Management of surgical stage III and IV endometrioid endometrial carcinoma: an overview.

This paper covers an overview of the literature on the management of advanced endometrial cancer, concentrating on patients with histopathologic endometrioid type of tumors. The different treatment modalities are described and management recommendations are proposed.The standard surgical procedure includes an extrafacial total hysterectomy with bilateral salpingo-oophorectomy, collection of peritoneal washings for cytology, and exploration of the intraabdominal contents. In cases of extensive disease in the abdomen, an optimal surgical cytoreduction is associated with improved survival. Further treatment with radiotherapy may be indicated based on the pathological staging information to improve loco-regional control. Primary radiotherapy is indicated in cases where surgery is contraindicated. Systemic treatment can either be hormone therapy or chemotherapy. Progesterons are the cornerstone of hormone therapy. Prognostic factors for response are the presence of high levels of progesterone and estrogen receptors and low grade histology. Paclitaxel is the most active single agent drug. The combination therapy with paclitaxel and carboplatin is adopted as first choice in patients with endometrial cancer because of the efficacy and low toxicity, although not proven in a randomized trial.The literature on the management of patients with advanced endometrial cancer is discussed in detail. Each stage of advanced disease is presented separately, and management recommendations are proposed, and alternative approaches are given.Ongoing clinical trials are described, and the focuses of ongoing research are mentioned.

Management of recurrent endometrioid endometrial carcinoma: an overview.

In this paper, an overview of the literature on the management of recurrent endometrial cancer is presented, focusing on patients with histopathologic endometrioid type of tumors. The different treatment modalities are described, and a management recommendation scheme is presented. Indications for surgical treatment depend on resectability, site and size of the tumor, and performance status of the patient. Indications for radiotherapy depend on the site of the recurrence and also on the initial therapy received. When considering systemic treatment for patients with recurrent endometrial cancer, it is important to take into account the general health status and condition of the patient as well as which prior therapy the patient has received. The treatments of choice for patients with hormone-sensitive tumors (positive receptor levels, low-grade tumors, and long disease-free interval) are progestagens as first-line treatment and tamoxifen as second-line treatment. Patients with high-grade tumors, negative hormone receptor levels, and short treatment-free interval are best treated with chemotherapy. Paclitaxel, doxorubicin, and cisplatin are the most active combination therapy for these patients but with significant toxicity. In phase II studies, the combination therapy with paclitaxel and carboplatin seems to be as effective but less toxic and can be administered in outpatient clinic. The literature on the management of patients with recurrent endometrial cancer is discussed in detail. The different sites of recurrent disease (ie, local, regional, and/or distant) are evaluated separately; management recommendations are proposed, and alternative approaches are given.

Molecular analysis of human endometrium: short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling.

Tibolone, a tissue-selective compound with a combination of estrogenic, progestagenic, and androgenic properties, is used as an alternative for estrogen or estrogen plus progesterone hormone therapy for the treatment of symptoms associated with menopause and osteoporosis. The current study compares the endometrial gene expression profiles after short-term (21 days) treatment with tibolone to the profiles after treatment with estradiol-only (E(2)) and E(2) + medroxyprogesterone acetate (E(2) + MPA) in healthy postmenopausal women undergoing hysterectomy for endometrial prolapse. The impact of E(2) treatment on endometrial gene expression (799 genes) was much higher than the effect of tibolone (173 genes) or E(2) + MPA treatment (174 genes). Furthermore, endometrial gene expression profiles after tibolone treatment show a weak similarity to the profiles after E(2) treatment (overlap 72 genes) and even less profile similarity to E(2) + MPA treatment (overlap 17 genes). Interestingly, 95 tibolone-specific genes were identified. Translation of profile similarity into biological processes and pathways showed that ER-mediated downstream processes, such as cell cycle and cell proliferation, are not affected by E2 + MPA, slightly by tibolone, but are significantly affected by E(2). In conclusion, tibolone treatment results in a tibolone-specific gene expression profile in the human endometrium, which shares only limited resemblance to E(2) and even less resemblance to E2 + MPA induced profiles.

Recurrent endometrial cancer: a retrospective study.

OBJECTIVE: The value of follow-up after treatment for endometrial cancer will be discussed. STUDY DESIGN: We evaluated our clinical experience, including mode of detection, of patients with recurrent endometrial cancer treated in the Erasmus Medical Centre in Rotterdam over a 20-year period. Clinical data and histopathological features from 64 patients were analyzed. Survival was analyzed with a Kaplan-Meier curve. RESULTS: Twenty-two patients had a local recurrence, 30 had a distant recurrence and 12 had simultaneous local and distant recurrent disease. Ninety-five percent of the local recurrences and 67% of the distant recurrences were detected within three years. Twenty-seven patients had a screen-detected recurrence, 34 had an interval screening recurrence and two had a chance finding recurrence. The overall survival rate at two years was 70% and at five years 53%. Patients with a screen-detected recurrence had a 5-year survival rate of 62%, while patients with interval screening and chance finding recurrences had a 5-year survival rate of 47%. CONCLUSION: A follow-up program in the first three years after primary treatment of endometrial cancer is useful in detecting recurrent disease. We have no reason to use a different program of follow-up in patients with low risk primary disease.

Stage III and IV endometrial cancer: a 20-year review of patients.

In advanced endometrial cancer, the importance of peritoneal cytology and optimal surgical cytoreduction remain subjects of discussion. We evaluated our clinical experience of 67 patients with FIGO stage III and IV endometrial cancer treated in the Erasmus Medical Centre in Rotterdam over a 20-year period with an emphasis on stage IIIA disease based on positive cytology only and optimal cytoreduction. Lymphadenectomy was not routinely performed and peritoneal cytology was examined in 74% of the patients. Stage IIIA disease was found in 33 patients, 10 of whom had positive cytology only. Analysis showed that incidence of recurrence and survival rates of patients with stage IIIA disease based on positive cytology only were comparable with stage IIIA disease based on other factors. In 50 patients, it was possible to remove all macroscopic tumor, whereas in 17 patients, an optimal cytoreduction was not achievable. The 2- and 5-year survival rates after optimal cytoreduction were 82.2% and 65.6%; where this could not be achieved, these figures were 50.8% and 40.6%. In advanced endometrial cancer patients, positive peritoneal cytology seems an important prognostic factor in stage IIIA disease if lymph node status is unknown. Survival is improved if optimal surgical cytoreduction is achievable.

Molecular portrait of the progestagenic and estrogenic actions of tibolone: behavior of cellular networks in response to tibolone.

Tibolone is a synthetic steroid with estrogenic effects on brain, vagina, and bone without stimulating the endometrium. During tibolone treatment, it is thought that the progestagenic properties of tibolone stimulate cell differentiation, which effectively counterbalances the growth-stimulating effects of the estrogenic properties of tibolone. The objective of this study was to characterize the expression profile that reflects the endometrial responses to the separated estrogenic (growth-inducing) and progestagenic (growth-inhibiting) actions of tibolone, thus gaining insight into the counteracting effect of these properties of tibolone on the endometrium. The estrogenic action of tibolone was studied in the estrogen-responsive ECC1 cell line (expressing estrogen receptor alpha), and the progestagenic action was studied in the progesterone-responsive cell line Ishikawa PRAB-36 (expressing PRA and PRB). The data showed that the progestagenic and estrogenic effects of tibolone produce different expression profiles with a narrow overlap in genes; however, both properties modulate the same biological processes. The final genetic network analysis indicated that the estrogenic effect of tibolone is potentially counterbalanced by the progestagenic metabolite of tibolone via differential regulation of similar cellular processes. For example, both progestagenic and estrogenic properties stimulate proliferation, but they exert the opposite effect on apoptosis. The apoptosis network was stimulated by the progestagenic properties of tibolone; in contrast, the estrogenic effect of tibolone suppressed the apoptosis network. The current results indicate that this differential regulation is realized through modulation of a different group of genes and rarely via contraregulation of the same set of genes.

Phase II study of fotemustine in patients with advanced ovarian carcinoma. A trial of the EORTC Gynecological Cancer Group.

30 patients with advanced ovarian cancer, all platinum pretreated, were treated with an induction cycle of fotemustine. Maintenance therapy was given to 6 patients. No objective response was observed among the 21 evaluable patients. The main toxicities were gastrointestinal, with grade 3 nausea and vomiting reported in 40% of the patients, and haematological, with grade 4 leucopenia reported in 2 patients and grade 4 thrombocytopenia in 5 patients. Therefore, no role has been demonstrated in our cohort for the use of fotemustine, a nitrosourea, in pretreated ovarian cancer.

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.

BACKGROUND: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.

Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma. A trial of the EORTC Gynaecological Cancer Group.

The aim of this study was to investigate the efficacy and toxicity of carboplatin given as monotherapy in endometrial adenocarcinoma. Cisplatin is one of the most active drugs in gynaecological cancer types, but at the cost of an associated high toxicity. In this high-risk population of endometrial cancer patients, it is necessary to have chemotherapy regimens with a low toxicity. Patients eligible for this study were those with histologically-confirmed endometrial adenocarcinoma with evidence of recurrent and/or metastatic disease. Carboplatin was administered every 4 weeks as a first- (dose: 400 mg/m(2)) or second- (dose: 300 mg/m(2)) line chemotherapy. Of the 64 patients who entered the trial, 60 were eligible, 53 patients were evaluable for toxicity and 47 for efficacy. A total of 169 cycles of carboplatin was given with a median of 2 cycles per patient (range 1-11 cycles) to a median cumulative dose of 798 mg/m(2) (range 290-3879 mg/m(2)). No grade 4 toxicity or toxic deaths occurred. White Blood Cell (WBC) toxicity grade 3 was noted five times, mainly in the radiotherapy pre-treated patients. Grade 3 non-haematological toxicity consisted mainly of nausea and vomiting (21%). There was a total of eight responses (3 Complete Responses (CR) and 5 Partial Responses (PR) with an overall response rate (ORR) of 13% (95% Confidence Interval (CI) 6-25). No responses occurred in patients treated with prior chemotherapy. In evaluable patients, the ORR in all patients (n=47) and in those receiving first-line chemotherapy (n=33) were, 17% (95% CI 8-31) and 24% (95% CI 11-42), respectively. After a median follow-up of 379 days, the median duration of response was 488 days (range 141-5303 days) with two very long responses in patients with a CR. Carboplatin has a low toxicity and is active in chemotherapy-naive advanced endometrial carcinoma patients. These results lead us to propose its use in association in first-line chemotherapy in recurrent or advanced endometrial carcinoma patients. The choice of the initial dose can be determined according to whether the patients have received prior radiotherapy treatment.

Administration of low molecular weight heparin within two hours before caesarean section increases the risk of wound haematoma.

A retrospective analysis of the relation between time interval from prophylactic administration of low molecular weight heparin (LMWH) to delivery and the occurrence of wound haematoma was performed in all women, who had a caesarean section in 1998. After administration of LMWH within 2 hours of surgery, the percentage of women with a wound haematoma was significantly larger (12% vs 3%). Multivariate regression analysis, including other risk factors for wound haematoma, indicated administration of LMWH within 2 hours prior to delivery as the only statistically significant factor, which influenced the development of wound haematoma (odds ratio = 5.3, 95% CI = 1.2-22.8).

Risk indicators for neonatal early-onset GBS-related disease. A case-control study.

Risk indicators play an important role in the active prevention of neonatal Early-Onset GBS-related Disease (EOD). We studied the associations between potential risk indicators and the occurrence of EOD by means of a case-control study. All cases of EOD delivered in the Academic Medical Centre in Amsterdam between January 1988 and December 1995 were included. For each case we selected 3 controls, matched for date and time of birth. The association between continuous risk indicators and the occurrence of EOD was assessed using spline functions. Multivariable logistic regression analysis was performed to determine which risk indicators contributed independently. Forty-one cases were compared with 123 controls. In the multivariable analysis, gestational age < 37 weeks and intrapartum temperature > or = 37.4 degrees C showed to be statistically significant risk indicators for EOD, with odds ratios of 2.5 per week gestation and 1.6 per 0.1 degree C, respectively. After cesarean section the risk of EOD was significantly decreased (OR 0.13). Of the other potential risk indicators only prelabor rupture of membranes showed an increased risk, although the association was not statistically significant. Prolonged duration of ruptured membranes had no additional merit. Risk indicators that should be taken into account in strategies to prevent EOD are increased maternal temperature and decreased gestational age.