First-line Therapy For Women Research Articles

Les hyperplasies de l’endomètre

Endometrial hyperplasias can be divided into two categories based on the presence or absence of cytological atypia and further classified as simple or complex according to the extent of architectural abnormalities. They are usually diagnosed because of irregular bleeding in perimenopause. Hysteroscopy with a biopsy gives a more accurate diagnosis than transvaginal ultrasonography, sonohysterography, or blind curettage. Endometrial hyperplasias with no cytological atypia, regarded as a response to unopposed endogenous estrogenic stimulation, are normally treated with progestins. The intra-uterine route (levonorgestrel intra-uterine system) is more effective and better tolerated than the oral route. Either conservative surgery (endometrial resection, thermal ablation) or radical surgery (hysterectomy) in the case of other genital diseases is performed on women who did not respond to medical treatment. Endometrial hyperplasias with cytological atypia, considered as intra-epithelial neoplasias, are traditionally treated by hysterectomy. The absence of management protocols in the literature offers various treatment options and indications. Gonadotropin-releasing hormone agonists, danazol, or aromatase inhibitor are effective, but have adverse effects and are expensive. Endometrial ablation can be performed as a first line therapy in women suffering from bleeding related to hyperplasia without cytological atypia. Medical treatment may be offered to young women suffered from hyperplasias with cytological atypia and desiring pregnancy.

Phase II Trial of Capecitabine and Weekly Paclitaxel As First-Line Therapy for Metastatic Breast Cancer

The taxanes and capecitabine have synergistic antitumor activity in preclinical models. This trial was designed to determine the efficacy and tolerability of weekly paclitaxel plus capecitabine as first-line treatment for metastatic breast cancer (MBC). Participants had histologically proven breast cancer, with measurable metastatic disease by Response Evaluation Criteria in Solid Tumors Group. Exclusion criteria included prior taxane therapy or any prior capecitabine or infusional fluorouracil. Participants received capecitabine 825 mg/m2/dose orally bid (1,650 mg/m2/d) for days 1 to 14. Paclitaxel 80 mg/m2 was administered intravenously weekly on days 1 and 8. Cycles were repeated every 3 weeks. Responders (complete or partial) or those with stable disease were treated until progression of disease or intolerable toxicity. Fifty-five women were enrolled; 94% received study therapy as first-line treatment for MBC. In the intent-to-treat population, objective responses (partial) were achieved in 30 patients (55%; 95% CI, 40% to 69%), and six additional patients had stable disease for 6 months or longer (clinical benefit rate of 65%). The median duration of response was 10 months (range, 2.5 to 18.7 months). Dose modifications and reductions were common, particularly for capecitabine, leading to a delivered dose-intensity of 75% for capecitabine and 91% for paclitaxel. The most frequent grade 3 to 4 treatment-related adverse events were hand-foot skin reaction (n = 10); neutropenia (n = 7); fatigue (n = 4); and leukopenia, diarrhea, and pain (n = 3 each). Capecitabine in combination with weekly paclitaxel is an active and tolerable regimen as first-line therapy for women with MBC.

Randomized Phase III Study of Trastuzumab, Paclitaxel, and Carboplatin Compared With Trastuzumab and Paclitaxel in Women With HER-2–Overexpressing Metastatic Breast Cancer

This randomized, multicenter, phase III trial evaluated the efficacy and safety of trastuzumab and paclitaxel with or without carboplatin as first-line therapy for women with HER-2-overexpressing metastatic breast cancer (MBC). HER-2 overexpression was defined as immunohistochemical staining scores of 2+ or 3+. Between November 1998 and May 2002, 196 women with HER-2-overexpressing MBC were randomly assigned to six cycles of either trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m2 every 3 weeks (TP), or trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m2 and carboplatin area under the time-concentration curve = 6 every 3 weeks (TPC) followed by weekly trastuzumab alone. Baseline characteristics of the 196 patients were well balanced between study arms. Objective response rate (ORR) was 52% (95% CI, 42% to 62%) for TPC versus 36% (95% CI, 26% to 46%) for TP (P = .04). Median progression-free survival (PFS) was 10.7 months for TPC and 7.1 months for TP (hazard ratio [HR], 0.66; 95% CI, 0.59 to 0.73; P = .03). Improved clinical outcomes with TPC were most evident in HER-2 3+ patients, with an ORR of 57% (95% CI, 45% to 70%) v 36% (95% CI, 25% to 48%; P = .03) and median PFS of 13.8 v 7.6 months (P = .005) for TPC and TP, respectively (HR, 0.55; 95% CI, 0.46 to 0.64). Both regimens were well tolerated, and febrile neutropenia and neurotoxicity occurred infrequently; grade 4 neutropenia occurred more frequently with TPC (P < .01). The addition of carboplatin to paclitaxel and trastuzumab improved ORR and PFS in women with HER-2-overexpressing MBC. This well-tolerated regimen represents a new therapeutic option.

Uterine Fibroid Embolization

Uterine fibroid embolization (UFE) is a minimally invasive therapy for the treatment of symptomatic uterine fibroids and offers an alternative to conventional myomectomy and hysterectomy. This review focuses on recent publications evaluating UFE and concludes that it is a safe treatment option, providing substantial improvement in both health-related quality of life and symptom control for most patients, with a very low rate of major complications. The durability of these outcomes appears similar to those obtained with myomectomy; however, a direct comparative long-term study is needed. Recent comparative studies have begun to provide more insight in to UFE outcomes compared with outcomes achieved with myomectomy and hysterectomy. UFE should be considered a first line therapy for women with symptomatic uterine fibroids. Additional research will continue to provide us with information as to the ideal candidates for UFE and may provide us with better tools to predict patient outcomes.

Two Concurrent Phase II Trials of Paclitaxel/Carboplatin/Trastuzumab (Weekly or Every-3-Week Schedule) as First-Line Therapy in Women with HER2-Overexpressing Metastatic Breast Cancer: NCCTG Study 983252

Purpose The efficacy and tolerability of 2 different schedules of paclitaxel/carboplatin/trastuzumab for HER2-overexpressing metastatic breast cancer (MBC) were evaluated in this parallel multicenter phase II trial. Patients and Methods Patients received every-3-week therapy (n = 43) consisting of a 200 mg/m 2 dose of paclitaxel/carboplatin area under the curve (AUC) of 6 mg/mL per minute and trastuzumab (an initial 8 mg/kg dose and subsequent 6 mg/kg doses) administered every 21 days for 8 cycles or weekly therapy (n = 48) consisting of an 80-mg/m 2 dose of paclitaxel/carboplatin AUC of 2 mg/mL per minute for 3 of 4 weeks, with weekly trastuzumab (an initial 4-mg/kg dose and subsequent 2-mg/kg doses) administered every 4 weeks for 6 cycles. Trastuzumab was continued until disease progression or unacceptable toxicity. HER2 status was confirmed by a central laboratory review. Results The overall response rate (ORR) with every-3-week therapy was 65% (90% confidence interval [CI], 51%–77%), with a median time to disease progression of 9.9 months and median overall survival (OS) time of 2.3 years. The ORR with weekly therapy was 81% (90% CI, 70%–90%), with a median time to disease progression of 13.8 months and a median OS time of 3.2 years. Hematologic and nonhematologic toxicities occurred significantly less frequently with weekly therapy versus every-3-week therapy: grade 3/4 neutropenia (52% vs. 88%); grade 3 thrombocytopenia (4% vs. 30%); and grade 3 neurosensory toxicity (2% vs. 19%), respectively. Conclusions Every-3-week and weekly regimens of paclitaxel/carboplatin/trastuzumab are highly active in women with HER2-overexpressing MBC. However, fewer patients developed severe neutropenia, leukopenia, or thrombocytopenia with the weekly schedule.

A Phase II Trial of Docetaxel and Carboplatin as First-Line Chemotherapy for Metastatic Breast Cancer: NCCTG Study N9932

Objective: A phase II multi-institutional clinical trial conducted to evaluate the efficacy and tolerability of docetaxel and carboplatin as first-line therapy for women with metastatic breast cancer. Methods: Patients had histologically confirmed metastatic breast cancer with at least one measurable lesion. Prior adjuvant chemotherapy was permitted, provided that at least 12 months had elapsed between any prior taxane and platinum therapy. Patients received docetaxel 75 mg/m² with carboplatin AUC 6 mg/ml·min every 21 days until disease progression or prohibitive toxicity. Results: All 53 patients enrolled were evaluable for response and toxicity. Median number of cycles delivered was 6. Overall response rate was 60%, with 3 complete responses (6%) and 29 partial responses (54%). Median time to disease progression was 9.6 months. Median survival time was 20.4 months. Myelosuppression was the predominant toxicity, with grade 3 or 4 neutropenia occurring in 94% of patients and 15% of patients experiencing febrile neutropenia. The overall incidence (grades 1–3) of neurosensory toxicity was 57% and neuromotor toxicity was 25%, respectively, with grade 3 toxicity occurring in 4% of patients each. Conclusions: The combination of docetaxel and carboplatin is highly active in metastatic breast cancer. Prophylactic growth factor support is recommended in any further evaluation of this combination in the treatment of patients with breast cancer.

Should insulin-sensitizing drugs be used in the treatment of polycystic ovary syndrome?

Insulin resistance is a central feature of polycystic ovary syndrome (PCOS). Hyperinsulinaemia contributes to anovulation, hyperandrogenism, infertility and early pregnancy loss in women with PCOS. Chronic hyperinsulinaemia also predisposes women with PCOS to increased risks of diabetes and cardiovascular events. Current data indicate that metformin, either as monotherapy or in combination with clomiphene in clomiphene-resistant patients, is an effective treatment for anovulation in PCOS. Initial evidence also suggests that insulin sensitizers may have a role in preventing early pregnancy loss. Of the available insulin-sensitizing agents, metformin has been the agent most frequently studied in PCOS, and has the least undesirable pregnancy safety profile. Ameliorating the metabolic syndrome associated with insulin resistance in PCOS with metformin may also prevent long-term cardiovascular and diabetes complications, pending further evidence. Based on these data, metformin should be a first-line therapy for women with PCOS.

Male breast cancer.

Treatments for men with breast cancer are based largely on accepted regimens for women with the disease. Surgical treatment of the primary tumor should be a mastectomy. Lymph node assessment can be done by conventional axillary node dissection or, similar to selected women with small primary tumors, by sentinel node dissection. Decisions regarding adjuvant systemic treatment should be made on the same basis as for women. Axillary node status, tumor size, hormone receptor status, and the health of the patient are important considerations in determining what adjuvant treatment is offered. The role of radiation after mastectomy in men is not well defined, but radiation should be used in patients at high risk for local recurrence. For patients with metastatic disease, treatment is based on the hormone receptor status of the tumor and is similar to the treatment for women. Because most men with breast cancer have hormone receptor-positive disease, hormonal therapy is a mainstay of treatment and tamoxifen remains the front-line drug of choice, although the latest generation of aromatase inhibitors have supplanted tamoxifen as a first-line therapy for women. As a second-line hormonal therapy for men, orchiectomy or a luteinizing hormone-releasing hormone agonist with or without an antiandrogen are reasonable alternatives. There are no reports regarding the use of the antiestrogen fulvestrant in men, but its mechanism of action and efficacy in women suggest that it will be a useful agent in hormone receptor-positive male breast cancer. For men with hormone-resistant disease, palliative chemotherapy with the same agents used for treatment of women with breast cancer is appropriate.

Docetaxel-anthracycline combinations in metastatic breast cancer.

The taxanes and anthracyclines have emerged as the most active agents for treating women with advanced breast cancer. As such, investigation of the two drug classes in combination regimens has been eagerly pursued. The rationale for combining docetaxel with an anthracycline includes high clinical activity of each individual agent, lack of complete clinical cross resistance, and non-overlapping toxicity profiles. Phase II trials of the docetaxel combinations with either doxorubicin or epirubicin showed high activity, with acceptable tolerability in patients with metastatic breast cancer. Consequently, three randomized trials have compared docetaxel-anthracycline-based regimens with standard anthracycline-based polychemotherapies as first-line therapy for women with advanced breast cancer. Improved outcome was reported in favor of the docetaxel-anthracycline combinations, with manageable hematologic toxicity and favorable non-hematologic safety profiles. Therefore, docetaxel-anthracycline combinations represent a validated option in first-line treatment for women with advanced breast cancer, and are further evaluated as adjuvant treatment for early stage breast cancer, with already promising prospects and the potential to change the natural history of breast cancer.

Contemporary management of hyperlipidemia in women.

The objective of this paper is to review prospective, large-scale studies of lipid-lowering therapy and hormone replacement therapy, and to provide clinical recommendations for the management of hyperlipidemia in women within the context of the revised National Cholesterol Education Program (NCEP) guidelines. Recent English language literature derived from a MEDLINE search (January 1990-July 2001) and bibliographies of relevant papers were reviewed, and data were abstracted from identified papers. Hyperlipidemia is largely undertreated in women. Previously, hormone replacement therapy (HRT) was considered first-line treatment for the management of hypercholesterolemia to prevent coronary artery disease (CAD) in women. Recent studies, however, show no benefit of HRT for secondary prevention of coronary events, despite its beneficial effects on lipids. Large-scale, controlled clinical trials indicate that women, even those with only moderately elevated cholesterol, benefit from the lipid-lowering effects of statins for both high-risk primary and secondary prevention of CAD. Based on this evidence, the recently revised NCEP guidelines recommend statins as first-line therapy for women with hyperlipidemia, an approach that is supported by the American Heart Association and the American College of Cardiology. With its emphasis on aggressive intervention for persons with multiple risk factors, the new guidelines substantially increase the number of women eligible for pharmacological therapy. All women with hyperlipidemia should receive counseling regarding lifestyle approaches for lowering cholesterol. The decision to use HRT should be made in the context of other conditions hormones may affect. Alternative hormonal regimens for lipid management may include selective estrogen receptor modulators and phytoestrogens, but results of randomized clinical trials are necessary before firm recommendations can be made regarding their clinical value in preventing CAD.

INSULIN-LOWERING MEDICATIONS IN POLYCYSTIC OVARY SYNDROME

A growing body of evidence suggests that serum hyperinsulinemia contributes to the excess ovarian androgen secretion observed in women with PCOS. As a group, women with PCOS are hyperinsulinemic and insulin resistant when compared with weight-matched normal women, but not all PCOS subjects display clear metabolic defects. The small studies using insulin-sensitizing drugs have demonstrated conclusively that a reduction in serum insulin levels is associated with a reduction of ovarian androgen secretion in PCOS, providing further evidence that hyperinsulinemia contributes to hyperandrogenism by increasing ovarian androgen secretion and reducing SHBG. The improvement of serum androgen levels with multiple different drug classes with different mechanisms of actions suggests an effect mediated by reduction in circulating insulin levels rather than a direct ovarian effect of the drugs. Although the studies published to date have increased understanding of the pathophysiologic mechanisms of PCOS, before these drugs can be recommended as first-line therapy for women, longer term clinical trials are needed to compare their safety and efficacy with other established therapies, such as oral contraceptive pills and antiandrogens. Because of the potential direct and unique beneficial effects of these medications on metabolism, studies must be performed to evaluate their efficacy in combination with other therapies, especially oral contraceptives. It is likely that subsets of patients who cannot tolerate traditional medications will be better managed with insulin sensitizers as first-line therapy; however, to date, the optimal way to identify these subjects is unknown. Whether therapy should be limited to subjects with documented hyperinsulinemia also remains unknown.

A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma

BACKGROUND This Phase II multicenter study evaluated the efficacy and toxicity of paclitaxel (200 mg/m2 by 3-hour infusion) with carboplatin (area under the curve 6 mg/mL per minute) administered every 3 weeks as first-line therapy for women with metastatic breast carcinoma. METHODS Eligible patients had measurable metastatic disease and an Eastern Cooperative Oncology Group performance status of 0–2. Prior adjuvant chemotherapy, including anthracycline-based therapy, was allowed, as was prior hormonal therapy as part of either adjuvant treatment or treatment for metastasis. Prior therapy with taxanes or platinum was not allowed. RESULTS A total of 53 patients were enrolled in this study, with 50 patients evaluable for response and toxicity. The overall response rate was 62% (95% confidence interval [CI], 48–75%); 16% of patients had complete responses and 46% had partial responses. The median time to progression was 7.3 months (95% CI, 5.9–12.9), and the 12-month survival estimate was 72% (95% CI, 61–86%). Therapy was generally well tolerated. Grade 3–4 neutropenia was the predominant toxicity, observed in 82% of patients, but there were no episodes of febrile neutropenia or sepsis. Hematopoietic growth factors were not routinely necessary. Grade 3 peripheral neuropathy occurred in 16% of patients. CONCLUSIONS Paclitaxel (200 mg/m2) with carboplatin (area under the curve 6 mg/mL per minute) demonstrated substantial efficacy in patients with metastatic breast carcinoma, and the 12-month survival rate of 72% was encouraging. This therapy represents a viable option for patients with metastatic disease. Cancer 2000;88:124–31. © 2000 American Cancer Society.

Paclitaxel plus doxorubicin as first-line treatment for breast cancer?

Paclitaxel in combination with doxorubicin significantly prolongs median time to disease progression in patients with metastatic breast cancer, according to the results of a multinational phase III study.1The combination also improves overall survival. The study, which was presented at the 10th European Conference on Clinical Oncology [Vienna, Austria; September 1999] compared the paclitaxel and doxorubicin combination with fluorouracil plus doxorubicin and cyclophosphamide (FAC), which is considered to be standard first-line therapy for women with metastatic disease. Patients who received paclitaxel plus doxorubicin had a significantly longer time to disease progression, greater response to treatment and improved overall survival duration, compared with patients who received FAC. Leading investigators from the trial say that the paclitaxel regimen is superior to the FAC regimen, and warrants immediate further development.

Vinorelbine as first-line chemotherapy for advanced breast cancer in women 60 years of age or older

Older patients with advanced breast cancer are less likely to receive chemotherapy than younger patients. Vinorelbine is an attractive alternative in this setting because of its clinical activity and low frequency of side effects. This multicenter, phase II trial was designed to assess the safety and efficacy of intravenous vinorelbine as first-line therapy in women > or = 60 years old. Fifty-six women (median age, 72 years; range 60-84 years), with measurable advanced breast cancer and no prior chemotherapy for metastatic disease, were enrolled and included in the analysis. Vinorelbine 30 mg/m2 was administered weekly for 13 weeks and then every two weeks until development of progressive disease; doses were reduced or delayed to manage toxicity. The objective response rate was 38% (95% confidence interval (95% CI): 24%-51%); median duration of response, nine months; median time to disease progression in all patients, six months. The major dose-limiting toxicity was hematologic, which led to a median dose intensity of 20.6 mg/m2/week. Grade 3-4 nonhematologic toxicity consisted of asthenia (7%); nausea and generalized pain (5%); vomiting, chest pain, abdominal pain, and elevated AST (4%); fever, diarrhea, constipation, and injection site reaction (2%). Neurotoxicity and alopecia were grade 1-2 and relatively infrequent. Vinorelbine offers a promising alternative for the management of advanced breast cancer in elderly patients who are concerned about the subjective side effects of cytotoxic chemotherapy. The dose-limiting toxicity is neutropenia, which is readily managed with dose adjustment. Nonhematologic toxicity, including gastrointestinal side effects, is minimal. Randomized studies are warranted to compare the activity of vinorelbine with that of other regimens in elderly patients.

A randomized controlled trial of medroxyprogesterone acetate and psychotherapy for the treatment of pelvic congestion

The value of medroxyprogesterone acetate (MPA) and of psychotherapy in the treatment of lower abdominal pain due to pelvic congestion was assessed in a randomized controlled trial. Eighty-four women with abnormal pelvic venography were assigned to one of four treatment groups: MPA alone, MPA plus psychotherapy, placebo alone, and placebo plus psychotherapy. Women were treated for 4 months and thereafter followed up regularly for 9 months with pain assessments, pelvic ultrasound scanning, and hormone measurements. During treatment, MPA showed a significant benefit in terms of a reduction in visual analogue scale pain score, with 73% of women reporting at least 50% improvement compared with 33% of those treated with placebo. At 9 months after the end of therapy there was no overall significant effect of MPA or psychotherapy, but there was an interaction between MPA and psychotherapy, with 71% of the women in this group showing a greater than or equal to 50% reduction in pain score. Therapy with MPA is a useful first-line therapy for women with pain associated with demonstrable pelvic congestion.