP) treatment cause a greater decrease in B-human chorionic gonadotropin (B-hCG) concentrations and less blood loss? Summary answer The addition of letrozole to the combined CSP treatment does not result in a greater decrease in B-hCG concentrations or less blood loss. What is known already There is no reference treatment for CSP as the limited number of cases precludes the extrapolation of results. In our center we successfully use two-step treatment with methotrexate followed by hysteroscopic removal of products of conception (POC). The time in between is needed to achieve a decrease in the trophoblast's vital potential (B-hCG fall) and its vascularization. The suppression of estradiol production by letrozole may interfere with the physiological effect of progesterone, which is essential for the maintenance of pregnancy. Additional administration of letrozole could further reduce the vital potential of the pregnancy, resulting in a lower rate of complications. Study design, size, duration A prospective cohort tertiary single-center study (consent no. 1072.6120.321.2020) was conducted among women with CSP from January 2021 to December 2022. Only women with increasing concentrations of B-hCG and consent of the Bioethics Committee for termination of pregnancy were included. Women with decreasing B-hCG concentrations were excluded. All enrolled women gave informed written consent to participate in the study. Participants/materials, setting, methods All women received a single dose of 100 mg MTX intravenously and 50 mg MTX in intra-amniotic injection (day 0), along with 30 mg potassium chloride in case of positive fetal heartbeat (FH). Women who consented were additionally given letrozole 5 mg orally (day 0) for 10 days. B-hCG concentration was measured on day 0,4,7. After obtaining satisfactory decrease in B-hCG and POC vascularization, women underwent hysteroscopic evacuation of POC. Blood loss parameters were measured. Main results and the role of chance The study included 28 women aged 27-41, with a gestational age of 6-12 weeks. FH was present in 17/28 (60.7%) women. Of the 28 women, 16 (57.1%) received additional letrozole (arm 1). There was no significant difference between arm 1 vs. arm 2 (without letrozole) in terms of gestational age (7.69±1.54 vs. 8.00±2.09 weeks, p = 0.85), FH positivity (10/16, 62.5% vs. 7/12, 58.33%; p = 1), BMI (25.39±5.08 vs. 26.24±6.51; p = 0.82), day 0 B-hCG (47656.89± 37747.87 vs. 51870.83± 45838.87 mIU/ml; p = 0.89) and day 0 hemoglobin (Hb) (12.98±0.74 vs. 12.74±1.26 g/dl; p = 0.57). Timing of hysteroscopy was not significantly different between arm 1 vs. arm 2 (day 22.19± 14.44 vs. 31.42± 25.83; p = 0.42). The dynamics of B-hCG decline in arm 1 vs. arm 2 between days 4-0 (-3295.67± 15133.13 vs. −6883.00± 20029.88 mIU/ml; p = 0.71) and 7-4 (-13137.82± 13765.14 vs. −19145.75± 23526.70 mIU/ml; p = 0.68) was not significantly different. There were no differences between arm 1 vs. arm 2, in decrease in Hb concentration on day 1 post-hysteroscopy (-1.79± 1.67 vs. −2.19± 1.68 g/dl, p = 0.53), blood loss volume (318.75± 437.37 vs. 591.67 ± 744.02 ml; p = 0.29) and rate of hemorrhage (4/16, 25% vs. 3/12, 25% cases, p = 1). Limitations, reasons for caution The limitations of the study are the small sample size, the single-center nature of the study, and the arbitrarily set dosing regimen of letrozole. Wider implications of the findings The results do not support the use of letrozole in the above regimen as an adjunct to combined CSP treatment. Trials with a larger sample size and with a different letrozole dosing regimen are needed to confront the results. Trial registration number 072.6120.321.2020

Extending letrozole treatment duration is effective in inducing ovulation in women with polycystic ovary syndrome and letrozole resistance

To evaluate whether extending letrozole (LE) treatment duration could induce ovulation in women with polycystic ovary syndrome (PCOS) who previously failed to ovulate after a 5-day regimen of 5 mg LE daily for at least 1 ovulation induction cycle, defined as "LE resistance". Retrospective cohort study. Tertiary care academic medical center. A total of 69 women with PCOS and LE resistance were included. The duration of LE treatment was increased in a stepwise manner (named as "2-step extended LE regimen"): a 7-day regimen of 5 mg LE daily was prescribed in the first ovulation induction cycle, and if ovulation did not occur, a 10-day regimen was prescribed in the subsequent cycle. Ovulation rate was the primary outcome. Clinical pregnancy rate, live birth rate, spontaneous ovulation rate, and ovarian hyperstimulation syndrome rate were the secondary outcomes. Of the 69 patients, 48 ovulated after the 7-day and 16 after the 10-day regimen. Overall, the cumulative ovulation rate reached 92.75% (64/69) after the 2-step extended LE regimen, with a cumulative clinical pregnancy rate of 31.88% (22/69) and a cumulative live birth rate of 24.63% (17/69). All patients ovulated spontaneously without exogenous trigger agents and none experienced ovarian hyperstimulation syndrome. Extending LE treatment duration is a feasible method for inducing ovulation in women with PCOS and LE resistance.

WHAT IS THE IDEAL LETROZOLE REGIMEN FOR OVULATION INDUCTION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME?

To determine the optimal letrozole regimen for ovulation induction (OI) in women with polycystic ovary syndrome (PCOS)

Ovulation induction regimens are associated with a higher rate of livebirth after frozen single-blastocyst transfer among women with polycystic ovary syndrome.

BackgroundHormone replacement therapy (HRT) regimen was suggested to be associated with a decreased rate of livebirth and a higher risk of hypertensive disorders of pregnancy (HDP) after frozen cleavage stage embryo transfer in women with polycystic ovary syndrome (PCOS). With the dramatically increased use of elective single embryo transfer, there is great need to explore the impacts of different endometrial preparation regimens on frozen single-blastocyst transfer in women with PCOS.MethodsIn this study, a total of 3941 women who diagnosed with PCOS and underwent single-blastocyst transfer during their first cycles of frozen embryo transfer (FET) between March 2012 and December 2020 were included. We retrospectively compared the pregnancy and neonatal outcomes after frozen single-blastocyst transfer with endometrial preparation by HRT regimen (n = 3540), ovulation induction by human menopausal gonadotropin (hMG) regimen (n = 226), and ovulation induction by letrozole regimen (n = 175).ResultsAfter adjustment for confounders with multivariable logistic regression, the hMG regimen group [(58.4% vs. 49.6%; adjusted odds ratio (aOR): 1.43; 95% confidence interval (CI): 1.09-1.89)] and letrozole regimen group (58.9% vs. 49.6%; aOR: 1.42; 95% CI: 1.04-1.93) were associated with a higher rate of livebirth (primary outcome), compared with the group with HRT regimen. As to the secondary outcomes, the rate of pregnancy loss in the hMG regimen group (22.8% vs. 30.3%; aOR: 0.69; 95% CI: 0.48-1.00) and letrozole regimen group (16.9% vs. 30.3%; aOR: 0.48; 95% CI: 0.30-0.78) was also lower than that in the HRT regimen group. The pregnancy outcomes between the hMG regimen group and the letrozole regimen group were similar. We did not observe significant difference in the incidences of maternal and neonatal complications among these three groups.ConclusionOvulation induction regimen with letrozole or hMG for endometrial preparation was associated with a higher livebirth rate and a lower pregnancy loss rate in frozen single-blastocyst transfer cycles among women with PCOS.

Extended Letrozole Regimen for Treatment of Clomiphene Resistant Polycystic Ovary Syndrome Patients

Extended Letrozole Regimen for Treatment of Clomiphene Resistant Polycystic Ovary Syndrome Patients

Association between Letrozole Dose and Pregnancy Rate in Clomiphene-Resistant Women with Polycystic Ovary Syndrome Randomized Controlled Trial

Abstract Background Among couples experiencing difficulty conceiving, unexplained infertility is a fairly common diagnosis, occurring in approximately 10–20% of cases. One of the options available to women with unexplained infertility is ovulation induction, which is most commonly achieved using clomiphene citrate. Aim of the Work To evaluate the effect of high dose letrozole protocol (7.5 mg, 10 mg for 5 days compared with standard letrozole protocol 5 mg for 5 days) in the management of clomiphene-resistant women with polycystic ovary syndrome. Patients and Methods Randomized controlled clinical trial. The current study was conducted in Ain Shams University Maternity Hospital. The study included a total of 120 women. The study population was randomized using a Computer generated randomization system into 3 groups: Group A: standard letrozole regimen (5mg /day starting from day 2 to for 5 days). Group B received letrozole (7.5 mg/day from day 2 for 5 days). Group C received letrozole (10 mg/day from day 2for 5 days). Results We found that there were insignificant differences between study groups as regard age, BMI and Duration of infertility p-value 0.997,0.873,0.927 respectively, there was insignificant differences between study groups as regard parity and Ovulation status p-value 0.575,0.897 respectively, there was insignificant differences between study groups as regard serum level of FSH,LH, E2 and Testosterone p-value 0.911, 0.821, 0.811, 0.954 respectively. Conclusion It seems that the use of higher doses of letrozole improve endometrial thickness and follicle number but it offers no advantage in terms of pregnancy rates over the lower (2.5 mg) dose.

Extended Letrozole Regimen Co-treatment With Gonadotropin Releasing Hormone Antagonist Protocol Versus Gonadotropin Releasing Hormone Antagonist Protocol in Poor Responders Undergoing IVF-ET

Extended Letrozole Regimen Co-treatment With Gonadotropin Releasing Hormone Antagonist Protocol Versus Gonadotropin Releasing Hormone Antagonist Protocol in Poor Responders Undergoing IVF-ET

To Study the Efficacy on Fertility Outcome by short term Letrozole versus Extended Letrozole Regimen in Clomiphene Citrate Resistant PCOS Women

To Study the Efficacy on Fertility Outcome by short term Letrozole versus Extended Letrozole Regimen in Clomiphene Citrate Resistant PCOS Women

Abstract P1-15-02: Long term follow-up of the neo-adjuvant pilot trial evaluating activity of letrozole in combination with bevacizumab in post-menopausal women with newly diagnosed estrogen and/or progesterone receptor positive primary breast cancer

Abstract Introduction: Vascular endothelial growth factor overexpression has been associated with resistance to anti-estrogen therapy (Cancer Res 2008; 68: 6232); our preclinical data showed that anti-VEGF therapy reverse resistance to estrogen therapy. We postulated that anti-VEGF therapy would enhance anti-estrogen therapy and thus designed a pilot study to assess the feasibility and efficacy of neoadjuvant letrozole and bevacizumab in post-menopausal women with stage II/III, ER/PR positive breast cancer. Patients and Methods: Eligible patients were treated with a neo-adjuvant regimen of letrozole, 2.5 mg/day (PO) and bevacizumab 15 mg/kg every 3 weeks (IV) for a total of 24 weeks prior to surgical treatment of their breast cancer. Patients were followed for toxicity at three week intervals and for tumor assessment at 6 week intervals. Research tumor biopsies were taken before and 6 weeks after initiation of therapy. The primary endpoint was pathological complete remission (pCR). Patients with inflammatory breast cancer were excluded. Results: Twenty six patients were enrolled and 25 were treated (one patient had a TIA the day before initiation of therapy). The regimen was well tolerated with 2 patients taken off-study due to uncontrolled hypertension. Objective clinical response occurred in 68% of the patients (17/25), 16% with CR and 52% with partial response (PR). Sixteen percent of the patients (4/25) had clinical stable disease (SD) and 2 patients progressed (PD) while on therapy. Three patients had pCR and 1 patient had microscopic residual tumor cells in the LNs but not in the breast (pCR 16%). Thirty two percent of the patients attained stage 0 or 1 status. None of the pCR patients received adjuvant chemotherapy and none have relapsed after a median follow-up of 6.1 years (range, 5.8+ to 7.5+). Eight of the 13 patients with PR did not receive chemotherapy and only one relapsed with a median follow-up of 6.2 years (range, 3.7 to 7.7+). At a median follow-up of 6.4 years, 88% of the patients have not relapsed and 12% relapsed (1 PD [basal-like], 1 PR [Luminal B], 1 SD [HER2] relapsed at 1.7, 4, and 6.8 years respectively). Of the 17 patients with CR and PR, only 1 has relapsed (6%). Next Generation Sequencing Analysis and evaluation of markers of proliferation/apoptosis are underway. Conclusion: Combination neoadjuvant therapy with letrozole and bevacizumab was well tolerated and resulted in an impressive pCR of 16%. At a median of 6.4 years, the relapse free survival is 88% for all comers and 94% for responding patients (Luminal A and B). Full correlation of clinical and genomic/biomarker analysis will be presented at the time of the meeting. This encouraging data has led The Breast Cancer Translational Research Consortium to complete a randomized phase II trial (TBCRC002) of letrozole ± bevacizumab in this patient population. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-15-02.

Effect of letrozole on uterine artery Doppler flow indices prior to first‐trimester termination of pregnancy: a randomized controlled trial

We previously demonstrated that a sequential regimen of letrozole and misoprostol resulted in a marked reduction in the serum estradiol concentration and in a higher efficacy of first-trimester termination of pregnancy than misoprostol alone. The aim of this study was to evaluate the effect of letrozole on uterine artery Doppler flow indices during early pregnancy. This was a randomized controlled trial. Thirty women requesting termination of pregnancy up to 63 days' gestation were randomized into two groups: a letrozole group receiving 10 mg of letrozole, daily, for 3 days, and a control group receiving a placebo for 3 days. Serum estradiol, progesterone and human chorionic gonadotropin (hCG) concentrations were measured before drug administration and then daily for 6 days. Ultrasound scanning for fetal viability and measurement of the pulsatility (PI) and resistance (RI) indices of the uterine arteries was performed before drug administration, and then on day 3 and day 7 after starting letrozole or placebo. All pregnancies were terminated by surgical evacuation on day 7 or day 8. Uterine artery PI and RI decreased significantly in the letrozole group, but not in the control group. Serum estradiol concentrations were significantly lower in the letrozole group than in the control group from day 2 onwards. Serum progesterone and hCG concentrations were comparable for the two groups throughout the 7 days. There were significantly more women in the letrozole group with vaginal bleeding. We have demonstrated that the use of letrozole in the first trimester of pregnancy suppresses serum estradiol levels but results in an increase in blood flow to the uterus. Further studies should be carried out to elucidate the mechanism of letrozole pretreatment in medical abortion.

4 EFFECT OF A PROLONGED AROMATASE INHIBITOR TREATMENT ON PRE-OVULATORY OVARIAN FOLLICLES IN CATTLE

Letrozole, a non-steroidal aromatase inhibitor, prevents the body from producing its own oestrogen. The potential use of this compound for herd synchronization is supported by previous studies in which letrozole treatment increased mean plasma LH concentrations, prolonged the period of dominance of the extant dominant follicle and delayed emergence of the next follicular wave. Heifers given a 3-day regimen of letrozole exhibited greater corpus luteum diameter indicative of a luteotrophic effect. The objective of the present study was to test the hypothesis that letrozole treatment during the development of the preovulatory follicular wave will delay ovulation. Post-pubertal beef heifers were given 2 luteolytic doses of PGF (12 h apart) and monitored by ultrasonography for ovulation. Ovarian follicular wave emergence was synchronized by ultrasound-guided transvaginal follicular ablation 5 to 8 days after PGF-induced ovulation (Day –1 = follicular ablation, Day 0 = wave emergence) and a luteolytic dose of PGF was given 60 and 72 h later. On Day 1, heifers were divided randomly into 2 groups (n = 15/group) and given an intravaginal device containing 1 g of letrozole or a blank device (control). The intravaginal devices were removed on Day 7, or at the time of ovulation, whichever occurred first. The ovaries were monitored by ultrasonography and a blood sample was collected daily from day of ablation to 12 days post-ovulation. Single point measurements were analysed by t-tests and serial data were analysed by analysis of variance for repeated measures. Multiple contrasts were made by Tukey's test. The interval from placement of the intravaginal device to ovulation was longer in letrozole-treated animals (6.1 ± 0.25 vs 5.1 ± 0.26 days, P < 0.01). Compared with controls, the day-to-day diameter profile of the dominant follicle of the ovulatory wave was larger (P < 0.05) and the maximum diameter greater (14.6 ± 0.51 vs 12.4 ± 0.53 mm; P < 0.01) in letrozole-treated heifers. The diameter profile of the corpus luteum formed post-letrozole treatment did not differ between groups; however, plasma P4 concentrations were higher (P < 0.01) in heifers treated with letrozole. In summary, a slow-release intravaginal letrozole device delayed ovulation by 24 h and induced the formation of a corpus luteum that secreted higher levels of progesterone. A slow-release intravaginal letrozole device may become useful for the development of an aromatase inhibitor-based protocol to control ovulation for herd synchronization and to enhance fertility by increasing circulating progesterone concentrations during the first 7 days post-AI or embryo transfer in cattle. Supported by the Natural Sciences and Engineering Research Council of Canada and Bioniche Life Sciences Inc.

Extended high dose letrozole regimen versus short low dose letrozole regimen as an adjuvant to gonadotropin releasing hormone antagonist protocol in poor responders undergoing IVF-ET*

Objective. To compare the efficacy and cost-effectiveness of extended high dose letrozole regimen/HPuFSH-gonadotropin releasing hormone antagonist (GnRHant) protocol with short low dose letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.Methods. In this randomized controlled trial, 136 women who responded poorly to GnRH agonist long protocol in their first IVF cycle were randomized into two equal groups using computer generated list and were treated in the second IVF cycle by either extended letrozole regimen (5 mg/day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days) combined with HPuFSH-GnRHant protocol or short letrozole regimen (2.5 mg/day from cycle day 3–7) combined with HPuFSH-GnRHant protocol.Results. There were no significant differences between both groups with regard to number of oocytes retrieved and clinical pregnancy rate (5.39 ± 2.08 vs. 5.20 ± 1.88 and 22.06% vs. 16.18%, respectively).The total gonadotropins dose and medications cost per cycle were significantly lower in extended letrozole group (44.87 ± 9.16 vs. 59.97 ± 14.91 ampoules and 616.52 ± 94.97 vs. 746.84 ± 149.21 US Dollars ($), respectively).The cost-effectiveness ratio was 2794 $ in extended letrozole group and 4616 $ in short letrozole group.Conclusion. Extended letrozole regimen/HPuFSH-GnRHant protocol was more cost-effective than short letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.

A prospective double-blinded, randomized, placebo-controlled trial on the use of letrozole pretreatment with misoprostol for second-trimester medical abortion

Background The aim of this randomized trial was to evaluate the abortion rate of combined regimen of letrozole and misoprostol in second-trimester abortion. Study Design This was a randomized, double-blinded, placebo-controlled trial of 130 women requesting legal termination of pregnancy at gestational age between 12 and 20 weeks. Letrozole 7.5 mg or placebo were given for 3 days, followed by misoprostol 400 mcg vaginally every 3 h up to a maximum of five doses on the third day. Results The abortion rate in 24 and 48 h were similar for the letrozole and placebo groups (24 h: 93.8% vs. 90.8%, respectively, p=.718; 48 h: 98.5% vs. 95.4%, respectively, p=.496). The median induction-to-abortion interval was also similar for the letrozole and placebo groups (9.6 h vs. 10.6 h, p=.145). All the side effects were comparable between the two groups. Conclusion The use of letrozole pretreatment (7.5 mg daily for 3 days) with misoprostol in second-trimester abortion does not significantly improve the abortion rate of the misoprostol-only regimen.

Extended letrozole regimen versus clomiphene citrate for superovulation in patients with unexplained infertility undergoing intrauterine insemination: A randomized controlled trial

BackgroundThe aim of this randomized controlled trial was to compare the efficacy of extended letrozole regimen with clomiphene citrate in women with unexplained infertility undergoing superovulation and intrauterine insemination (IUI).MethodsTwo hundred and fourteen patients with unexplained infertility were randomized into two equal groups using computer generated list and were treated by either letrozole 2.5 mg/day from cycle day 1 to 9 (extended letrozole group, 211 cycles) or clomiphene citrate 100 mg/day from cycle day 3 to 7 (clomiphene citrate group,210 cycles). Intrauterine insemination was performed 36 to 40 hours after HCG administration.ResultsBoth groups were comparable with regard to number of mature follicles (2.24 +/- 0.80 Vs 2.13 +/- 0.76) and the day of HCG administration. Serum estradiol was significantly greater in clomiphene citrate group (356 +/- 151 Vs 822 +/- 302 pg/ml, P = < 0.001) and the endometrial thickness was significantly greater in extended letrozole group (9.10 +/- 1.84 Vs 8.18 +/- 1.93 mm, P = < 0.001).The pregnancy rate per cycle and cumulative pregnancy rate were significantly greater in extended letrozole group (18.96% Vs 11.43% and 37.73% Vs 22.86%, respectively).ConclusionThe extended letrozole regimen had a superior efficacy as compared with clomiphene citrate in patients of unexplained infertility undergoing superovulation and IUI.Trial registrationClinicalTrials.gov, NCT01232075