First-line Treatment For Women Research Articles

Treatment and prognosis of idiopathic generalized epilepsy in adults

Treatment of idiopathic generalized epilepsy (IGE) always includes regular use of antiepileptic drugs (AED) and patient counseling. Although the International League against Epilepsy and the National Institute of Clinical Excellence recently provided very useful guidelines, the treatment of epilepsy should always respect the individual characteristic of each patient. Counseling of patients to establish normal life style and avoidance of seizure precipitants is always necessary. Monotherapy with valproate as first line treatment is usually based on its superior efficacy over all other AED in all seizures and syndromes of IGE. However, valproate may be poorly tolerated by some patients, and is considered unsafe for the fetuses of pregnant women. Levetiracetam is alternative first line treatment in women of reproductive age planning pregnancy. Drugs used for therapy of focal or partial seizures (carbamazepine, oxcarbazepine, pregabalin, etc.) often exacerbate absences and/or myoclonus and are contraindicated in juvenile myoclonic epilepsy (JME) and other IGE syndromes with these seizure types. In general, the prognosis of IGE in adults is better than that of focal and symptomatic epilepsies, but lifelong treatment may be necessary, particularly in JME patients. Social outcome in IGE, especially in JME, may be unfavorable, even after a good seizure control.

MONARCH 3: A randomized phase III study of anastrozole or letrozole plus abemaciclib, a CDK4/6 inhibitor, or placebo in first-line treatment of women with HR+, HER2-locoregionally recurrent or metastatic breast cancer (MBC).

TPS624 Background: Abemaciclib (LY2835219), a cell cycle inhibitor of CDK4/CDK6, demonstrated a clinically manageable safety profile and single-agent anti-tumor activity in MBC; all tumor responses were observed in hormone receptor positive (HR+) disease (Tolaney SM, Rosen LS, Beeram M, et al. San Antonio Breast Cancer Symposium, 2014, Abstract P5-19-13). Non-steroidal aromatase inhibitors (NSAI, letrozole and anastrazole), approved in the first-line setting for postmenopausal women with HR+ MBC, are being evaluated in combination with abemaciclib for safety and tolerability in a phase Ib study (NCT02057133) and in the present study (NCT02246621) to assess clinical efficacy. Methods: MONARCH 3 is a randomized, double-blind, placebo-controlled, phase III study of abemaciclib + NSAI vs placebo + NSAI in locoregionally recurrent (not amenable to curative treatment) breast cancer or MBC, with no prior systemic therapy in this disease setting. Patients will be randomized 2:1, and stratified by nature of disease (visceral vs bone-only metastases vs other) and prior (neo)adjuvant endocrine therapy (aromatase inhibitor vs other vs none). Abemaciclib 150 mg or placebo will be given continuously PO every 12 hours until progression, along with anastrozole 1 mg or letrozole 2.5 mg once daily at the investigator’s discretion, and assessments will occur every 28 days. Postmenopausal women with HR+, HER2- disease, a disease-free interval > 12 mos after completion of (neo)adjuvant endocrine therapy, ECOG PS ≤ 1, adequate organ function, and measurable disease or nonmeasurable bone-only disease (RECIST v1.1) are eligible. The primary endpoint is progression-free survival (PFS); a key secondary endpoint is overall survival (OS). The study has 80% power to detect an increase in PFS of approximately 40% (hazard ratio = 0.714). Assuming a median PFS of 10 mos in the control arm, this corresponds to a 4-mo increase in the median PFS. PFS and OS will be hierarchically tested to maintain an overall type I error rate of 2.5%. Enrollment began November 2014; planned enrollment is 450 patients. Clinical trial information: NCT02246621.

Updates from the 2014 San antonio breast cancer symposium.

The san antonio breast cancer syposium (SABCS 2014) was an exciting one this year. Data from the SOFT trial was presented that had potential implications on the treatment of pre menapausal women with hormone receptor positive breast cancer. In a phase II trial fulvestrant was found to significantly improve progression free and overall survival compared to anastrazole in the first line treatment of women with hormone receptor positive metastatic breast cancer. We saw a number of intersting abstracts looking at trying to refine the role of platinums and exploring the role of blocking PD-1 among women with triple receptor negative breast cancer. We also saw the results of a number of trials trying to refine standard chemotherapeutic regimens. Here we will review some fon the most interesting abstracts presented this year at SABCS 2014.

Targeting HSP90 in breast cancer: Enchant-1 (NCT01677455) phase 2 proof of concept study of ganetespib in first-line treatment of women with metastatic breast cancer.

TPS665^ Background: Hsp90 is a chaperone protein required for the activation of several client proteins critical to breast cancer growth and aggressiveness, including HER2, HIF1-α, EGFR, ER, PI3K, AKT, p53 and VEGFR. Ganetespib, a novel Hsp90 inhibitor, has preclinical activity in HER2+, ER+/PR+ and triple negative breast cancer (TNBC) models. Clinical trials showed a favorable safety profile with early signals of activity in patients (pts) with HER2+ disease, as well as TNBC. The ENCHANT-1 trial aims to further evaluate ganetespib single-agent activity in metastatic breast cancer (mBC) and identify biomarkers predictive of outcome. Methods: ENCHANT-1 is an international, Phase 2 study in 1st line mBC. Pts are assigned to one of the following 3 cohorts: Cohort A, HER2 amplified (n=35), Cohort B, TNBC (n=35), Cohort D, Hormone receptor (HR) positive (n=35). Pts with previously untreated mBC are eligible for treatment with ganetespib twice weekly on a 3 out of 4 wk schedule, for a total of up to 12 wks. HER2+ and HR+ pts must have received prior anti-HER2 therapy and endocrine therapy, respectively. At disease progression, pts will receive combination therapy of weekly ganetespib (150 mg/m2) and weekly paclitaxel (80 mg/m2) on a 3 out of 4 wk schedule. Primary endpoint: ORR assessed using RECIST1.1 criteria. Key secondary endpoints include metabolic response assessed by PET/CT at wk 3 utilizing modified EORTC criteria. Tumor genetic signature and proteomic profiling are performed on patient’s tumors in an effort to develop biomarkers of response. At the time of submission, a total of 46 pts were enrolled; TNBC (n= 38) and HER2+ (n=8). Clinical trial information: NCT01677455.

Classification of and Risk Factors for Estrogen Deprivation Pain Syndromes Related to Aromatase Inhibitor Treatments in Women With Breast Cancer: A Prospective Multicenter Cohort Study

Aromatase inhibitors (AIs) are the first-line treatment in women with breast cancer for total estrogen depletion. Half the treated women may develop pain, and this condition may therefore be seen as a clinical model of pain related to estrogen deprivation. In this prospective multicenter study, we classified AI-related pain syndromes and identified their predictors. A 1-year, prospective, multicenter cohort study, with 6 visits, was carried out on 135 women with early-stage breast cancer and no pain at the start of AI treatment. At initial assessment, we investigated clinical (demographic and psychosocial, cancer characteristics and treatment, sleep, quality of life), biological (sex hormones, vitamin D, bone biomarkers, oxidative stress, immunologic and inflammatory markers), environmental, and genetic (polymorphism for pain mechanisms) risk factors for pain. During 1 year of follow-up, 77 women (57%) developed pain, leading to AI discontinuation in 12 cases. Five pain syndromes were identified: joint pain (36%), diffuse pain (22%), tendinitis (22%), neuropathic pain (9%), and mixed pain (11%), which are mostly persistent (57%), with diffuse and joint pains the most intense. Risk factors for the development of pain included higher levels of anxiety and impaired quality of life at the initial assessment, whereas cancer characteristics, genetic background, inflammation, and immunologic and hormonal status at baseline were not significant predictors. PerspectiveThis article presents a classification of AI–related pain syndromes induced by estrogen deprivation that were previously described as arthralgia, but not as neuropathic, diffuse, and mixed pain. This estrogen deprivation–related condition represents a clinical model of pain, and our study identified mostly psychological risk factors for pain development.

The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate – a randomised controlled trial

BackgroundClomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI.Methods/DesignWe started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI.Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included.Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total).An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm).DiscussionThe trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women.Trial registration numberNetherlands Trial register NTR1449

A multicenter phase I–II study of docetaxel plus epirubicin plus bevacizumab as first-line treatment in women with HER2-negative metastatic breast cancer

PurposeTo assess the efficacy and toxicity of docetaxel (D) plus epirubicin (E) in combination with bevacizumab (B) [DEB regimen] as front-line treatment in patients with metastatic breast cancer (MBC). Patients and methodsWomen with previously untreated HER2-negative MBC received B (15 mg/kg), E (75 mg/m2) and D (75 mg/m2) with prophylactic G-CSF support every 3 weeks (q3w) for up to 9 cycles followed by B (15 mg/kg q3w) until disease progression. Primary endpoint was the overall response rate (ORR). Circulating tumor cells (CTCs) were evaluated using the CellSearch system at different time points during therapy. ResultsEighty-three women were enrolled with median age 62 years, performance status 0–1 in 93%, triple negative disease in 12% and liver metastases in 47%. In an intention to treat analysis, complete response was achieved in 13 (15.7%) and partial response in 42 (50.6%) (overall response rate 66.3%; 95% CI 56.09–76.44%). The median time to progression was 20.1 months and the 1-year overall survival rate 82.3%. Grade 3–4 neutropenia occurred in 37%, febrile neutropenia in 10%, anemia in 4%, thrombocytopenia in 2% and diarrhea in 2% of patients. There were two deaths possibly related to study treatment (sigmoid perforation n = 1; sudden death n = 1). Moreover, one patient developed pulmonary embolism and another one myocardial infarction while on treatment. Although DEB administration significantly reduced the proportion of patients presenting CTCs, the detection of ≥5 or ≥1 CTCs before treatment initiation was significantly associated with worse progression-free survival (p = 0.001 and p = 0.004) and overall survival (p = 0.001 and p = 0.027), respectively. ConclusionsThe DEB regimen is a very active but also potentially toxic combination in MBC. Detection of CTCs before treatment is associated with worse outcome. Clinicaltrials.govNCT00705315

Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer.

Ovarian cancer is the eighth most common cancer in women and it is usually diagnosed at an advanced stage. The majority of ovarian tumours are epithelial in origin. Women with relapsed epithelial ovarian cancer (EOC) often have a reduced performance status with a limited life expectancy, therefore maintaining quality of life with effective symptom control is the main purpose of treatment. Drug treatment of relapsed disease is directed by the platinum-free interval: relapsed platinum-sensitive disease is usually re-treated with platinum-based therapy and platinum-resistant disease challenged with non-platinum drugs. However, the side-effects of chemotherapy agents may be severe and optimal treatment regimens are unclear. Pegylated liposomal doxorubicin (PLD), which contains a cytotoxic drug called doxorubicin hydrochloride is one of several treatment modalities that may be considered for single-agent treatment of relapsed EOC, or used in combination with other drugs. To assess the efficacy and safety of PLD in women with relapsed epithelial ovarian cancer (EOC). We searched the Cochrane Gynaecological Cancer Group (CGCG) trials register, CENTRAL, MEDLINE and EMBASE from 1990 to February 2013. We also searched online registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. Randomised controlled trials (RCTs) that evaluated PLD in women diagnosed with relapsed epithelial ovarian cancer. Two review authors independently abstracted data to a pre-designed data collection form and assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions guidelines. Where possible, we pooled collected data in meta-analyses using RevMan 5.2 software. We included 14 RCTs that evaluated PLD alone or in combination with other drugs. Four RCTs contributed no data to the meta-analyses. Two studies compared PLD plus carboplatin (carbo) to paclitaxel (PAC)/carbo in women with platinum-sensitive relapsed EOC. Overall survival (OS) was similar for these treatments, however progression-free survival (PFS) was longer with PLD/carbo (1164 participants; hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.74 to 0.97; I² = 7%; P value 0.01). PLD/carbo was associated with significantly more anaemia and thrombocytopenia than PAC/carbo, whereas PAC/carbo was associated with significantly more alopecia, neuropathies, hypersensitivity reactions and arthralgias/myalgias. PLD/carbo was well-tolerated and women receiving this treatment were significantly less likely to discontinue treatment than those receiving PAC/carbo (two studies, 1150 participants; risk ratio (RR) 0.38, 95% CI 0.26 to 0.57; I² = 0%; P < 0.00001).Five studies compared other agents to PLD alone. None of these agents were associated with significantly better survival or severe adverse-event profiles than PLD. Topotecan and gemcitabine were associated with significantly more haematological severe adverse events than PLD, and patupilone was associated with significantly more severe neuropathies and diarrhoea. Severe hand-foot syndrome (HFS) occurred consistently more frequently with PLD than the other drugs.Three studies compared PLD combination treatment to PLD alone. Two combinations resulted in a significantly longer PFS compared with PLD alone: trabectedin (TBD)/PLD (one study, 672 women; HR 0.79, 95% CI 0.65 to 0.96; P value 0.02) and vintafolide (EC145)/PLD (one study, 149 women; HR 0.63, 95% CI 0.41 to 0.97; P value 0.04). TBD/PLD appeared to benefit the partially platinum-sensitive subgroup only. Further studies are likely to have an important impact on our confidence in these estimates. TBD/PLD was associated with significantly more haematological and gastrointestinal severe adverse events than PLD alone, whereas EC145/PLD appeared to be well-tolerated.For platinum-resistant relapsed EOC, the median PFS and OS for single-agent PLD across seven included studies was 15 weeks and 54 weeks, respectively. Severe HFS occurred significantly more frequently in women receiving a 50 mg/m² dose of PLD than those receiving less than 50 mg/m² (17% versus 2%, respectively; P value 0.01). In platinum-sensitive relapsed epithelial ovarian cancer, PLD/carbo is more effective than PAC/carbo and is better tolerated; PLD/carbo should therefore be considered as first-line treatment in women with platinum-sensitive relapsed EOC. PLD alone is a useful agent for platinum-resistant relapsed EOC, however it remains unclear how it compares with other single agents for this subgroup and in what order these agents should be used. There is insufficient evidence to support the use of PLD in combination with other agents in platinum-resistant relapsed EOC.

Double-blind, randomized, parallel group, phase III study to demonstrate equivalent efficacy and comparable safety of CT-P6 and trastuzumab, both in combination with paclitaxel, in patients with metastatic breast cancer (MBC) as first-line treatment.

629 Background: CT-P6(C) is an anti-HER2 MoAb, a biosimilar to trastuzumab (T). This trial is a global phase III study to compare C with T, both in combination with paclitaxel (P) as first-line treatment in women with HER2+ MBC. Methods: 475 patients with centrally confirmed HER2+ MBC were randomized to receive either C+P (n=244) or T+P (n=231). Patients had to have a baseline LVEF ≥50% and no history of serious cardiac disease. Study medication was as follows: C or T 8 mg/kg i.v. (day 1), followed by 3-weekly C or T 6 mg/kg. P (175 mg/m23-weekly) was co-administered. The primary endpoint was overall response rate (ORR) as determined by independent review. Pooled analysis with data from phase I/IIb (NCT01084863) and III studies (NCT01084876) was predefined and endorsed by the EMA. Patient safety was monitored throughout the study by an independent data monitoring committee. Treatment was continued until disease progression, death or patient’s withdrawal. Results: In the pooled ITT population, ORR was 57% for C+P and 62% for T+P (difference: 5%; 95% CI: -0.14, 0.04) during the first 8 cycles of treatment. The limits of the 95% CIs for the difference in the proportions of responders were contained within the pre-defined range [-0.15, 0.15] required for equivalence. Median time to progression and median time to response were 11.07 vs. 12.52 months (P =0.10), and 1.38 vs. 1.38 months (P =0.37) for C+P and T+P, respectively. Frequency of treatment-related AEs is shown in the Table. Conclusions: Equivalence of C and T was observed for ORR in patients with HER2+ MBC in combination with P as first-line therapy. Secondary efficacy endpoints also supported the comparability between C and T. C was well tolerated with a safety profile comparable to that of T. Clinical trial information: NCT01084876. [Table: see text]

Spotlight on Denosumab in Postmenopausal Osteoporosis†

Denosumab (Prolia®) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU, and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function, and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral, and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.

Tesetaxel, an advanced-generation oral taxane, as first-line treatment in women with metastatic breast cancer.

TPS123 Background: Taxanes such as docetaxel and paclitaxel are among the most active agents in metastatic breast cancer (MBC). Tesetaxel is an active novel taxoid that overcomes disadvantages of these standard agents. Among other features, the drug is taken by mouth as an oral capsule. Tesetaxel is not a substrate for P-glycoprotein, a major cause of taxane resistance. The drug is not associated with hypersensitivity reactions, thus obviating the need for both premedications and extended medical/nursing observation. Preclinical studies in human tumor xenografts show activity in taxane-resistant BC as well as reduced peripheral neuropathy. In dose-ranging studies, 8 of 13 evaluable patients (pts) (62%) with MBC achieved prolonged stable disease (SD) (i.e., up to 24 cycles) when the drug was administered once every 3 weeks (wks). A phase II trial of tesetaxel (27-35 mg/m2 p.o. Q3 wks) showed a 38% partial response (PR) rate among 34 pts who had progressed after an anthracycline-containing regimen. Based on these favorable data, we have initiated a multicenter study to assess the efficacy and safety of tesetaxel as 1st-line therapy in MBC. Methods: Eligible patients have: Stage IV, HER2-negative MBC; ECOG PS 0-1; adequate organ function; no prior chemotherapy for MBC, although 1 adjuvant regimen is allowed. Tesetaxel is administered Q3 wks at a starting dose of 27 mg/m2 p.o., which can be increased to 35 mg/m2 depending on tolerability. A Simon mini-max two-stage design is being used. Target accrual is 25 pts. Response rate, per RECIST 1.1 criteria, is the primary endpoint. Other objectives include progression-free survival and safety. Assuming initial results are favorable, we will examine a weekly dosing schedule in a second pt cohort.

Use of Diuretics in Women for Management of Hypertension

Cardiovascular disease remains the number one killer of women in the United States. Hypertension is considered a major cardiovascular risk factor, but remains poorly controlled in women. Thiazide diuretics are recommended as first line treatment in women with hypertension based on numerous outcomes studies demonstrating decreased risk of cardiovascular events. However, despite definitive evidence demonstrating clinical benefits and generic availability, diuretic-based therapy is underutilized. This article will focus on the role of thiazide diuretics for hypertension, discuss the mechanism by which diuretics lower blood pressure, describe outcomes studies that support their use in women, and provide practical considerations for use and monitoring. Keywords: Cardiovascular disease, blood pressure, diuretics, hypertension, thiazides, women

Denosumab

Denosumab (Prolia®) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.

Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer

BackgroundThe purpose of this study was to compare docetaxel plus epirubicin versus docetaxel plus capecitabine combinations as front-line treatment in women with advanced breast cancer (ABC). Patients and MethodsPreviously untreated patients with ABC were randomly assigned to receive docetaxel 75 mg/m2 plus epirubicin 75 mg/m2 (DE) on day 1 or docetaxel 75 mg/m2 on day 1 plus capecitabine 950 mg/m2 orally twice daily on days 1–14 (DC) in 21-day cycles. Previous anthracycline-based (neo)-adjuvant chemotherapy was allowed if completed >1 year before enrollment. The primary objective of the study was to compare time to disease progression (TTP). ResultsOne hundred and thirty-six women were treated on each arm and median TTP was 10.6 versus 11.0 months (P = 0.7), for DE and DC, respectively. According to RECIST criteria we observed 15 (11%) versus 11 (8%) complete responses and 55 (40%) versus 61 (45%) partial responses (P = 0.8), with DE and DC, respectively. Severe toxicity included grade 3–4 neutropenia (57% versus 46%; P = 0.07), febrile neutropenia (11% versus 8%; P = 0.4), hand–foot syndrome (0% versus 4%; P = 0.02), grade 2–3 anemia (20% versus 7%; P = 0.001) and asthenia (12% versus 6%; P = 0.09) with DE and DC, respectively. ConclusionsThe DE and DC regimens have similar efficacy but different toxicity. Either regimen can be used as front-line treatment of ABC.

Phase III Studies of Bevacizumab (B) in Combination with Chemotherapy in Patients with HER2-Negative Metastatic Breast Cancer (MBC): Summary of Selected Adverse Events.

Abstract BackgroundA number of chemotherapy agents are used in the first-line treatment of patients with HER2-negative MBC. Three multicenter, randomized Phase III trials have demonstrated significant improvements in progression-free survival (PFS) when adding B to chemotherapy (C) in the first line treatment of women with MBC. These include E2100 (n=722), an open-label trial evaluating weekly paclitaxel (P) +/- B 15 mg/kg; AVADO (n=736), a placebo-controlled, double-blind trial evaluating docetaxel every 3 weeks +/- B 7.5mg/kg or B 15 mg/kg; RIBBON-1 (n=1237), a placebo-controlled, double-blind trial assessing capecitabine (C), Taxane (T) or Anthracycline (A) +/- B 15 mg/kg.Bevacizumab has a characteristic safety profile across a number of different tumor types when used as either a single agent or in combination with chemotherapy. Selected adverse events from breast cancer phase III trials will be summarized to show how different types of chemotherapy affect the adverse event (AE) rates in the first-line MBC setting.MethodsGrade 3–5 non-hematological events and Grade 4 or 5 hematological events using the NCI-CTC Version 2 (E2100) and the NCI CTCAE Version 3 (AVADO and RIBBON-1) are recorded and are summarized for B-related AEs by individual treatment arm from these three studies. These AEs included arterial tumor embolism (ATE), gastrointestinal perforation, hypertension, left ventricular systolic dysfunction, venous thromboembolism, proteinuria, bleeding, and wound-healing complications.ResultsAnalyzing the incidence of known B-related AEs in the placebo arms and B-containing arms of the E2100, AVADO, and RIBBON-1 studies, we found that hypertension ranged from 0 to 2% for patients in the placebo arms and from 2.8 to 16% for patients in the B-containing arms (E2100, 16.0%; the AVADO study, B 7.5 mg/kg cohort, 0%; the AVADO study B 15 mg/kg cohort, 2.8% for; the RIBBON-1 capecitabine cohort, 9.4%; the RIBBON-1 taxane cohort, 8.9%; and the RIBBON-1 anthracycline cohort, 10.0%). For all other B-related AEs the differences between the placebo arms and the B-containing arms were of smaller magnitude. Treatment discontinuation rates in the B-containing arms varied across trials, ranging from 11.9% to 27.9% compared with 4.0 to 19% for the placebo arms. By chemotherapy backbone, treatment discontinuation rates for patients receiving B were higher relative to the placebo arm for the taxane cohort (7.8% vs. 24.1%) and the anthracycline cohort (4.0% vs. 14.3%). There was no difference in treatment discontinuations for patients in the capecitabine cohort (11.9% for both arms).ConclusionsThe addition of B to chemotherapy is associated with an increased frequency of selected adverse events that have been observed across randomized MBC studies. Treatment discontinuation rates for adverse events vary across trials and may be a function of the chemotherapy agent, dose, and schedule. With the exception of hypertension, bevacizumab-related Grade 3–5 adverse events occurred in fewer than 5% of patients. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6083.

Phase II Trial of Docetaxal Plus Imatinib Mesylate in the Treatment of Patients With Metastatic Breast Cancer

Background Inhibition of the platelet-derived growth factor receptor (PDGFR) might improve the efficacy of chemotherapy by lowering interstitial tumor pressure and allowing increased tumor penetration by cytotoxic agents. In this phase II trial, we added imatinib, a PDGFR inhibitor, to docetaxel in the first-line treatment of women with metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received a maximum of 1 previous chemotherapy regimen were eligible for this trial. Initially, patients received oral imatinib 600 mg daily and docetaxel 30 mg/m 2 on days 1, 8, and 15 of a 28-day cycle. The imatinib dose was lowered from 600 mg to 400 mg daily because of toxicity (primarily gastrointestinal) observed in the first 15 patients. Patients were evaluated for response (Response Evaluation Criteria in Solid Tumors) after 8 weeks of therapy; treatment continued in responding/stable patients until tumor progression or unacceptable toxicity. The primary endpoint was the overall response rate. Results Thirty-seven patients entered this trial between May 2005 and March 2008. This regimen was relatively poorly tolerated, even after reduction of the imatinib dose, primarily because of gastrointestinal toxicity (nausea, vomiting, and diarrhea). Eight patients (22%) stopped therapy because of toxicity before the 8-week initial evaluation. Six of 37 enrolled patients (16%; 95% CI, 4.3%-28.1%) had partial responses; an additional 4 patients had stable disease for > 6 months. The median progression-free and overall survivals were 9.3 months and 15.4 months, respectively. Conclusion When compared with previous results with single-agent docetaxel, the combination of weekly docetaxel plus imatinib was tolerated relatively poorly and produced a low objective response rate. The efficacy of weekly docetaxel is not improved by concurrent administration of imatinib as a PDGFR inhibitor.

A Phase II Randomized Crossover Study of Liposomal Doxorubicin Versus Weekly Docetaxel in the First-line Treatment of Women With Metastatic Breast Cancer

Purpose We aim to compare the efficacy and toxicity of liposomal doxorubicin and weekly docetaxel as first-line treatments for patients with metastatic breast cancer (MBC). Patients and Methods Patients who had received no previous chemotherapy for MBC were eligible. Previous hormonal therapy, adjuvant chemotherapy, and radiation therapy were allowed. Patients were randomized to receive liposomal doxorubicin 40 mg/m 2 intravenously [I.V.] every 28 days orweekly docetaxel 36 mg/m 2 I.V. days 1, 8, and 15, repeated every 28 days. Patients with objective response or stable disease after 2 cycles continued treatment until tumor progression or unacceptable toxicity. At progression, patients were allowed to cross over to the other regimen. The trial was designed to detect a true difference of 10% in response rate with an 80% power. Results Between March 2001 and July 2007, 102 patients were randomized. The 2 groups had similar demographics; 68% of patients had received previous adjuvant chemotherapy. Liposomal doxorubicin and weekly docetaxel produced similar objective response rates (28% vs. 31%), disease control rates (48% vs. 44%), and progression-free survival (6.5 months vs. 5.5 months). Both agents were well tolerated. Both agents produced crossover responses as second-line treatment (liposomal doxorubicin, 35%; weekly docetaxel, 14%). Conclusion Liposomal doxorubicin is well tolerated and has activity similar to weekly docetaxel in the first-line treatment of patients with MBC.

Valproate Linked to Increased Prenatal Risks

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessValproate Linked to Increased Prenatal RisksJun YanJun YanSearch for more papers by this authorPublished Online:15 May 2009https://doi.org/10.1176/pn.44.10.0023Valproate, an epilepsy drug also used to treat bipolar disorder, is linked to lower IQ scores at age 3 in children exposed to the drug before birth than in children whose mothers took other antiepileptic drugs during pregnancy, a study published in the April 4 New England Journal of Medicine showed.From 1999 to 2004, U.S. and U.K. researchers enrolled 303 pregnant women with epilepsy who were taking lamotrigine, phenytoin, carbamazepine, or valproate in a prospective, observational study known as the Neurodevelopmental Effects of Antiepileptic Drugs study. The researchers conducted follow-up assessments, especially in terms of neurological development, in the children. Women who were not taking any antiepileptic drugs during pregnancy were not included.The average IQ score of 3-year-old children who had in utero exposure to valproate was 92, which was statistically significantly lower than that of children exposed to lamotrigine (average IQ 101), phenytoin (99), or carbamazepine (98). The comparisons among lamotrigine, phenytoin, and carbamazepine were not statistically different. The authors also found a dose-dependent relationship between valproate and IQ score.That valproate exposure carries a higher risk of birth defects than other antiepileptics, such as lamotrigine and carbamazepine, is not new knowledge, Torbjorn Tomson, M.D., a professor of clinical neuroscience at the Karolinska Institute in Sweden, pointed out in an editorial. The worthwhile discovery of this study was the differential effects on children's long-term cognitive development associated with various antiepileptics. This was the largest prospective study so far on the effects of antiepileptics on cognitive development.This study was reported in several media outlets, including the New York Times and the Associated Press, with broad headlines such as“ I.Q. Harmed by Epilepsy Drug in Utero,” without clearly presenting the context that the study was a comparison between valproate and other antiepileptic drugs.Untreated epilepsy, as well as untreated bipolar disorder, poses a significant risk of harm to pregnant women and their fetuses. For many pregnant patients, stopping medication is not an option. Therefore, accurately describing the different risks among drugs in the same class is critically important for physicians and patients. The authors concluded that valproate should not be used as a first-line treatment for women who are pregnant or may become pregnant. In addition, “discussion of the risks of valproate should be balanced with consideration of the risks of uncontrolled seizures,” Tomson recommended.An abstract of “Cognitive Function at 3 Years of Age After Fetal Exposure to Antiepileptic Drugs” is posted at<content.nejm.org/cgi/content/short/360/16/1597>.▪ ISSUES NewArchived

Treatment of endometriosis-related pain options and outcomes

Endometriosis-associated pain represents a challenge for both the patient and the health care provider since it is often difficult to design treatment strategies resulting in improvement of the symptoms. The association between endometriosis stage and severity of pelvic symptoms is limited. Surgery is generally considered the first line treatment in women affected, at least in those who have not been previously operated, but there are several situations in which medical treatments are useful. Given their good tolerability, minor metabolic effects and low cost, progestogens with or without the addition of estrogens, can be considered the drugs of choice and are currently the only safe and inexpensive alternative to surgery. Progestogens are effective in controlling pain symptoms in approximately three of four women with endometriosis. There is little or no difference in the effectiveness of GnRH agonist and add-back treatment in comparison with other medical treatments for endometriosis while the surgical interruption of pelvic nerve pathways entail some clinically relevant risks.

Clinicians' views on the NICE guideline on the management of female urinary incontinence

SummaryIn October 2006, the National Institute for Health and Clinical Excellence (NICE) released Guideline No. 40: The management of female urinary incontinence. The objective of this study was to investigate the opinions of members of the British Society of Urogynaecology (BSUG) regarding the recommendations contained in the guideline. A closed format questionnaire using stems taken directly from the NICE guideline was sent to all UK-based members of BSUG. There was a 64% response rate. When asked if the guidance overall reflected their current practice, 56.8% agreed/strongly agreed. In terms of changing their practice to comply fully with the guideline, 53.3% disagreed/strongly disagreed. There were two major areas of disagreement. Some 80% of respondents disagreed that preoperative cystometry was not necessary in ‘clinically pure’ stress urinary incontinence; 72% of respondents disagreed that immediate release oxybutynin should be the first-line treatment for women with an overactive bladder (OAB). A smaller proportion disagreed with the statements on the use of duloxetine. The majority of the guidance formalises current practice among gynaecologists and urogynaecologists practicing in the UK. There are significant concerns regarding some of the recommendations, and the results indicate that over half of the respondents would not change their practice to follow these recommendations.