Psychologic impact of follow-up after low-risk gestational trophoblastic disease.

OBJECTIVE: To investigate the psychological consequences of hCG measurements during follow-up in patients with low-risk gestational trophoblastic disease. The length of follow-up of patients with molar pregnancy and spontaneous normalization of the hCG level is currently discussed, in consideration of the low incidence of recurrent disease. STUDY DESIGN: Patients registered in the Dutch Central Registry of Hydatidiform Mole between January 2006 and December 2007 were eligible for this study. Patients received a questionnaire containing questions about follow-up and anxiety and stress during this period. RESULTS: Seventy-six patients were eligible for the study. An inverted correlation (r = -0.35, p = 0.003) was found between the age of patients and the level of anxiety. Anxious patients scored higher for fear of recurrence (r = 0.49, p < 0.0001), of infertility (r = 0.40, p = 0.001) and of conceiving again (r = 0.30, p = 0.01). They experienced the measurements as a burden (r = 0.35, p = 0.003). Fewer patients (24%) were insecure before the monthly hCG measurement, compared to 51% during weekly measurements. The majority of women (80%) completed the follow-up and confirmed that they would come for weekly and monthly hCG measurements if it were optional. CONCLUSION: Follow-up after low-risk GTD has psychologic consequences but provides reassurance as well. Therefore, women tend to accept the offered surveillance and refrain from pregnancy. Women with GTD should be counseled about the minor risk of recurrence and the consequences of follow-up.

Size of sentinel-node metastasis and chances of non-sentinel-node involvement and survival in early stage vulvar cancer: results from GROINSS-V, a multicentre observational study.

BACKGROUND: Currently, all patients with vulvar cancer with a positive sentinel node undergo inguinofemoral lymphadenectomy, irrespective of the size of sentinel-node metastases. Our study aimed to assess the association between size of sentinel-node metastasis and risk of metastases in non-sentinel nodes, and risk of disease-specific survival in early stage vulvar cancer. METHODS: In the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V), sentinel-node detection was done in patients with T1-T2 (<4 cm) squamous-cell vulvar cancer, followed by inguinofemoral lymphadenectomy if metastatic disease was identified in the sentinel node, either by routine examination or pathological ultrastaging. For the present study, sentinel nodes were independently reviewed by two pathologists. FINDINGS: Metastatic disease was identified in one or more sentinel nodes in 135 (33%) of 403 patients, and 115 (85%) of these patients had inguinofemoral lymphadenectomy. The risk of non-sentinel-node metastases was higher when the sentinel node was found to be positive with routine pathology than with ultrastaging (23 of 85 groins vs three of 56 groins, p=0.001). For this study, 723 sentinel nodes in 260 patients (2.8 sentinel nodes per patient) were reviewed. The proportion of patients with non-sentinel-node metastases increased with size of sentinel-node metastasis: one of 24 patients with individual tumour cells had a non-sentinel-node metastasis; two of 19 with metastases 2 mm or smaller; two of 15 with metastases larger than 2 mm to 5 mm; and ten of 21 with metastases larger than 5 mm. Disease-specific survival for patients with sentinel-node metastases larger than 2 mm was lower than for those with sentinel-node metastases 2 mm or smaller (69.5%vs 94.4%, p=0.001). INTERPRETATION: Our data show that the risk of non-sentinel-node metastases increases with size of sentinel-node metastasis. No size cutoff seems to exist below which chances of non-sentinel-node metastases are close to zero. Therefore, all patients with sentinel-node metastases should have additional groin treatment. The prognosis for patients with sentinel-node metastasis larger than 2 mm is poor, and novel treatment regimens should be explored for these patients.

Primary surgery versus primary radiation therapy with or without chemotherapy for early adenocarcinoma of the uterine cervix.

BACKGROUND: For early squamous cell carcinoma of the uterine cervix, the outcome is similar after either primary surgery or primary radiotherapy. There are reports that this is not the case for early adenocarcinoma (AC) of the uterine cervix: some studies have reported that the outcome is better after primary surgery. There are no systematic reviews about surgery versus chemoradiation in the treatment of cervical cancer. OBJECTIVES: The objectives of this review were to compare the effectiveness and safety of primary surgery for early stage AC of the uterine cervix with primary radiotherapy or chemoradiation. SEARCH STRATEGY: We searched Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2009, MEDLINE (1950 to July week 5, 2009), EMBASE (1980 to week 32, 2009) and we also searched the related articles feature of PubMed and the Web of Science. We also checked the reference lists of articles. SELECTION CRITERIA: Studies of treatment of patients with early AC of the uterine cervix were included. Treatment included surgery, surgery followed by radiotherapy, radiotherapy and chemoradiation. DATA COLLECTION AND ANALYSIS: Forty-three studies were selected by the search strategy and thirty studies were excluded. Twelve studies were considered for inclusion. Except for one randomised controlled trial (RCT), all other studies were retrospective cohort studies with variable methodological quality and had limitations of a retrospective study. Comparing the results from these retrospective studies was not possible due to diverging treatment strategies. MAIN RESULTS: Analysis of a subgroup of one RCT showed that surgery for early cervical AC was better than RT. However, the majority of operated patients required adjuvant radiotherapy, which is associated with greater morbidity. Furthermore, the radiotherapy in this study was not optimal, and surgery was not compared to chemoradiation, which is currently recommended in most centres. Finally, modern imaging techniques, i.e. MR-imaging and PET-CT-scanning, allow better selection of patients and node negative patients can now be more easily identified for surgery, there by reducing the risk of 'double trouble' caused by surgery and adjuvant radiotherapy. AUTHORS' CONCLUSIONS: We recommend surgery for early stage AC of the uterine cervix in carefully staged patients. Primary chemoradiation remains a second best alternative for patients unfit for surgery; chemoradiation is probably first choice in patients with (MRI or PET-CT-suspected) positive lymph nodes.

Pelvic exenteration for primary and recurrent gynaecological malignancies.

OBJECTIVE: Analyse the outcome of pelvic exenteration for gynaecological malignancies in a tertiary referral center. Post-operative in-hospital morbidity, long-term morbidity, disease free and overall survival rates were studied. STUDY DESIGN: Between 1991 and 2004, 42 patients underwent an anterior, total or posterior exenteration for gynaecological malignancies. Follow-up was obtained from patient files; disease free and overall survival were calculated and prognostic factors were studied. RESULTS: A pelvic exenteration was performed in 14 patients for primary and 28 patients for recurrent gynaecological cancers. In-hospital complications occurred in 19 patients (45%) of whom seven patients needed a reoperation (17%). Late complications occurred in 31 patients (75%); 21 reinterventions were performed (50%). Five-year disease free and overall survival was, respectively, 48 and 52%. Age, type of surgery, histology, localisation of the tumour, lateral wall involvement, completeness of resection and primary versus recurrent cancer were not identified as prognostic factors for recurrence or survival. CONCLUSION: Long-term survival is possible in about 50% of patients after pelvic exenteration for gynaecological cancers, but is associated with significant post-operative morbidity.

Concomitant radiotherapy and hyperthermia for primary carcinoma of the vagina: a cohort study.

OBJECTIVE: To evaluate the supplementary value of adding hyperthermia to radiotherapy in patients with primary vaginal cancer. STUDY DESIGN: Cohort of 44 patients diagnosed with primary vaginal cancer between 1990 and 2002 was assessed. Survival rates and median survival of patients with primary vaginal cancer undergoing radiotherapy with and without hyperthermia were compared. Hyperthermia was solely added to radiotherapy in case of a tumor size >4 cm in diameter for FIGO stage III disease. RESULTS: The calculated overall 5-year survival of primary vaginal cancer was 63%. In comparison to histologic high grade tumors, higher survival rates for histologic low grade tumors were calculated. For FIGO stage III of disease, the addition of hyperthermia to radiotherapy for tumors >4 cm in diameter resulted similar survival rates and median survival when compared to those achieved by radiotherapy as monotherapy in tumors of <4 cm in diameter. CONCLUSIONS: The addition of hyperthermia to radiotherapy might result in better survival rates in primary vaginal cancer for tumors >4 cm in diameter. The supplementary effect of hyperthermia to radiotherapy may be a feasible and beneficial approach in the treatment of vaginal cancer.

Cervical cancer in developing countries: how can we reduce the burden? Awareness raising, screening, treatment and palliation.

Cervical cancer is an important health problem in developing countries. Most women present with advanced disease, resulting in low cure rates. Screening by Visual Inspection with the Aid of Acetic Acid and optionally HPV DNA detection as a second test is technically feasible. However, the majority of women appear to be reluctant to attend a screening clinic. This is probably due to lack of knowledge and a low priority of women's health in local communities. There is an obvious need to obtain more knowledge on communities' perceptions and understanding of cervical cancer. Furthermore, we need more information on what issues should be addressed in order to perform cervical cancer screening in an acceptable manner. Treatment of cervical cancer in developing countries is highly dependent on the resources and skills available. Efforts to provide adequate palliation should be enhanced as relief of troublesome symptoms can often be achieved by relatively simple and low-cost measures.

The role of chemo-radiotherapy in the management of locally advanced carcinoma of the vulva: single institutional experience and review of literature.

OBJECTIVE: To retrospectively investigate the outcome and toxicity of concurrent chemo-radiotherapy in the treatment of locally advanced vulvar cancer (LAVC). PATIENTS AND METHODS: Between 1996 and 2007, 28 consecutive patients with LAVC were treated with chemoradiation (20 primary tumors and 8 loco-regional recurrences). Treatment consists of 2 separate courses of external-beam radiotherapy (40 Gy-2 weeks split-20 Gy). During each course of radiotherapy, 5-fluorouracil (1000 mg/m/d), was given as a continuous intravenous infusion over the first 4 days, and mitomycin-C (10 mg/m on day 1), as a bolus intravenous injection. Outcome measures were rates of complete and partial response, loco-regional control, progression-free survival, overall survival, and toxicity. RESULTS: The median follow-up was 42 months and the median age of patients was 68 years. Twenty patients (72%) achieved complete remission, 4 patients (14%) partial remission, for an overall response rate of 86%. Four patients (14%) had progressive disease directly after chemo-radiotherapy. The actuarial rates of loco-regional control, progression-free survival and overall survival at 4 years were 75%, 71%, and 65%, respectively. There was no treatment break for acute toxicity. Vulvar desquamation was the main acute treatment-related side effect (93%). Three patients developed transient grade 2 neutropenia or thrombocytopenia. Mild skin fibrosis and atrophy (n = 6, 21%), radiation ulcer (n = 4, 14%, in one patient treatment was needed), telangectasia (n = 3, 11%), and lymphoedema (n = 2, 7%) were the most common late toxicity of chemoradiation. CONCLUSION: These data support the use of concurrent chemoradiotherapy as an effective alternative to primary ultra-radical surgery to treat LAVC with an acceptable toxicity profile.

Sentinel node dissection is safe in the treatment of early-stage vulvar cancer.

PURPOSE: To investigate the safety and clinical utility of the sentinel node procedure in early-stage vulvar cancer patients. PATIENTS AND METHODS: A multicenter observational study on sentinel node detection using radioactive tracer and blue dye was performed in patients with T1/2 (< 4 cm) squamous cell cancer of the vulva. When the sentinel node was found to be negative at pathologic ultrastaging, inguinofemoral lymphadenectomy was omitted, and the patient was observed with follow-up for 2 years at intervals of every 2 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS: From March 2000 until June 2006, a sentinel node procedure was performed in 623 groins of 403 assessable patients. In 259 patients with unifocal vulvar disease and a negative sentinel node (median follow-up time, 35 months), six groin recurrences were diagnosed (2.3%; 95% CI, 0.6% to 5%), and 3-year survival rate was 97% (95% CI, 91% to 99%). Short-term morbidity was decreased in patients after sentinel node dissection only when compared with patients with a positive sentinel node who underwent inguinofemoral lymphadenectomy (wound breakdown in groin: 11.7% v 34.0%, respectively; P < .0001; and cellulitis: 4.5% v 21.3%, respectively; P < .0001). Long-term morbidity also was less frequently observed after removal of only the sentinel node compared with sentinel node removal and inguinofemoral lymphadenectomy (recurrent erysipelas: 0.4% v 16.2%, respectively; P < .0001; and lymphedema of the legs: 1.9% v 25.2%, respectively; P < .0001). CONCLUSION: In early-stage vulvar cancer patients with a negative sentinel node, the groin recurrence rate is low, survival is excellent, and treatment-related morbidity is minimal. We suggest that sentinel node dissection, performed by a quality-controlled multidisciplinary team, should be part of the standard treatment in selected patients with early-stage vulvar cancer.

Weekly systemic cisplatin plus locoregional hyperthermia: an effective treatment for patients with recurrent cervical carcinoma in a previously irradiated area.

PURPOSE: Patients with recurrent cervical carcinoma within a previously irradiated area respond poorly to chemotherapy. We have treated these patients with simultaneous cisplatin and hyperthermia (CDDP + HT) and investigated response, toxicity, palliative effect and survival. MATERIALS AND METHODS: Between 1992 and 2005 47 patients received CDDP + HT. Response was evaluated by gynaecologic examination and CT-scan. The Common Toxicity Criteria (CTC) were used for evaluation of toxicity and palliative effect. The Kaplan-Meier method was used to estimate survival, and Cox regression analysis to evaluate the influence of prognostic factors. RESULTS: The objective response rate was 55%, palliation was achieved in 74% and operability in 19% of patients. Two patients are currently disease free at 9 years and 18 + months following treatment and 2 remained disease free until death by other causes. The median survival was 8 months and was influenced by duration of disease free interval and tumour diameter. Grade 3-4 haematological toxicity was observed in 36% of patients and renal toxicity was maximum grade 2. CONCLUSION: CDDP + HT results in a high response rate and acceptable toxicity in patients with recurrent cervical cancer.

Treatment and prognosis of post term choriocarcinoma in The Netherlands.

INTRODUCTION: Antecedent term pregnancy is an adverse prognostic factor in Gestational Trophoblastic Disease (GTD). In The Netherlands, patients with post term choriocarcinoma are considered high-risk independent of WHO score. In the present study, we assessed whether post term choriocarcinoma always has to be considered high-risk, requiring first line treatment with combination chemotherapy, or whether a subgroup of patients is distinguishable in which single-agent Methotrexate is a safe alternative. PATIENTS AND METHODS: The study is a retrospective multicenter cohort study. Patients registered by the Dutch Working Party on Trophoblastic Disease between 1986 and 2004 with choriocarcinoma after a non-molar pregnancy were eligible. Hospital and outpatient records of the patients were reviewed. RESULTS: In total, 68 patients with non-molar choriocarcinoma were registered of whom 44 had an antecedent term pregnancy. Most post term patients (77%) were high-risk according to the WHO staging system. The majority of patients presented with metrorraghia and high hCG levels. Lung and liver metastases were common (respectively 64% and 28%), probably caused by a delay in diagnosis (median interval 16 weeks). Patients were often Methotrexate-resistant (75%). Overall survival was 86% in patients with a post term choriocarcinoma. CONCLUSIONS: Although term pregnancy is an adverse prognostic factor in GTD, current survival is comparable to the general survival in high-risk patients. A subgroup of patients in which monotherapy would be sufficient could not be identified. Immediate administration of combination chemotherapy seems justified, even in those few cases when scoring systems would suggest low- or medium-risk disease.

Optimal treatment of premature ovarian failure after treatment for Hodgkin's lymphoma is often withheld.

BACKGROUND: The purpose of this study is to determine: 1. the effect of treatment for Hodgkin's lymphoma on ovarian function, and 2. the interventions to relieve postmenopausal symptoms. METHODS: Seventy-seven consecutive patients treated between 1989 and 2003 in the Rotterdam region for Hodgkin's lymphoma stages I and II were approached for this study. A questionnaire consisting of 45 questions was carried out to evaluate premature menopausal symptoms, hormonal replacement therapy and use of contraception, menstrual cycle, and subsequent pregnancies. RESULTS: After informed consent 67 patients were willing to participate in the study and 66 patients filled in a questionnaire. After antitumor treatment 13 patients developed treatment-related premature ovarian failure, 35 patients had a spontaneous cycle, and 18 patients could not be classified as they used hormonal contraception. Women who developed treatment-related premature ovarian failure had a significantly higher mean age at the start of treatment for Hodgkin's lymphoma than women who remained premenopausal (p < 0.002). Only 6 of these 13 women (46%) received hormonal substitution. In all, 21 women conceived after antitumor treatment, and 28 children were born. All pregnancies were the result of spontaneous conception. CONCLUSIONS: The effect of antitumor treatment for Hodgkin's lymphoma on ovarian function is age dependent (odds ratio of 1.18 per year). There is a striking inconsistency regarding the management of ovarian protection before and during antitumor treatment. Premenopausal women who undergo therapy for Hodgkin's lymphoma should be offered hormonal substitution therapy after loss of ovarian function.

BRCA1 and p53 protein expression in cultured ovarian surface epithelial cells derived from women with and without a BRCA1 germline mutation.

AIM: Mutations in the BRCA1 and TP53 genes are early genetic events leading to (hereditary) ovarian carcinoma. The human ovarian surface epithelium (OSE) is considered the tissue of origin of at least a subset of these tumours. Therefore, OSE cell cultures derived from women harbouring BRCA1 germline mutations can be a potential model to study hereditary ovarian carcinogenesis. In fact, previous in vitro studies indicate phenotypical differences between OSE from women with and without such germline mutations. Therefore, we have assessed whether differences in the expression of BRCA1 and p53 proteins in cultured OSE cells could contribute to these observations. STUDY DESIGN: Thirty-two OSE cultures derived from women harbouring a BRCA1 mutation (Predisposed OSE [POSE]) and ten cultures from women without a cancer predisposition (Non predisposed OSE [NPOSE]) were grown under standard conditions. Immunocytochemistry was performed to assess the expression of the BRCA1- and p53 proteins. Ki67 immunocytochemical expression was assessed to determine possible differences in cell cycle status between the two groups. In addition, to study whether wild type p53 was expressed, induction of p53 by cis-platinum was assessed by Western blot. RESULTS: On the basis of Ki67 expression, three different groups were analyzed. In the group with all cultures that expressed Ki67 no significant difference was observed in BRCA1 (P = 0.19) and p53 expression (P = 0.09). In the group with moderate to high Ki67 expression no difference in BRCA1 expression (P = 0.50) was observed. However, p53 expression was significantly lower in the case group (P = 0.01). The same observation for p53 was made in the group with only high Ki67 expression (P = 0.02). Furthermore, the expression of both BRCA1 and p53 positively correlates with Ki67 expression. In POSE and NPOSE, p53 was induced by cis-platinum to a similar extent. CONCLUSION: Our study indicates differences in the expression of p53, but not in the expression of BRCA1 between POSE and NPOSE. In addition, our findings do suggest the absence of losses of the wild type BRCA1 and p53 genes in the studied OSE cultures. This indicates that losses in these genes cannot account for observed differences in phenotypical traits between POSE and NPOSE, but that differences in levels of p53 might contribute.

Lymphoepithelioma-like carcinoma of the uterine cervix: absence of Epstein-Barr virus, but presence of a multiple human papillomavirus infection.

BACKGROUND: Cervical lymphoepithelioma-like carcinoma (LELC) is a rare variant of squamous cell carcinoma of the cervix. Association with Epstein-Barr virus (EBV) is still controversial. EBV has been demonstrated in Asian women with cervical LELC. In Western women, human papillomavirus (HPV) might play a role in the etiology. CASE: We describe a 44-year-old Caucasian woman with a lymphoepithelioma-like carcinoma of the cervix without EBV, but in the presence of multiple HPV infection. CONCLUSION: Our case supports a possible different pathway of development of cervical LELC in Western women as compared to Asian women.

The impact of performance status on survival in patients of 80 years and older with vulvar cancer.

OBJECTIVE: There are no data available on the impact of performance status on outcome in patients with vulvar cancer. It was the objective of this study to determine the impact of performance status on survival in a group of elderly patients. METHODS: A retrospective review of records of patients with vulvar cancer aged 80 years or greater and treated in a gynecological referral center was performed. Multiple clinical and pathological variables together with performance status were assessed and the impact on overall survival was determined both by univariate and multivariate analysis. RESULTS: Of 75 patients aged 80 years or older, 57 (76%) had standard treatment. The patients who had standard treatment were characterized by an earlier clinical stage and a better performance status compared with patients who had nonstandard treatment. When preoperatively available parameters of all patients were assessed in relation to survival in the total group, Eastern Cooperative Oncology Group (ECOG) performance status was the only independent prognostic indicator for survival. When all clinical and histopathological variables were assessed in the subgroup who had standard treatment, both ECOG performance status and extracapsular lymph node involvement were independent prognostic variables for overall survival. Age was not a significant prognostic variable. CONCLUSIONS: ECOG performance status is the only available pretreatment variable with independent prognostic value for survival in this group of elderly patients with vulvar cancer. These data show the importance of individualizing the treatment of patients with vulvar cancer. Performance status takes a more important place than age in the management process of these patients.

Feasibility of central co-ordinated EMA/CO for gestational trophoblastic disease in the Netherlands.

OBJECTIVE: In the Netherlands, high risk gestational trophoblastic disease (GTD) patients are treated in different referral hospitals with a national working party on trophoblastic tumours having a co-ordinating function. Our purpose was to evaluate whether this policy is a satisfactory alternative to complete centralisation. DESIGN: A retrospective study of all etoposide, methotrexate, actomycin D, cyclophosphamide and vincristine (EMA/CO)-treated women in the Netherlands between 1986 and 1997. Data regarding risk factors, treatment results and toxicity were collected. SETTING: Ten hospitals; 2 general, 6 academical and 2 oncology centres. POPULATION: Fifty EMA/CO-treated women registered by the central registration unit of the Dutch Working Party on Trophoblastic Disease. METHODS: Patients files and quarterly reports of the Dutch Working Party. MAIN OUTCOME MEASURES: Cure rate and consistency of treatment in different hospitals. RESULTS: EMA/CO treatment was administered in 10 different hospitals. All patients were discussed during the meetings of the Dutch Working Party and overall, 86% of patients were cured. Consistency in treatment was good. CONCLUSIONS: Cure rates were comparable with results of single institution series. We conclude that treatment of high risk GTD patients in different referral hospitals with concentration of expertise in a working party is a good alternative to centralisation of treatment in GTD specialised hospitals.

Cultures of ovarian surface epithelium from women with and without a hereditary predisposition to develop female adnexal carcinoma.

AIM: Conflicting evidence exists on whether in vivo morphological characteristics can distinguish Ovarian Surface Epithelium (OSE) of ovaries obtained from women with and without a predisposition to develop female adnexal (ovarian and fallopian tube) carcinoma. This study aims to detect differences in growth potential and morphology that are maintained or specifically expressed in vitro. STUDY DESIGN: Ovarian surfaces were scraped to retrieve OSE cells from 56 women at hereditary high risk for female adnexal carcinoma, of whom 33 are BRCA1 and four are BRCA2 mutation carriers (Predisposed OSE, POSE) and from 26 women without such risk (Non Predisposed OSE, NPOSE). Number of passages and total cell yield until last passage, as well as morphology was compared between both groups. To confirm morphology, the expression of epithelial, mesothelial, and fibroblast markers was assessed. RESULTS: Both POSE and NPOSE cultures displayed similar growth potential and morphology. The expression of epithelial markers cyto-keratins 7 and 8 was similar between both groups. Only in cultures in which cells did not uniformly exhibit these markers, the percentage of cells expressing these markers was significantly lower at last passage when compared to the initial culture. In these latter cultures, cells that were morphologically indistinguishable from fibroblasts were observed. Mesothelial marker calretinin was expressed in 75% of cells of both POSE and NPOSE cultures and correlates with cyto-keratins 7 and 8 expression. CA 125 expression was equally low in POSE and NPOSE cultures (4.3%). Fibroblast markers FSM and vimentin were expressed in 100% and collagen IV was expressed in 16% of cells in all cultures. CONCLUSION: OSE cells derived from women with a hereditary predisposition to develop female adnexal cancer possess similar in vitro characteristics as OSE from women without this predisposition. On basis of our results, it seems advisable to study only 100% cyto-keratins 7 and 8 positive OSE cultures, since contamination of fibroblasts in some primary OSE cultures cannot be ruled out.