The efficacy of topical imiquimod in high-grade cervical intraepithelial neoplasia: A systematic review and meta-analysis.

OBJECTIVE: A major side effect of cervical excision for high-grade cervical intraepithelial neoplasia (CIN) is premature birth. A non-invasive treatment for reproductive age women is warranted. The aim of the present study was to determine the efficacy of topical imiquimod in the treatment of high-grade CIN, defined as a regression to ≤CIN 1, and to determine the clearance rate of high-risk human papillomavirus (hr-HPV), compared with surgical treatment and placebo. METHODS: Databases were searched for articles from their inception to February 2023.The study protocol number was INPLASY2022110046. Original studies reporting the efficacy of topical imiquimod in CIN 2, CIN 3 or persistent hr-HPV infections were included. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist. RESULTS: Five studies were included (n = 463). Histological regression to ≤CIN 1 was 55% in imiquimod versus 29% in placebo, and 93% in surgical treatment. Imiquimod-treated women had a greater odds of histological regression to ≤CIN 1 than placebo (odds ratio [OR] 4.17, 95% confidence interval [CI] 2.03-8.54). In comparison to imiquimod, surgical treatment had an OR of 14.81(95% CI 6.59-33.27) for histological regression to ≤CIN 1. The hr-HPV clearance rate was 53.4% after imiquimod and 66% after surgical treatment (95% CI 0.62-23.77). CONCLUSIONS: The histological regression rate is highest for surgical treatment followed by imiquimod treatment and placebo.

Acute and long-term toxicity in patients undergoing induction chemotherapy followed by thermoradiotherapy for advanced cervical cancer.

OBJECTIVES: To determine rates of vascular toxicity, acute kidney injury (AKI), chronic kidney disease (CKD) and survival in high-risk cervical cancer patients treated with platinum-based induction chemotherapy followed by thermoradiotherapy. METHODS: Between January 1999 and April 2017, patients with large primary tumors (>6cm) and/or para-aortic lymph node (LN) metastases >1 cm and/or para-iliac LN >2 cm were included. Patient and tumor characteristics, Common Toxicity Criteria v4.03 scores, laboratory tests and treatment data were retrieved from patient records. CT scans were reviewed for the presence of thrombo-embolic events (TEE). The study protocol was approved by the Medical Ethics Review Committee of Erasmus MC, Rotterdam (MEC2017-133). RESULTS: The 105 included patients had a mean age of 47.9 years (range 22-79) and a median follow-up time of 43 months (IQR 14-72). Median tumor size was 6.0 cm (range 2.6-11.5), 30% had a clinical FIGO stage ≥ IIIB and 42% had enlarged para-aortic LN. Cisplatin-based therapy was started in 86 patients (82%), of whom 30 (35%) switched to carboplatin and 47% of patients completed six cycles of platinum-based chemotherapy. All patients received external beam radiotherapy as planned, 98 patients (93%) underwent brachytherapy as planned or received an external boost, and 95 patients (90%) completed all five planned hyperthermia treatments. During cisplatin chemotherapy, 34 patients experienced AKI (39%). At last follow-up, 35% of patients had chronic renal toxicity (GFR 59 - 15/min/1.73 m2). At presentation, a TEE was present in 10 (10%) and another 23 (22%) patients experienced a TEE (18% venous, 4% arterial) during chemotherapy. Five-year overall survival was 58% (95% CI 47.8-68.6 SE 0.053). CONCLUSION: Achieving a five-year overall survival of 58%, platinum-based induction chemotherapy followed by thermoradiotherapy is an effective treatment for advanced-stage high-risk cervical cancer. However, treatment is accompanied by an unacceptably high prevalence of chemotherapy-associated TEE and acute kidney injury, as well as chronic kidney disease. Future studies should investigate the role of carboplatin in reducing toxicity and the effect of thromboprophylaxis in high-risk patients.

Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe.

OBJECTIVE: Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN. METHODS: We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up. RESULTS: Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was diagnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor ≥30 mm. Bilateral radiotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence. CONCLUSION: The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.

Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer.

OBJECTIVE: In the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC) <70 years of age. LSS consists of immunohistochemical (IHC) staining for loss of mismatch repair (MMR) protein expression, supplemented with MLH1 methylation analysis if indicated. Test results are evaluated by the treating gynaecologist, who refers eligible patients to a clinical geneticist. We evaluated the implementation of this guideline. METHODS: From the nation-wide pathology database we selected all women diagnosed with EC < 70 years of age, treated from 1.6.2016-1.6.2017 in 14 hospitals. We collected data on the results of LSS and follow up of cases with suspected LS. RESULTS: In 183 out of 204 tumours (90%) LSS was performed. In 41 cases (22%) MMR protein expression was lost, in 25 cases due to hypermethylation of the MLH1 promotor. One patient was known with a pathogenic MLH1 variant. The option of genetic counselling was discussed with 12 of the 15 remaining patients, of whom three declined. After counselling by the genetic counsellor nine patients underwent germline testing. In two no pathogenic germline variant was detected, two were diagnosed with a pathogenic PMS2 variant, and five with a pathogenic MSH6 variant, in concordance with the IHC profiles. CONCLUSION: Coverage of LSS was high (90%), though referral for genetic counselling could be improved. Gynaecologists ought to be aware of the benefits and possible drawbacks of knowing mutational status, and require training in discussing this with their patients.

The Effect of the Time Interval Between Radiation and Hyperthermia on Clinical Outcome in 400 Locally Advanced Cervical Carcinoma Patients.

Background: Addition of deep hyperthermia to radiotherapy results in improved local control (LC) and overall survival compared to radiotherapy alone in cervical carcinoma patients. Based on preclinical data, the time interval between radiotherapy, and hyperthermia is expected to influence treatment outcome. Clinical studies addressing the effect of time interval are sparse. The repercussions for clinical applications are substantial, as the time between radiotherapy and hyperthermia should be kept as short as possible. In this study, we therefore investigated the effect of the time interval between radiotherapy and hyperthermia on treatment outcome. Methods: We analyzed all primary cervical carcinoma patients treated between 1996 and 2016 with thermoradiotherapy at our institute. Data on patients, tumors and treatments were collected, including the thermal dose parameters TRISE and CEM43T90. Follow-up data on tumor status and survival as well as late toxicity were collected. Data was analyzed using Cox proportional hazards analysis and Kaplan Meier analysis. Results: 400 patients were included. Kaplan Meier and univariate Cox analysis showed no effect of the time interval (range 30-230 min) on any clinical outcome measure. Besides known prognostic factors, thermal dose parameters TRISE and CEM43T90 had a significant effect on LC. In multivariate analysis, the thermal dose parameter TRISE (HR 0.649; 95% CI 0.501-0.840) and the use of image guided brachytherapy (HR 0.432; 95% CI 0.214-0.972), but not the time interval, were significant predictors of LC and disease specific survival. Conclusions: The time interval between radiotherapy and hyperthermia, up to 4 h, has no effect on clinical outcome. These results are re-ensuring for our current practice of delivering hyperthermia within maximal 4 h after radiotherapy.

Characteristics of Lynch syndrome associated ovarian cancer.

OBJECTIVE: To describe clinical characteristics of Lynch syndrome associated ovarian cancer and the efficacy of surveillance in the early detection of these ovarian cancers. METHODS: All Lynch syndrome associated ovarian cancer cases identified in either the Dutch Lynch syndrome registry (DLSR) between 1987 and 2016, and/or the cohort at the University Medical Center Groningen (UMCG) between 1993 and 2016 were included. Clinical data on age at diagnosis, mutation type, histological type, FIGO stage, treatment, follow-up and gynecological surveillance were collected. RESULTS: A total of 46/798 (6%) women in the DLSR and 7/80 (9%) in the UMCG cohort were identified as LS associated ovarian cancer patients. The median age at ovarian cancer diagnosis was 46.0 years (range 20-75 years). The most frequently reported histological type was endometrioid adenocarcinoma (40%; n = 21) and serous carcinoma (36%; n = 19). Most tumors (87%; n = 46) were detected at an early stage (FIGO I/II). Forty-one of 53 (77%) patients were diagnosed with ovarian cancer before LS was diagnosed. In the other 12/53 (23%) women, ovarian cancer developed after starting annual gynecological surveillance for LS; three ovarian cancers were screen-detected in asymptomatic women. Overall survival was 83%. CONCLUSION: Ovarian cancer in women with LS has a wide age-range of onset, is usually diagnosed at an early stage with predominantly endometrioid type histology and a good overall survival. The early stage at diagnosis could not be attributed to annual gynecological surveillance.

A nurse-led sexual rehabilitation intervention after radiotherapy for gynecological cancer.

PURPOSE: Although vaginal dilator use after combined pelvic radiation therapy and brachytherapy (RT/BT) is recommended to prevent vaginal shortening and stenosis, women fail to use them and experience sexual problems. A nurse-led sexual rehabilitation intervention targeting sexual recovery and vaginal dilatation was developed. Its feasibility was investigated during a prospective, longitudinal, observational pilot study. METHODS: Four oncology nurses were specifically trained to conduct the intervention. Gynecologic cancer patients treated with RT/BT were assessed using (i) questionnaires on frequency of dilator use (monthly), sexual functioning, and sexual distress (at baseline and 1, 6, and 12 months) and psychological and relational distress (at 1, 6, and 12 months); (ii) semi-structured interviews (between 6 and 12 months); and (iii) consultation recordings (a random selection of 21 % of all consults). RESULTS: Twenty participants were 26-71 years old (mean = 40). Eight participants discontinued participation after 3 to 9 months. At 6 months after RT, 14 out of 16 (88 %), and at 12 months 9 out of 12 (75 %), participants dilated regularly, either by having sexual intercourse or by using dilators. Sexual functioning improved between 1 and 6 months after RT, with further improvement at 12 months. Most participants reported that the intervention was helpful and the nurses reported having sufficient expertise and counseling skills. CONCLUSIONS: According to the pilot results, the intervention was feasible and promising for sexual rehabilitation and regular dilator use after RT. Its (cost-)effectiveness will be investigated in a randomized controlled trial.

A Structured Assessment to Decrease the Amount of Inconclusive Endometrial Biopsies in Women with Postmenopausal Bleeding.

OBJECTIVE: To determine whether structured assessment of outpatient endometrial biopsies decreases the number of inconclusive samples. DESIGN: Retrospective cohort study. SETTING: Single hospital pathology laboratory. POPULATION: Endometrial biopsy samples of 66 women with postmenopausal bleeding, collected during the usual diagnostic work-up and assessed as insufficient for a reliable histological diagnosis. METHODS: Endometrial biopsy samples were requested from the pathology laboratories. The retrieved samples were systematically reassessed by a single pathologist specialized in gynecology. MAIN OUTCOME MEASURE: Disagreement between initial assessment and conclusion after structured reassessment. RESULTS: We retrieved 36 of 66 endometrial biopsy samples from six different pathology laboratories. Structured reassessment of the retrieved samples by a single pathologist specialized in gynecology did not change the conclusion in 35 of the 36 samples. The remaining sample contained a large amount of endometrial tissue and the diagnosis at reassessment was endometrial hyperplasia without atypia. All other samples contained insufficient material for a reliable diagnosis. CONCLUSION: A structured reassessment of endometrial biopsies samples, which were classified as inconclusive due to insufficient material, did not change the conclusion. Although it might be helpful for pathologists to have diagnostic criteria for adequacy and/or inadequacy of an endometrial biopsy sample, the gain in efficiency is likely to be small.

Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I.

OBJECTIVE: In 2008 GROINSS-V-I, the largest validation trial on the sentinel node (SN) procedure in vulvar cancer, showed that application of the SN-procedure in patients with early-stage vulvar cancer is safe. The current study aimed to evaluate long-term follow-up of these patients regarding recurrences and survival. METHODS: From 2000 until 2006 GROINSS-V-I included 377 patients with unifocal squamous cell carcinoma of the vulva (T1, <4 cm), who underwent the SN-procedure. Only in case of SN metastases an inguinofemoral lymphadenectomy was performed. For the present study follow-up was completed until March 2015. RESULTS: Themedian follow-up was 105 months (range 0­179). The overall local recurrence ratewas 27.2% at 5 years and 39.5% at 10 years after primary treatment, while for SN-negative patients 24.6% and 36.4%, and for SN-positive patients 33.2% and 46.4% respectively (p = 0.03). In 39/253 SN-negative patients (15.4%) an inguinofemoral lymphadenectomy was performed, because of a local recurrence. Isolated groin recurrence rate was 2.5% for SN-negative patients and 8.0% for SN-positive patients at 5 years. Disease-specific 10-year survival was 91% for SN-negative patients compared to 65% for SN-positive patients (p b .0001). For all patients, 10-year disease-specific survival decreased from 90% for patients without to 69% for patients with a local recurrence (p b .0001).

Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction.

BACKGROUND: Previous studies have reported a breast cancer (BC) risk reduction of approximately 50% after risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 mutation carriers, but may have been subject to several types of bias. The purpose of this nationwide cohort study was to assess potential bias in the estimated BC risk reduction after RRSO. METHODS: We selected BRCA1/2 mutation carriers from an ongoing nationwide cohort study on Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON). First, we replicated the analytical methods as previously applied in four major studies on BC risk after RRSO. Cox proportional hazards models were used to calculate hazard ratios and conditional logistic regression to calculate odds ratios. Secondly, we analyzed the data in a revised design in order to further minimize bias using an extended Cox model with RRSO as a time-dependent variable to calculate the hazard ratio. The most important differences between our approach and those of previous studies were the requirement of no history of cancer at the date of DNA diagnosis and the inclusion of person-time preceding RRSO. RESULTS: Applying the four previously described analytical methods and the data of 551 to 934 BRCA1/2 mutation carriers with a median follow-up of 2.7 to 4.6 years, the odds ratio was 0.61 (95% confidence interval [CI] = 0.35 to 1.08), and the hazard ratios were 0.36 (95% CI = 0.25 to 0.53), 0.62 (95% CI = 0.39 to 0.99), and 0.49 (95% CI = 0.33 to 0.71), being similar to earlier findings. For the revised analysis, we included 822 BRCA1/2 mutation carriers. After a median follow-up period of 3.2 years, we obtained a hazard ratio of 1.09 (95% CI = 0.67 to 1.77). CONCLUSION: In previous studies, BC risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated because of bias. Using a design that maximally eliminated bias, we found no evidence for a protective effect.

Long-term results of a randomised phase III trial of weekly versus three-weekly paclitaxel/platinum induction therapy followed by standard or extended three-weekly paclitaxel/platinum in European patients with advanced epithelial ovarian cancer.

BACKGROUND: Weekly paclitaxel/carboplatin might improve survival in platinum-resistant epithelial ovarian cancer (EOC). We compared efficacy of first-line weekly to three-weekly paclitaxel/cis- or carboplatin (PCw and PC3w) induction therapy, followed by either three or six PC3w cycles. PATIENTS AND METHODS: In this multicentre, randomised phase III trial with 2×2 design, patients with FIGO stage IIb-IV EOC were randomised to six cycles PCw (paclitaxel 90mg/m(2), cisplatin 70mg/m(2) or carboplatin AUC 4) or three cycles PC3w (paclitaxel 175mg/m(2), cisplatin 75mg/m(2) or carboplatin AUC 6), followed by either three or six cycles PC3w. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were response rate (RR) and toxicity. RESULTS: Of 267 eligible patients, 133 received PCw and 134 PC3w. The first 105 patients received cisplatin, after protocol amendment the subsequent 162 patients received carboplatin. Weekly cisplatin was less well tolerated than weekly carboplatin. All PC3w cycles were well tolerated. At the end of all treatments, RR was 90.8% with no differences between the treatment arms. After a follow-up of median 10.3years (range 7.1-14.8), median PFS was 18.5 (95% confidence interval (CI) 15.9-21.0) months for PCw and 16.4 (95% CI 13.5-19.2) months for PC3w (p=0.78). Median OS was 44.8 (95% CI 33.1-56.5) months for PCw and 41.1 (95% CI 34.4-47.7) months for PC3w (p=0.98). CONCLUSIONS: There was no benefit in terms of OS, PFS or RR for a weekly regimen nor for extended chemotherapy as first-line treatment for EOC in European patients.

Long-term results of weekly paclitaxel carboplatin induction therapy: an effective and well-tolerated treatment in patients with platinum-resistant ovarian cancer.

BACKGROUND: Weekly paclitaxel/cisplatin is effective in platinum-resistant epithelial ovarian cancer (EOC). To reduce toxicity, paclitaxel/cisplatin was replaced by paclitaxel/carboplatin. PATIENTS AND METHODS: Patients with progressive EOC after prior 3-weekly paclitaxel/carboplatin were treated with six cycles weekly paclitaxel 90 mg/m(2) and carboplatin area under the curve (AUC) 4 mg/ml/min, followed by six cycles 3-weekly paclitaxel/carboplatin. End-points were progression free survival (PFS), overall survival (OS), response rate (RR) and toxicity. RESULTS: Median progression free interval after last platinum was 9 (0-81) months in 108 patients; 43 were platinum-resistant, of whom 13 started weekly paclitaxel/carboplatin <6 months after progression. During 633 weekly cycles grade 3/4 toxicity included; thrombocytopenia 8%, neutropenia 30%, febrile neutropenia 0.5%. Non-haematologic toxicity was low. Treatment was delayed in 16%, and dose reduced in 2% of cycles. RR was 58% for platinum-resistant and 76% for platinum-sensitive patients, median PFS were 8 (range 1-21) and 13 (1-46) months, median OS 15 (1-69) and 26 (4-93) months, respectively. The 13 platinum-resistant patients with a platinum-therapy free interval <6 months had a significant shorter PFS (4 versus 10 months, p=0.035) and OS (9 versus 15 months, p=0.002). CONCLUSION: Six cycles weekly paclitaxel/carboplatin followed by six 3-weekly cycles is well-tolerated and highly active in platinum-resistant and platinum-sensitive patients.

Increased incidence and improved survival in endometrioid endometrial cancer diagnosed since 1989 in The Netherlands: a population based study.

OBJECTIVES: To measure progress against endometrioid endometrial carcinoma (EEC) in the Netherlands by analyzing trends in incidence, survival and mortality simultaneously. STUDY DESIGN: Descriptive study of incidence, survival and mortality rates of women with EEC in the Netherlands. Rates were age-standardized to the European standard population. Population-based data were extracted from the nationwide Dutch Cancer Registry (NCR) between 1989 and 2009. Mortality data since 1989 came from Statistics Netherlands. European age standardized incidence rates were calculated according to age, histology and stage. Five year relative survival estimates were calculated in four periods. Optimal progress against cancer is defined as decreasing incidence and/or improving survival accompanied by declining mortality. RESULTS: 80% of the 32,332 patients newly diagnosed with a corpus uteri malignancy had an EEC. The incidence of EEC rose significantly from 11/100,000 to 15/100,000, being most pronounced in women with FIGO stage IB and in the group with grade 1&2 tumours (P<0.05). Coinciding with the increased incidence, 5-year relative survival increased, especially for patients aged 60-74 years, in women with FIGO stage I, and in histology group grade 1&2, being 87%, 94% and 93%, respectively, during 2005-2009. CONCLUSION: The incidence of EEC (being 80% of corpus uteri cancer) increased markedly between 1989 and 2009, especially in women of 60-74 years. Five-year survival for patients with EEC increased from 83 to 85%. Progress against EEC has been less than was assumed previously, because mortality proportionally decreased only slightly, and because of the increasing incidence although survival improved.

The impact of uterine re-curettage, pre-evacuation and week-one level of hCG on the number of chemotherapy courses in treatment of post molar GTN.

BACKGROUND: Post molar GTN was reported to occur in 7.5-20% of patients following evacuation of complete hydatidiform moles and in 2.5-7.5% following evacuation of partial moles. The role of uterine re-curettage in post molar GTN is not clear. OBJECTIVES: Study of the correlation of pre-evacuation and week- one level of hCG, and uterine re-curettage to the number of chemotherapy courses in treatment of post molar GTN. PATIENTS AND METHODS: This retrospective study included 29 cases of post molar GTN through reviewing their medical records. RESULTS: There were 25 cases (86.21) of low risk, and 4 cases of high risk score (13.79%). The 3 year survival was 96.6%. There were non-significant correlation of age, parity, pre-evacuation level and hCG in week-1 to number of chemotherapy courses, while uterine re-curettage was significantly correlated to number of chemotherapy courses (p = 0.04). CONCLUSION: Uterine re-curettage was significantly correlated to less number of chemotherapy courses in patients with post molar GTN (p = 0.04). Pre-evacuation and week-1 hCG were not correlated to number of chemotherapy cycles. A large prospective randomized trial to clarify the beneficial effect of uterine re-curettage is recommended.

Diagnostic strategies for postmenopausal bleeding.

Postmenopausal bleeding (PMB) is a common clinical problem. Patients with PMB have 10%-15% chance of having endometrial carcinoma and therefore the diagnostic workup is aimed at excluding malignancy. Patient characteristics can alter the probability of having endometrial carcinoma in patients with PMB; in certain groups of patients the incidence has been reported to be as high as 29%. Transvaginal sonography (TVS) is used as a first step in the diagnostic workup, but different authors have come to different conclusions assessing the accuracy of TVS for excluding endometrial carcinoma. Diagnostic procedures obtaining material for histological assessment (e.g., dilatation and curettage, hysteroscopy, and endometrial biopsy) can be more accurate but are also more invasive. The best diagnostic strategy for diagnosing endometrial carcinoma in patients with PMB still remains controversial. Future research should be focussed on achieving a higher accuracy of different diagnostic strategies.

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.

What is the recurrence rate of postmenopausal bleeding in women who have a thin endometrium during a first episode of postmenopausal bleeding?

OBJECTIVE: To determine the incidence and significance of recurrent postmenopausal bleeding among women diagnosed with an endometrial thickness < or =4 mm after a first episode of postmenopausal bleeding. METHODS: Consecutive patients not using hormone replacement therapy (HRT) presenting with a first episode of postmenopausal bleeding and an endometrial thickness < or =4 mm at transvaginal ultrasonography (TVU) were managed expectantly. In case of recurrent bleeding, the patient was evaluated according to the hospital's local policy with TVU, office endometrial sampling, hysteroscopy or dilatation and curettage (D&C) or a combination of these tests. We evaluated the incidence of recurrent bleeding, potential risk factors for recurrent bleeding, and the diagnosis made after recurrent bleeding. RESULTS: A total of 607 patients were registered with a first episode of postmenopausal bleeding, of whom 249 had an endometrial thickness < or =4 mm. Follow-up took place with a median of 174 weeks (range: 4-250 weeks). During follow-up, 25 of the 249 patients (10%; 95% CI: 6.6-14%) had recurrent bleeding. Median time until recurrence of bleeding was 49 weeks (range: 9-186 weeks). Two patients with recurrent bleeding turned out to have an endometrial carcinoma (8%; 95% CI: 2.2-25%), and 1 patient had a malignant melanoma. Time since menopause, age, body mass index, hypertension, diabetes and anticoagulants were not predictive for recurrent bleeding. CONCLUSION: The recurrence rate after a first episode of postmenopausal bleeding managed expectantly is low and cannot be predicted by patient characteristics. Patients with recurrent bleeding should be re-evaluated, as they bear a considerable risk of carcinoma.

Inadequate office endometrial sample requires further evaluation in women with postmenopausal bleeding and abnormal ultrasound results.

OBJECTIVE: To determine whether further histologic assessment can be omitted after office sampling produced a nondiagnostic specimen. METHODS: Data were retrieved from a prospective cohort study of 913 women presenting with postmenopausal bleeding. This study was limited to women with an endometrial thickness either 5 mm or greater or that could not be measured, and in whom an endometrial biopsy performed in the office yielded nondiagnostic results. RESULTS: Endometrial thickness was nonreassuring or unknown in 516 women, of whom 403 (78.1%) underwent office endometrial sampling. In 66 women the amount of tissue obtained was not sufficient for pathologic characterization. Further investigation revealed an endometrial malignancy in 3 of these 66 women and atypical hyperplasia in 1. CONCLUSION: In women with postmenopausal bleeding and a nonreassuring transvaginal ultrasound evaluation, a nondiagnostic office endometrial sample does not rule out endometrial cancer and further endometrial sampling is advisable.

The relation between age, time since menopause, and endometrial cancer in women with postmenopausal bleeding.

The objective is to assess among women with postmenopausal bleeding the relationship of age and time since menopause on one hand and the presence of endometrial cancer and atypical hyperplasia on the other hand. In a multicenter prospective cohort study, 614 women presenting with postmenopausal bleeding were included. Women underwent transvaginal sonography and, in cases where the endometrial thickness was >4 mm, endometrial sampling. Splines were used to assess the association between each of the continuous variables and (pre)malignancy of the endometrium. Subsequently, univariate and multivariate analysis were performed. The average age for women without (pre)malignancy was 61.7 years (SD 9.8). As malignant and premalignant cases were found to have similar age, these subgroups were merged in the analyses. Age was an independent predictor of (pre)malignancy. In women younger than 55 years, the odds ratio was 1.9 (95% CI: 1.1-3.3) for each year under 55 years of age and 1.03 (95% CI: 1.00-1.06) for each year over 55 years of age. The risk of (pre)malignancy of the endometrium was 4.9% in women less than 3 years postmenopausal versus 19.7% in women more than 20 years postmenopausal. However, in a multivariate analysis only age contributed to the prediction of risk. This study demonstrates that, in postmenopausal women with vaginal bleeding, the risk of (pre)malignancy of the endometrium is low in women under 50 years of age, increases considerably until 55 years of age, and rises only modestly with further advancing age. Future studies should explore whether these findings can be incorporated in the diagnostic work-up of women with postmenopausal bleeding.