The identification of patients at high risk for recurrent disease after treatment for early-stage cervical cancer.

OBJECTIVE: To investigate prognostic factors in patients with recurrent cervical cancer after treatment of early-stage disease in order to identify high-risk patients who might benefit from alternative treatment strategies. STUDY DESIGN: The authors retrospectively analyzed clinical and pathology data from 130 recurrent cervical cancer patients after surgical treatment for early-stage disease. Patients were compared with a recurrence-free control group matched for age, FIGO Stage, and adjuvant treatment. Univariate and multivariate Cox regression analyses were performed to determine prognostic factors for recurrence and survival. RESULTS: Of 889 patients, 130 (14.6%) developed recurrent disease after primary treatment for early-stage cervical cancer. Local or loco-regional metastasis was observed in 45%, distant metastasis in 31%, and combined pelvic and distant metastasis in 24%. Median survival after recurrence was 12 months (range 1-107 months). Median five-year survival was 96% in the control group and 29% in the recurrence group. Tumor size ≥ 40 mm and lymph node metastasis were independent unfavorable prognostic factors for overall survival (OS) and disease-free survival (DFS). The number of positive lymph nodes (≥ one) and bilateral occurrence of pelvic lymph node metastasis were associated with adverse clinical outcome. CONCLUSIONS: Tumor size ≥ 40 mm and lymph node metastasis were independent unfavorable prognostic factors in surgically treated, early-stage cervical cancer patients. The combination of these factors was particularly associated with recurrence. Future trials should focus on the role of alternative adjuvant treatment strategies in patients at high risk of recurrent disease (e.g., by chemotherapy, immunotherapy or combinations thereof).

Nerve-sparing radical hysterectomy versus conventional radical hysterectomy in early-stage cervical cancer. A systematic review and meta-analysis of survival and quality of life.

BACKGROUND AND AIMS: Survival after radical hysterectomy (RH) for early-stage cervical cancer is good. Hence quality of life (QOL) after treatment is an important issue. Nerve-sparing radical hysterectomy (NSRH) improves QOL by selectively sparing innervation of bladder, bowel and vagina, reducing therapy-induced morbidity. However, the oncological outcome and the functional outcome after NSRH are subjects of debate. We aim to present the best possible evidence available regarding both QOL and survival after NSRH in early-stage cervical cancer. METHODS: Systematic review and meta-analysis on studies comparing NSRH and RH. RESULTS: Forty-one studies were included, and 27 were used for the meta-analysis. There was no difference in 2-, 3- and 5-year overall survival: the risk ratios (RRs) were respectively 1.02 (95% CI 0.99-1.05, n=879), 1.01 (95% CI 0.95-1.08, n=1324) and 1.03 (95% CI 0.99-1.08, n=638). No difference was found in 2-, 3- and 5-year disease-free survival: RR 1.01 (95% CI 0.95-1.05, n=1175), 0.99 (95% CI 0.94-1.03, n=1130) and 1.00 (95% CI 0.95-1.06, n=933) respectively. Post-operative time to micturition was significantly shorter in the NSRH group: standardized mean difference (SMD) -0.84 (CI 95% -1.07 to -0.60). CONCLUSIONS: NSRH can be considered safe and effective for early-stage cervical cancer since short- and long-term survival do not differ from those of conventional RH, while bladder function after NSRH is significantly less impaired.

Barrel index of bulky cervical tumours and intrauterine fluid determined by MRI as additional prognostic factors for survival.

OBJECTIVE: to investigate whether morphologic characteristics determined by magnetic resonance imaging (MRI) can discriminate between bulky cervical tumours with a favourable or worse prognosis. MATERIALS AND METHODS: MRI examinations were performed in 24 patients with cervical cancer Stage >or= 1B2. The ratio between tumour width and length (barrel index: BI) and the presence of intrauterine fluid retention were related to survival in a multivariate regression analysis. RESULTS: BI and intracavital fluid were predictors of survival, independent from tumour diameter and other known important factors for survival. A cut-off value of 1.40 for the BI proved to be the best prognostic factor with respect to recurrence and death: the hazard ratios of BI > 1.40 as compared to BI

Near-infrared fluorescence sentinel lymph node biopsy in vulvar cancer: a randomised comparison of lymphatic tracers.

This study aims to confirm the feasibility of near-infrared (NIR) fluorescence imaging for sentinel lymph node (SLN) biopsy in vulvar cancer and to compare the tracer indocyanine green (ICG) bound to human serum albumin (HSA) versus ICG alone. Women received 99mTc-nanocolloid and patent blue for SLN detection. Subsequently, women randomly received ICG:HSA or ICG alone. In 24 women, 35 SLNs were intraoperatively detected. All SLNs detected were radioactive and NIR fluorescent and 27 (77%) were blue. No significant difference was found between ICG:HSA and ICG alone. This trial confirms the feasibility of NIR fluorescence imaging for SLN mapping in vulvar cancer.

CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients.

BACKGROUND: The CXC chemokine receptor (CXCR)7 is involved in tumour development and metastases formation. The aim of the present study was to determine protein expression of CXCR7, its putative co-receptors epidermal growth factor receptor (EGFR) and CXCR4, its predominant ligand CXCL12, their co-dependency and their association with survival in cervical cancer patients. METHODS: CXC chemokine receptor 7, EGFR, CXCR4 and CXCL12 expression were determined immunohistochemically in 103 paraffin-embedded, cervical cancers. Subsequently, associations with patient characteristics were assessed and survival analyses were performed. RESULTS: CXC chemokine receptor 7 was expressed by 43% of tumour specimens, in a large majority of cases together with either EGFR or CXCR4 (double positive), or both (triple positive). The CXCR7 expression was associated with tumour size (P=0.013), lymph node metastasis (P=0.001) and EGFR expression (P=0.009). CXC chemokine receptor 7 was independently associated with disease-free survival (hazard ratio (HR)=4.3, 95% confidence intervals (CI) 1.7-11.0, P=0.002), and strongly associated with disease-specific survival (HR=3.9, 95% CI 1.5-10.2, P=0.005). CONCLUSION: CXC chemokine receptor 7 expression predicts poor disease-free and disease-specific survival in cervical cancer patients, and might be a promising new therapeutic marker. In a large majority of cases, CXCR7 is co-expressed with CXCR4 and/or EGFR, supporting the hypothesis that these receptors assist in CXCR7 signal transduction.

The use of distilled water in the achievement of local hemostasis during surgery.

Distilled water is used worldwide to check on hemostasis at the end of pelvic oncological operations. Nevertheless, reports about this method are lacking. The aim of this study was to explain the method and to discuss possible side effects. After the addition of distilled water to the surgically exposed pelvis, rapid lysis of erythrocytes results in a transparent fluid in which a small source of bleeding is easily recognizable. A possible side effect of the lavage might be contribution to the formation of peritoneal adhesions by confusing the abdominal defence system. Systemic side effects are not to be expected. Although tumour cells might suffer from hypotonic distilled water lavage, the current use of distilled water at the end of surgery is probably not effective to lyse tumour cells. Our findings support the ongoing use of distilled water lavage to achieve hemostasis after extensive pelvic surgery.

Vaginal blood flow after radical hysterectomy with and without nerve sparing. A preliminary report.

Radical hysterectomy with pelvic lymphadenectomy (RHL) for cervical cancer causes damage to the autonomic nerves, which are responsible for increased vaginal blood flow during sexual arousal. The aim of the study of which we now report preliminary data was to determine whether a nerve-sparing technique leads to an objectively less disturbed vaginal blood flow response during sexual stimulation. Photoplethysmographic assessment of vaginal pulse amplitude (VPA) during sexual stimulation by erotic films was performed. Subjective sexual arousal was assessed after each stimulus. Thirteen women after conventional RHL, 10 women after nerve-sparing RHL, and 14 healthy premenopausal women participated. Data were collected between January and August 2006. The main outcome measure was the logarithmically transformed mean VPA. To detect statistically significant differences in mean VPA levels between the three groups, a univariate analysis of variance was used. Mean VPA differed between the three groups (P= 0.014). The conventional group had a lower vaginal blood flow response than the control group (P= 0.016), which tended also to be lower than that of the nerve-sparing group (P= 0.097). These differences were critically dependent on baseline vaginal blood flow differences between the groups. The conventional group follows a vaginal blood flow pattern similar to postmenopausal women. Conventional RHL is associated with an overall disturbed vaginal blood flow response compared with healthy controls. Because it is not observed to the same extent after nerve-sparing RHL, it seems that the nerve-sparing technique leads to a better overall vaginal blood flow caused by less denervation of the vagina.

An individual prediction of the future (disease-free) survival of patients with a history of early-stage cervical cancer, multistate model.

To evaluate the possibility to give a prediction of the future (disease-free) survival, given the fact that a patient with a history of early-stage cervical cancer has been disease free for a specific period after treatment. Between January 1984 and April 2005, 615 patients with cervical cancer stages I-IIA underwent radical hysterectomy with or without adjuvant radiotherapy. The Kaplan-Meier method was used to detect statistical significance and multistate risk models to estimate the influence of covariates and to generate predicted survival curves by simulation. Simulations were done for patients with positive lymph nodes (n= 123), patients with negative lymph nodes (n= 492), and 4 hypothetical patients. The 5-year cancer-specific survival and disease-free survival of the entire group was 84% and 76%, respectively. The probability of death of the two lymph node groups and the four hypothetical patients was demonstrated in predicted cumulative probability plots. It is possible with multistate risk models to give a detailed prediction of the future (disease-free) survival, given the fact that a patient has been disease free for a specific period after treatment. This possibility is an important step forward to improve the quality of cancer care.

The number of pelvic lymph nodes in the quality control and prognosis of radical hysterectomy for the treatment of cervical cancer.

AIMS: To determine if the number of removed lymph nodes in radical hysterectomy with lymphadenectomy (RHL) influences survival of patients with early stage cervical cancer and to analyze the relation of different factors like patient age, tumour size and infiltration depth with the number of nodes examined in node-negative early stage cervical cancer patients. METHODS: Of consecutive patients, who underwent RHL between January 1984 and April 2005, 331 had negative nodes (group A) without adjuvant therapy and 136 had positive nodes (group B). The Kaplan-Meier method and Cox regression model were used to detect statistical significance. Factors associated with excision of nodes were confirmed with linear regression models. RESULTS: The median number of removed nodes was 19 and 18 for group A and group B, respectively. There was no significant relationship between the number of removed nodes and the cancer specific survival (CSS) or disease free survival (DSF) for patients of group A (p=0.625 and p=0.877, respectively). The number of removed nodes in group B was not significantly associated with the CSS (p=0.084) but it was for the DSF (p=0.014). Factors like patient age, tumour size and infiltration depth were not associated with the number of nodes. CONCLUSIONS: No relation was found between the number of negative nodes examined after RHL for the treatment of early stage cervical cancer and CSS or DFS. However, a higher amount of removed lymph nodes leaded to a better DFS for patients with positive nodes. It is suggested that patients with positive nodes benefit from a complete pelvic lymphadenectomy and a sufficient yield of removed nodes.

Implementation of the laparoscopic simulator in a gynecological residency curriculum.

BACKGROUND: In view of the current emphasis on increasing patient safety and quality control in laparoscopic surgery, there is a growing need to improve laparoscopic training. This study was conducted to investigate if and when residents reached performance standards for basic laparoscopic skills on a boxtrainer and to analyze the current state of implementation of laparoscopic simulators in a gynecological residency curriculum. METHODS: Residents across all 6 years of residency (postgraduate year [PGY] 1-6) were tested once on our boxtrainer by performing five inanimate tasks (pipe cleaner, rubber band, beads, cutting circle, intracorporeal knot tying). A sumscore for the five tasks was calculated for each participant (sum of all scores). Scores were calculated by adding completion time and penalty points, thus rewarding both speed and precision. These data were compared with scores of laparoscopic experts, which were set as performance standards. RESULTS: Of the participants, 111 were residents (7 PGY1, 27 PGY2, 29 PGY3, 28 PGY4, 14 PGY5, 6 PGY6) and 8 were experts. At the end of residency, PGY6 residents reached the performance standard for all tasks except intracorporeal knot tying. It was not until PGY5 that residents reached the performance standard for the pipe cleaner task; PGY1, for rubber band; PGY5, for beads; PGY4, for circle cutting; and PGY6, for sumscore. Throughout residency PGY6 had a mean total of only 3.6 h of simulator training experience. No correlation was found between this previous voluntary simulator training experience and performance on our boxtrainer during this study (sumscore), and between previous voluntary simulator training and total laparoscopic procedures performed. In a combined multivariate analysis, sumscore performance remained significantly associated with the number of laparoscopic procedures performed by residents when they were working as as a primary surgeon (p = 0.002), and not with the cumulative hours of simulator training during residency prior to participating in this study (p = 0.15). CONCLUSIONS: In a current Dutch gynecological residency curriculum, residents do not reach all performance standards for basic laparoscopic skills on the boxtrainer. We conclude that the voluntary simulator training program has a substantial risk to fail and that the implementation of the laparoscopic skills simulator in the current residency curriculum is in its infancy.

Postoperative radiation therapy improves prognosis in patients with adverse risk factors in localized, early-stage cervical cancer: a retrospective comparative study.

The objective of this study was to assess the role of postoperative radiotherapy (RT) in early-stage cervical carcinoma with risk factors other than positive nodes, parametrial invasion, or positive margins and to compare outcomes using the Leiden University Medical Center (LUMC) modification of the Gynecologic Oncology Group (GOG) system with the GOG prognostic scoring system itself. Between January 1984 and April 2005, 402 patients with early-stage cervical cancer underwent radical hysterectomy. A total of 51 patients (13%) had two of the three risk factors and had pathologic tumor size (> or =40 mm), invasion (> or =15 mm), and capillary lymphatic space involvement, and were identified as the so-called high-risk (HR). We compared 34 patients who received RT based on the LUMC risk profile (67%) with 17 who did not (33%). The GOG score was calculated as well. We compared the GOG scores within the LUMC risk groups: HR+ (two out of three risk factors) and HR- (less than two out of three risk factors). Differences in 5-year cancer-specific survival (CSS) and 5-year disease-free survival (DFS) between the HR group treated with RT (86%, 85%) and without RT (57%; 43%) were statistically significant. The LUMC criteria did not significantly differ from the GOG risk profile, concerning recurrence, CSS, and DFS. HR patients benefit from adjuvant RT. The LUMC modification of the GOG system seems to be simpler and has a slightly higher threshold for the indication for RT but without a difference in outcome.

An observational longitudinal study to evaluate miction, defecation, and sexual function after radical hysterectomy with pelvic lymphadenectomy for early-stage cervical cancer.

The objective of this study was to evaluate the problems with miction, defecation, and sexuality after a radical hysterectomy with or without adjuvant radiotherapy for the treatment of cervical cancer stage I-IIA. This study included an observational longitudinal study of self-reported bladder, defecation, and sexual problems with a baseline score. Ninety-four women were included in the study. An age-matched control group consisted of 224 women. The patients showed significantly more negative effects on sexual function compared with both the controls and their situation before the treatment throughout 24 months of follow-up. The problems included less lubrication, a narrow and short vagina, senseless areas around the labia, dyspareunia, and sexual dissatisfaction. Up to 12 months after the treatment, the patients complained significantly more of little or no urge to urinate and diarrhea as compared with the controls. Adjuvant radiotherapy did not increase the risk of bladder dysfunction, colorectal motility disorders, and sexual functions. We conclude that a radical hysterectomy for the treatment of early-stage cervical carcinoma is associated with adverse effects mainly on sexual functioning.

Combining HPV and MIB-1 tests reduces the number of colposcopies in women with equivocal cytology.

BACKGROUND: In this study the MIB-1 immunostaining pattern as an index of cellular proliferation was analyzed in smears diagnosed as borderline dyskaryosis in order to establish whether the combination of human papillomavirus testing and MIB-1 staining could resolve equivocal cytology. METHODS: Conventional Pap smears of 108 women diagnosed as borderline dyskaryosis were stained with MIB-1 and the proliferation index was assessed. These women were evaluated by colposcopy, histological sampling, and human papillomavirus, semi-quantitative evaluated by hybrid Capture II test. RESULTS: All 64 human papillomavirus- and MIB-1-negative women had no underlying high-grade cervical intraepithelial neoplasia or cervical cancer. Forty of the 104 women with normal histology or cervical intraepithelial neoplasia I were positive for human papillomavirus, compared to only one positive MIB-1 test (i.e. proliferation index of more than 35%). CONCLUSIONS: Adding a MIB-1-test in human papillomavirus-positive women with equivocal cytology might reduce the number of colposcopies needed to predict > or = cervical intraepithelial neoplasia II. With this approach only four instead of 43 human papillomavirus-positive women would have been referred for colposcopy.

Can viral load, semi-quantitatively evaluated, of human papillomavirus predict cytological or histological outcome in women with atypical squamous or glandular cells of undetermined significance cytology?

OBJECTIVE: 1) To assess the regression to normal cytology in women with cervical smears diagnosed as atypical squamous or glandular cells of undetermined significance (ASCUS/AGUS) and absence or clearance of human papillomavirus (HPV) infection; 2) To evaluate the association between viral load, semi-quantitatively evaluated, and cytological or histological outcome. MATERIAL AND METHODS: In this cohort study HPV test and biopsy was taken in 148 women with ASCUS/AGUS cytology. After 12-18 months a HPV test and cervical smear were repeated in 121 women. RESULTS: Absence or clearance of HPV showed significantly more regression to normal cytology than persistent or newly acquired infected women, odds ratio 27 (95% confidence interval; 7-103). The viral load of the HPV test at enrollment was not correlated with the follow-up cytological outcome (Spearman correlation coefficient 0.2, p = 0.2). A marked association between viral load and histological outcome at enrollment was shown (Spearman correlation coefficient 0.43, p < 0.0001). CONCLUSION: Absence or clearance of HPV can predict regression to normal cytology. Viral load at enrollment cannot predict cytological regression. There was a marked association between viral load and the underlying CIN at enrollment. However, there was large overlapping of viral loads among the grades of CIN. Therefore, viral load is not a useful parameter to predict high-grade lesions in women with ASCUS/AGUS cytology.

Medical fellowship programme within the Gynaecological Cancer Group of the European Organisation for Research and Treatment of Cancer.

In 1962, the European Organisation for Research and Treatment of Cancer (EORTC) was founded, and in the course of the years it developed into the leading European organisation in cancer research. Currently, the EORTC is organised into (Pre-)Clinical Groups and Task Forces consisting of scientists and/or clinicians. One of these groups with a specific area of interest in cancer research is the Gynaecological Cancer Group (GCG). The EORTC offers fellowship programmes to physicians and scientists from all over the world to create a possibility to be temporarily linked to an EORTC group or a specific research project. Over the past decade, 76 research fellowships have been appointed at the EORTC Data Center. This paper shows an overview of the activities of one EORTC/GCG medical fellow.