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25.11.2003
 
Newsletter No 24
 
Gynecologic Oncology
  1. Using SERMs and aromatase inhibitors in breast cancer.
  2. Letrozole in postmenopausal women after five years of tamoxifen.
  3. Emerging role of aromatase inhibitors in the adjuvant setting.
  4. Serous borderline tumors of the ovary with noninvasive implants.
Gynecology
  1. Laparoscopic uterosacral ligament resection for dysmenorrhea associated with endometriosis.
  2. Coagulation or excision of ovarian endometriomas?
  3. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea.
  4. Progestogens for endometriosis.
Gynecologic Endocrinology and Reproductive Medicine
  1. Pronuclear morphology and chromosomal abnormalities.
  2. Ureaplasma parvum and Ureaplasma urealyticum in semen.
  3. Polycystic ovaries without PCOS: impact on fertility and fecundity.

1. Using SERMs and aromatase inhibitors in breast cancer.

Breast cancer is one of the most common cancers of women in the Western world. Despite modest achievements in the treatment of this disease, there is a substantial unmet medical need to reduce the occurrence of new breast cancers. In several prospective, placebo-controlled trials, the antiestrogen tamoxifen has been shown to reduce the incidence of both invasive cancer and preinvasive breast lesions. Meanwhile, numerous other selective estrogen receptor modulators (SERMs) are being developed and trials comparing tamoxifen to these agents are ongoing. The goal of these studies is not only to show superior chemopreventive efficacy of the newer SERMs, but also an improved side-effect profile. The proof-of-principle demonstrated with tamoxifen suggests that strategies inhibiting estrogen are a logical way forward in breast cancer prevention. Aromatase inhibitors, which antagonize estrogen by blocking its synthesis from androgens, offer an alternative way of preventing the effects of estrogen and its metabolites on the breast. In this paper, the available data on SERMs including tamoxifen and raloxifene in breast cancer prevention and the data pointing to the efficacy of aromatase inhibitors in this setting are outlined.

Reference

Strassmer-Weippl K, Goss PE. Prevention of breast cancer using SERMs and aromatase inhibitors. J Mammary Gland Biol Neoplasia. 2003 Jan;8(1):5-18.

2. Letrozole in postmenopausal women after five years of tamoxifen.

In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy--but not tamoxifen therapy of longer duration--prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve the outcome after the discontinuation of tamoxifen therapy. The study was a double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with breast cancer who have completed five years of tamoxifen therapy. The primary end point was disease-free survival. A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast--75 in the letrozole group and 132 in the placebo group--with estimated four-year disease-free survival rates of 93 percent and 87 percent, respectively, in the two groups (P< or =0.001 for the comparison of disease-free survival). A total of 42 women in the placebo group and 31 women in the letrozole group died (P=0.25 for the comparison of overall survival). Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P=0.07); the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants. It is concluded that, as compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival. Copyright 2003 Massachusetts Medical Society

Reference

Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 09.

3. Emerging role of aromatase inhibitors in the adjuvant setting.

Aromatase inhibitors (AIs) have been approved as second-line treatment for estrogen receptor-positive (ER+) metastatic breast cancer after first-line treatment with the selective estrogen receptor modulator (SERM) tamoxifen. Anastrozole and letrozole have also recently been widely approved as first-line endocrine therapy for postmenopausal women with hormone receptor-positive metastatic breast cancer. The three third-generation selective oral AIs approved for use in the United States include two nonsteroidal agents, anastrozole (Arimidex) and letrozole (Femara), and the irreversible steroidal inhibitor exemestane (Aromasin). Several major ongoing clinical trials with a variety of treatment regimens are comparing the relative efficacy of tamoxifen with the steroidal and nonsteroidal AIs in the adjuvant setting. The first strategy compares an AI against tamoxifen directly. Among these are the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (anastrozole), the BIG FEMTA (Femara-Tamoxifen Breast International Group) trial (letrozole), and the EXEM and TEAM (exemestane) trials. A second strategy is examining the use of an AI as an extension after the initial 5 years of tamoxifen. Examples of this trial design are the MA-17 (letrozole) and the National Surgical Adjuvant Breast and Bowel Project (NSABP B-33, exemestane) trials. A third approach is the use of these agents in sequence with tamoxifen as therapy within the initial 5 postoperative years. Examples of this approach are the International Collaboration Cancer Group trial (tamoxifen for 2-3 years followed by either tamoxifen or exemestane for the remainder of the 5-year period), the BIG FEMTA trial (patients are crossed over from tamoxifen to Ietrozole or letrozole to tamoxifen), and the Arimidex-Nolvadex (ARNO) trial (patients receiving tamoxifen are randomized either to continue with tamoxifen or to switch to anastrozole). A single trial is comparing tamoxifen and anastrozole as initial 5-year therapy, or a combination of the two. The study addressing this design is the ATAC trial. Finally, a small trial in Norway is comparing 2 years of an AI versus a placebo in very low-risk patients with receptor-positive breast tumors. Most adjuvant trials have companion studies associated with the main protocol. These are to determine the end-organ effects of the inhibitors and include measurements of quality of life, bone and lipid metabolism, and endometrial effects. This review addresses the clinical implications of these studies of AIs.

Reference

Goss PE. Emerging role of aromatase inhibitors in the adjuvant setting. Am J Clin Oncol. 2003 Aug;26(4):S27-33.

4. Serous borderline tumors of the ovary with noninvasive implants.

The objectives of this study were to describe the clinical characteristics and prognosis of surgically treated patients with stage II and III serous borderline tumors of the ovary with noninvasive implants. From 1990 to 2000, 16 patients with stage II and III ovarian serous borderline tumors and noninvasive implants were diagnosed and prospectively followed at the center. All patients underwent surgical treatment including staging and their pathology was reviewed. Fifteen patients had thorough surgical staging by laparotomy, while one patient was staged laparoscopically. No patient was treated with adjuvant therapy (radiation or chemotherapy) after surgical treatment and none were lost to follow-up. The mean age at diagnosis was 42 years (range 26-59). Fourteen patients were treated by abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and multiple peritoneal biopsies, while 2 patients were treated conservatively for fertility preservation. Two patients underwent pelvic and para-aortic lymph node dissection. Fifteen of 16 patients had ovarian surface involvement with tumor. All patients but 2 had clinical evidence of extraovarian disease at the time of surgery. The mean duration of follow-up was 60.7 months (range 2-134 months). Thirteen patients (81%) are alive without evidence of disease. Four patients (25%) required subsequent surgery for recurrent disease and all are still alive. Two patients have been treated with chemotherapy (paclitaxel/carboplatin) for progressive borderline disease, while an additional patient was treated after first relapse with chemotherapy for an invasive recurrence. It is concluded that carefully staged patients with advanced serous borderline tumors of the ovary and noninvasive implants have a good prognosis without adjuvant therapy.

Reference

Lackman F, Carey MS, Kirk ME, McLachlin CM, Elit L. Surgery as sole treatment for serous borderline tumors of the ovary with noninvasive implants. Gynecol Oncol. 2003 Aug;90(2):407-12.

5. Laparoscopic uterosacral ligament resection for dysmenorrhea associated with endometriosis.

The study was undertaken to evaluate the efficacy of laparoscopic resection of the uterosacral ligaments in women with endometriosis and predominantly midline dysmenorrhea. One hundred eighty patients undergoing operative laparoscopy as first-line therapy for stage I to IV symptomatic endometriosis were included. Patienrts were randomized for operative laparoscopy including uterosacral ligament resection or conservative surgery alone. Proportion of women with recurrence of moderate or severe dysmenorrhea 1 year after surgery was determined. No complications occurred. Among the patients who were evaluable 1 year after operative laparoscopy, 23 of 78 (29%) women who had uterosacral ligament resection and 21 of 78 (27%) women who had conservative surgery only reported recurrent dysmenorrhea. The corresponding numbers of patients at 3 years were 21 of 59 (36%) women and 18 of 57 (32%) women, respectively. Time to recurrence was similar in the two groups. Pain was substantially reduced, and patients in both groups experienced similar and significant improvements in health-related quality of life, psychiatric profile, and sexual satisfaction. Overall, 68 of 90 (75%) patients in the uterosacral ligament resection group and 67 of 90 (74%) patients in the conservative surgery group were satisfied at 1 year. It is concluded that the addition of uterosacral ligament resection to conservative laparoscopic surgery for endometriosis did not reduce the medium- or long-term frequency and severity of recurrence of dysmenorrhea.

Reference

Vercellini P, Aimi G, Busacca M, Apolone G, Uglietti A, Crosignani PG. Laparoscopic uterosacral ligament resection for dysmenorrhea associated with endometriosis: results of a randomized, controlled trial.Fertil Steril. 2003 Aug;80(2):310-9.

6. Coagulation or excision of ovarian endometriomas?

A systematic review was undertaken to determine whether coagulation or laser vaporization of endometriomas is associated with an increase in the risk of cyst recurrence compared with excision of the pseudocapsule. In the four comparative trials identified, endometrioma recurrence was reported in 39 of 212 (18.4%) women treated with coagulation or laser vaporization compared with 19 of 295 (6.4%) in those who underwent cystectomy. The odds ratios of endometrioma recurrence ranged from 1.41 to 9.38 with 95% CIs including unity in two studies. The common odds ratio was 3.09 (95% CI 1.78-5.36). Coagulation or laser vaporization of endometriomas without excision of the pseudocapsule seems to be associated with a significant increase in risk of cyst recurrence.

Reference

Vercellini P, Chapron C, De Giorgi O, Consonni D, Frontino G, Crosignani PG. Coagulation or excision of ovarian endometriomas? Am J Obstet Gynecol. 2003 Mar;188(3):606-10. Review.

7. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea.

This prospective, therapeutic, self-controlled clinical trial was conducted to ascertain whether long-term reduction of pain is obtained by continuous administration of an oral contraceptive (OC) in women with endometriosis-associated recurrent dysmenorrhea that does not respond to cyclic OC use. Fifty women were included in the study who underwent surgery for endometriosis in the previous year and experienced recurrent dysmenorrhea despite cyclic OC use. They were placed on continuous use of an OC containing ethinyl estradiol (0.02 mg) and desogestrel (0.15 mg) for 2 years. Dysmenorrhea variation during cyclic and continuous OC use and degree of satisfaction with continuous OC treatment were evaluated with a 100-mm visual analog scale and a 0- to 3-point verbal rating scale, respectively. In the study period, amenorrhea, spotting, and breakthrough bleeding were reported by 19 (38%), 18 (36%), and 13 (26%) women. The mean +/- SD number of >7-day bleeding episodes with consequent 7-day OC suspension was 5.5 +/- 2.1. The mean +/- SD dysmenorrhea visual analog scale and verbal rating scale scores were 75 +/- 13 and 2.4 +/- 0.5 at baseline and 31 +/- 17 and 0.7 +/- 0.6 at 2-year follow-up, respectively. Moderate or severe side effects were reported by 7/50 (14%) women. At final evaluation, 13 (26%) women were very satisfied, 27 (54%) were satisfied, 1 (2%) was uncertain, 8 (16%) were dissatisfied, and 1 (2%) was very dissatisfied. It is concluded that long-term continuous OC use can be proposed to women with symptomatic endometriosis and menstruation-related pain symptoms.

Reference

Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, Crosignani PG. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen.Fertil Steril. 2003 Sep;80(3):560-3.

8. Progestogens for endometriosis.

A MEDLINE and EMBASE search was performed to identify all studies published in the last decade in the English language literature on the use of progestogens for the treatment of endometriosis. It was aimed to clarify the biological rationale for treatment and define the drugs that can be used with their doses, routes of administration, efficacy and tolerability. Progestogens may prevent implantation and growth of regurgitated endometrium inhibiting expression of matrix metalloproteinases and angiogenesis, and they have several anti-inflammatory in-vitro and in-vivo effects that may reduce the inflammatory state generated by the metabolic activity of the ectopic endometrium, and the consequent immune response. Oral contraceptives increase the abnormally low apoptotic activity of the endometrium of women with endometriosis. Moreover, anovulation, decidualization, amenorrhoea and the establishment of a steady estrogen-progestogen milieu contribute to disease quiescence. Progestogens are effective in the control of pain symptoms in approximately three out of four women with endometriosis. Their effect does not seem to be inferior to that of other drugs used for the disease. Different compounds can be administered by the oral, intramuscular, subcutaneous, intravaginal or intrauterine route, each with specific advantages or disadvantages. Medical treatment plays a role in the therapeutic strategy when administered over a prolonged period of time. Given their good tolerability, minor metabolic effects and low cost, progestogens must therefore be considered drugs of choice and are currently the only safe and economic alternative to surgery. However, their contraceptive effectiveness limits their use to women who do not wish to have children in the short term.

Reference

Vercellini P, Fedele L, Pietropaolo G, Frontino G, Somigliana E, Crosignani PG. Progestogens for endometriosis: forward to the past. Hum Reprod Update. 2003 Jul-Aug;9(4):387-96.

9. Pronuclear morphology and chromosomal abnormalities.

This prospective analysis of pronuclear zygote morphology and preimplantation genetic diagnosis (PGD) for aneuploidy of the resulting embryos was performed to verify whether a correlation exists between pronuclear zygote morphology and the chromosomal condition of preimplantation embryos. Seventy-seven patients undergoing 107 PGD cycles because of advanced maternal age (77 cycles) or previous IVF failures (30 cycles) were included in the study. The rate of embryo development, proportion of euploid embryos, and distribution of chromosomal abnormalities were determined.The position of pronuclei within the ooplasm, the size and distribution of nucleoli, and the orientation of polar bodies with respect to pronuclei were highly predictive for the presence of complex chromosomal abnormalities in the developing embryos; zygotes with juxtaposed pronuclei, large-size nucleoli, and polar bodies with small angles subtended by pronuclei and polar bodies were the configurations associated with the highest rates of euploidy. It is concluded that the combination of the patterns related to pronuclear zygote morphology indicated four configurations where the proportion of chromosomally normal embryos was significantly higher compared with the other configurations, suggesting the validity of this scoring system for the selection of embryos generated by PGD patients.

Reference

Gianaroli L, Magli MC, Ferraretti AP, Fortini D, Grieco N. Pronuclear morphology and chromosomal abnormalities as scoring criteria for embryo selection. Fertil Steril. 2003 Aug;80(2):341-9.

10. Ureaplasma parvum and Ureaplasma urealyticum in semen.

This prospective study was performed to investigate the prevalence of ureaplasmas in semen and washed semen and to explore their effect on semen andrology variables. Three hundred forty-three men participating in an assisted reproductive technology (ART) treatment cycle were included in the study. The prevalence of ureaplasmas in semen and washed semen was tested by culture, polymerase chain reaction assays, and indirect immunofluorescent antibody assays. Ureaplasmas were detected in 73 of 343 (22%) semen samples and 29 of 343 (8.5%) washed semen samples. Ureaplasmas adherent to the surface of spermatozoa were demonstrated by indirect immunofluorescent antibody testing. Ureplasma parvum serovar 6 (36.6%) and U. urealyticum (30%) were the most prevalent isolates in washed semen. A comparison of the semen andrology variables of washed semen ureaplasma positive and negative groups demonstrated a lower proportion of nonmotile sperm in men ureaplasma positive for washed semen. The data show that ureaplasmas are not always removed from semen by a standard ART washing procedure and can remain adherent to the surface of spermatozoa.

Reference

Knox CL, Allan JA, Allan JM, Edirisinghe WR, Stenzel D, Lawrence FA, Purdie DM, Timms P. Ureaplasma parvum and Ureaplasma urealyticum are detected in semen after washing before assisted reproductive technology procedures. Fertil Steril. 2003 Oct;80(4):921-9.

11. Polycystic ovaries without PCOS: impact on fertility and fecundity.

This case-control study was performed to evaluate the effect on fertility of the appearance of polycystic ovaries in women who have no symptoms of polycystic ovary syndrome. Women with the appearance of polycystic ovaries on ultrasound and women with normal ovaries were compared. A questionnaire was used about previous subfertility, pregnancies, menstrual pattern, features of polycystic ovary syndrome, gynecological history, and individual lifestyle factors. Time to pregnancy (TTP) and relative risk (RR) of subfertility in symptomatic and asymptomatic subgroups of both groups were determined. Women with PCOs took longer TTP and were significantly less fertile if they were obese (RR = 2.6), had menstrual disturbances (RR = 4.6), hirsutism (RR = 2.5), and/or acne (RR = 2.7). Further reductions in fecundity occurred with an increasing number of symptoms (threefold, sevenfold, and 10-fold longer TTP with two, three, and four symptoms, respectively). The TTP of women with no symptoms was not significantly longer and they were not more likely to be subfertile than women with normal ovaries. These symptoms were not associated with significantly reduced fecundity in women with normal ovaries. These data suggest that the appearance of polycystic ovaries has no significant impact on fertility in women with no symptoms. Appearances alone do not reflect the pathological features of polycystic ovary syndrome, and additional diagnostic criteria should be considered. Obesity, menstrual disturbances, and/or hyperandrogenism are factors associated with subfertility in women with polycystic ovaries.

Reference

Hassan MA, Killick SR. Ultrasound diagnosis of polycystic ovaries in women who have no symptoms of polycystic ovary syndrome is not associated with subfecundity or subfertility. Fertil Steril. 2003 Oct;80(4):966-75.

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Gerhard Leyendecker