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Background: Before the era of immunotherapies and antibody-drug conjugates, there were limited chemotherapeutic options for patients with recurrent and metastatic cervical cancer. Combination therapies with cisplatin have shown some superiority over monotherapy. This study examined platinum-free treatment regimens, comparing a combination of topotecan and paclitaxel (TP) with topotecan and cisplatin (TC) in patients with recurrent or metastatic cervical cancer, with or without prior platinum-based treatment., Methods: The AGO-Zervix-1 Study (NCT01405235) is a prospective, randomized phase III study in which patients were randomly assigned at a 1:1 ratio to treatment within the control arm with topotecan (0.75 mg/m 2 ) on days 1-3 and cisplatin (50 mg/m 2 ) on day 1 every 3 weeks and in the study arm topotecan (1.75 mg/m 2 ) and paclitaxel (70 mg/m 2 ) on days 1, 8, and 15 every 4 weeks or treatment. The primary study aim was overall survival; progression-free survival, toxicity, and quality of life were secondary aims. The interim and final analysis is here reported after recruitment of 173 of 312 planned patients., Results: Median overall survival in the TP arm was 9.6 months, compared with 12.0 months in the TC arm (log-rank test, P = 0.33). Median progression-free survival rates were 4.4 months with TP and 4.2 months with TC (log-rank test, P = 0.47). Leukopenia and nausea/vomiting were more frequent in the cisplatin-containing arm. Otherwise, toxicity profiles were comparable. There were no differences in FACT-G-assessed quality of life., Conclusion: Platinum-based combination chemotherapy remains the standard of care chemotherapy regimen for patients with recurrent or metastatic cervical cancer., Competing Interests: Declaration of competing interest P.G. has received honoraria from Novartis, MSD, and AstraZeneca. I.V. reports Consulting fees from Agenus, AstraZeneca, Bristol Myers Squibb, Eisai, Genmab, GSK, Immunogen, Karyopharm, Mersana, MSD, Molecular Partners, Novocure, Novartis, Oncoinvent, Regeneron, Seagen, Verastem Oncology, Zai Lab, Zentalis. P.H. declares honoraria from Amgen, Astra Zeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis, Eisai, Mersana, Exscientia, Advisory Board participations from Astra Zeneca, Roche, GSK, Clovis, Immunogen, MSD, Miltenyi, Novartis, Eisai and Research Funding (Inst) from Astra Zeneca, Roche, GSK, Genmab, DFG, European Union, DKH, Immunogen, Seagen, Clovis, Novartis. The other authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: In a previous phase II trial, we showed that topical imiquimod (IMQ) therapy is an efficacious treatment for high-grade squamous intraepithelial lesion (HSIL). Aim of the present study was to investigate the non-inferiority of a 16-week topical, self-applied IMQ therapy compared to large loop excision of the transformation zone (LLETZ) in patients diagnosed with HSIL., Methods: Phase III randomized, controlled, multicenter, open trial performed by Austrian Gynecologic Oncology group. Patients with histologically proven cervical intraepithelial neoplasia (CIN)2 (30 years and older) or CIN3 (18 years and older) and satisfactory colposcopy were randomized to topical IMQ treatment or LLETZ. Successful treatment was defined as negative HPV high-risk test result 6 months after start of the treatment. Secondary endpoints were histological outcome and HPV clearance rates., Results: Within 3 years 93 patients were randomized, received the allocated treatment and were available for ITT analysis. In the IMQ group negative HPV test at 6 months after treatment start was observed in 22/51 (43.1%) of patients compared to 27/42 (64.3%) in the LLETZ group on ITT analysis (rate difference 21.2%-points, 95% two-sided CI: 0.8 to 39.1). In the IMQ group histologic regression 6 months after treatment was observed in 32/51 (63%) of patients and complete histologic remission was observed in 19/51 (37%) of patients. Complete surgical resection was observed in 84% after LLETZ., Conclusion: In women with HSIL, IMQ treatment results in lower HPV clearance rates when compared to LLETZ. LLETZ remains the standard for women with HSIL when treatment is required., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01283763, EudraCT number: 2012-004518-32., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Deficiency in butyrylcholinesterase (BChE), a condition commonly noticed in liver damage, inflammation, and malnutrition, has previously been associated with impaired prognosis in different malignancies. The aim of the present study was to investigate the value of pretreatment serum BChE levels as a prognostic biomarker in patients with cervical cancer treated with primary (chemotherapy-[chemo-])radiation therapy., Methods: We retrospectively evaluated data of a consecutive series of patients with cervical cancer treated with primary (chemo-)radiation therapy between 1998 and 2015. Pretreatment serum BChE levels were correlated with clinico-pathological parameters and response to treatment. Uni- and multivariate survival analyses were performed to assess the association between decreased serum BChE levels and progression-free (PFS), cancer-specific (CSS), and overall survival (OS)., Results: A total of 356 patients were eligible for inclusion into the present study. The median (IQR) pretreatment serum BChE level was 6180 (4990-7710) IU/l. Lower serum BChE levels were associated with lower BMI (p < 0.001), advanced tumor stage (p = 0.04), poor treatment response (p = 0.002), the occurrence of disease recurrence (p = 0.003), and the risk of death (p < 0.001). In uni- and multivariate analyses, low pretreatment serum BChE levels were independently associated with shorter PFS (HR 1.8 [1.2-2.6]; p = 0.002), CSS (HR 2.2 [1.4-3.5], p < 0.001), and OS (HR 2.0 [1.4-2.9]; p < 0.001)., Conclusions: Low pretreatment serum BChE levels are associated with advanced tumor stage and poor response to treatment, and serve as an independent prognostic biomarker for shorter PFS, CSS, and OS in patients with cervical cancer treated with primary (chemo-)radiation therapy.

Purpose: The aim of the present study was to assess the value of the Glasgow Prognostic Score (GPS) as a prognostic tool for predicting post-relapse survival (PRS) in patients with recurrent cervical cancer., Methods: We retrospectively evaluated the data of 116 patients with recurrent cervical cancer in whom serologic biomarkers had been assessed at the time of relapse. The GPS was calculated as follows: patients with elevated serum C-reactive protein levels and hypoalbuminemia were allocated a score of 2, and those with 1 or no abnormal value were allocated a score of 1 and 0, respectively. To assess the association between factors including the GPS and PRS, we performed uni- and multivariate survival analyzes., Results: After a median follow-up of 20.9 months from recurrence, a 5-year PRS rate of 25% (SE 4.7%) was observed. Only in 29.8% of the patients, recurrence was limited to the pelvis. In uni- and multivariate survival analyzes, the GPS [HR 1.6 (95% CI 0.9-2.4), p = 0.01], a history of radiation therapy as part of initial treatment [HR 2.7 (95% CI 1.1-6.9), p = 0.03], and the presence of peritoneal carcinomatosis or multiple sites of relapse [HR 4.2 (95% CI 1.9-9.3), p < 0.001] were associated with shorter PRS. The GPS correlated with higher squamous cell carcinoma antigen levels (p = 0.001), shorter median PRS (p = 0.009), and less intensive treatment for relapse (p = 0.02)., Conclusions: A higher GPS at the time of relapse, a history of radiation therapy, and the presence of peritoneal carcinomatosis or multiple sites of relapse are independently associated with shorter PRS in patients with recurrent cervical cancer.

Objectives: Recent data support the use of pembrolizumab in cervical cancer. The aim of this study was to investigate pembrolizumab in heavily pretreated patients with recurrent cervical cancer., Methods: Data from consecutive patients treated with pembrolizumab at a single academic institution were assessed. Programmed cell death ligand 1 (PD-L1) status and microsatellite instability were assessed from tumor samples. Irrespective of PD-L1 expression status, pembrolizumab was administered at fixed dose of 200 mg intravenously every 3 weeks. Treatment response was evaluated by computed tomography, using iRECIST (2017) criteria. Descriptive statistics were performed. Results from previous publications were summarized., Results: In total, 11 heavily pretreated patients with recurrent cervical cancer received pembrolizumab. Of these, 2 (18%) patients showed partial response and 2 (18%) patients showed disease stabilization on computed tomography, resulting in a clinical benefit rate of 36%. These 4 patients are still on treatment and durable antitumor activity of up to 52 weeks was observed. Treatment was generally well tolerated with 1 patient showing dose-limiting toxicity. Median overall survival was 26 (3-53) weeks, and a 6-month overall survival rate of 65% was observed. Of the 5 patients with high PD-L1 expression, 3 showed response to treatment., Conclusions: Pembrolizumab shows promising activity in heavily pretreated patients with recurrent cervical cancer in a real-life clinical setting. Treatment was generally well tolerated, and adverse effects were manageable. Growing evidence supports the use of pembrolizumab in this group of patients.

Background and Purpose: Patients with recurrent cervical cancer (RecCC) who received definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT) as primary treatment are currently treated in our institution with palliative intent by chemotherapy (CHT) combined with bevacizumab (BEV). We aim to evaluate the risk of gastrointestinal (GI)/genitourinary (GU) fistula formation in these patients., Materials and Methods: Data of 35 consecutive patients with RecCC treated initially with radiochemotherapy and IGABT were collected. Known and presumed risk factors associated with fistula formation were evaluated. Fistula rate was compared between patients receiving CHT or CHT+BEV., Results: Of the 35 patients, 25 received CHT and 10 patients received CHT+BEV. Clinical characteristics were comparable. Fistulae were reported in 6 patients: two fistulae (8%) in the CHT group, four (40%) in the CHT+BEV group. GU fistula occurred in the CHT+BEV group only (3/4). Of these 6 patients with fistulae, 5 (83%) had undergone previous invasive procedures after the diagnosis of RecCC and 1 patient had undergone pelvic re-irradiation; 3/6 patients had developed a local recurrence. No other risk factors for fistula formation were identified., Conclusion: In patients with RecCC after definitive radiochemotherapy including IGABT, the addition of BEV to CHT may increase the risk for GU fistula formation, particularly after invasive pelvic procedures. Future clinical studies are required to identify predictors for fistula formation to subsequently improve patient selection for the addition of BEV in the RecCC setting.

Background: To study the natural history of cervical intraepithelial neoplasia (CIN) during pregnancy and to compare the rates of persistence, progression and regression of CIN by colposcopically guided biopsy (CGB) during pregnancy with outcome in non-pregnant-women., Methods: A retrospective analysis of all pregnant women diagnosed with CIN at our outpatient clinic between 2005 and 2010 was performed. A CGB for histo-pathological analysis was obtained in all participants and observational management was performed. The histo-pathologic findings of initial and postpartum visits were collected. Rates of persistence, progression and regression of CIN were assessed. Results were compared to a matched control group of non-pregnant women where observational management was performed for at least three months. In addition a review of the literature and pooled analysis of published data was performed., Results: A total of 51 pregnant women with CIN were included into analysis. CIN 1, 2, and 3 was diagnosed by CGB in 33.3, 13.7 and 52.9% of all pregnant women, respectively. The postpartum histo-pathologic evaluation of the pregnant cohort revealed a significantly higher tendency to spontaneous regression (56.9 versus 31.4%, p = 0.010) and a considerably, but not significantly higher complete remission rate (41.2 versus 27.5%, p = 0.144) when compared to the non-pregnant cohort. In addition, we observed a significantly lower CIN persistence rate than in the non-pregnant cohort (39.2 versus 58.8%, p = 0.048). The progression rate was notably low in the pregnant cohort (3.9%) and no progression to invasive cancer was observed., Conclusions: CIN lesions show considerably high spontaneous regression rates postpartum. Once presence of invasive cancer is ruled out definitive treatment can be deferred to the postpartum period.

Purpose: The extent of conization seems to influence the risk of preterm birth. The aim of this study was to compare the cone volume after surgical resection with large loop excision of the transformation zone (LLETZ) and cold knife conization (CKC)., Methods: The present retrospective multi-center study comprises 804 consecutive women, who underwent LLETZ (n = 412) or CKC (n = 392) between 2004 and 2009. Univariate and multivariable analyses were performed to compare cone volumes removed by LLETZ and CKC and identify independent risk factors for large cone volume., Results: The median resected cone volume after LLETZ was significantly smaller [1.6 cm(3) (0.8-2.9)] than after CKC [2.1 cm(3) (1.4-3.5)] (<0.0001). Complete resection rates were comparable in both groups. Conization method, cone depth, and institution type were independent risk factors for removal of a large cone volume., Conclusion: CKC removes larger cone volumes than LLETZ without the advantage of higher complete resection rates.

Objective: Alternatives to surgical therapy are needed for the treatment of high-grade cervical intraepithelial neoplasia (CIN 2-3). We aimed to estimate the efficacy of a treatment with imiquimod, a topical immune-response modulator, in patients with CIN 2-3., Materials and Methods: Fifty-nine patients with untreated CIN 2-3 were randomly allocated to a 16-week treatment with self-applied vaginal suppositories containing either imiquimod or placebo. The main outcome was efficacy, defined as histologic regression to CIN 1 or less after treatment. Secondary outcomes were complete histologic remission, human papillomavirus (HPV) clearance, and tolerability. Assuming a two-sided 5% significance level and a power of 80%, a sample size of 24 patients per group was calculated to detect a 35% absolute increase in CIN 2-3 regression., Results: Histologic regression was observed in 73% of patients in the imiquimod group compared with 39% in the placebo group (P=.009). Complete histologic remission was higher in the imiquimod group (47%) compared with the placebo group (14%) (P=.008). At baseline, all patients tested positive for high-risk HPV. Human papillomavirus clearance rates were increased in the imiquimod group (60%) compared with the placebo group (14%) (P<.001). In patients with HPV-16 infection, complete remission rates were 47% in the imiquimod group compared with 0% in the placebo group (P=.003). Microinvasive cancer was observed in three of 59 (5% [1-14%]) patients, all within the placebo group. Topical imiquimod treatment was well tolerated, and no high-grade side effects were observed., Conclusion: Topical imiquimod is an efficacious and feasible treatment for patients with CIN 2-3.

Introduction: Recent large epidemiologic population-based studies identified gamma-glutamyltransferase (GGT) as a marker for increased cervical cancer incidence. Furthermore, high levels of GGT seem to increase the risk of progression of high-grade cervical dysplasia to invasive carcinoma. Therefore, we evaluated the association between pre-therapeutic serum GGT levels, tumor stage and prognosis in patients with cervical cancer., Materials and Methods: In this multi-center trial, pre-therapeutic GGT levels were examined in 692 patients with cervical cancer. GGT levels were correlated with clinico-pathological parameters. Patients were assigned to previously described GGT risk groups and uni- and multivariable survival analyses were performed., Results: GGT serum levels were associated with FIGO stage (p<0.0001) and age (r=0.2, p<0.0001) but not with lymph node involvement (p=0.85), and histological type (p=0.98). High-risk GGT group affiliation (p=0.01 and p<0.0001) was associated with poor disease-free and overall survival in a univariate analysis, but not in a multivariable Cox-regression model (p=0.59 and p=0.171). We further investigated the association between prognosis and GGT and observed a linear correlation between GGT and prognosis. Therefore we were not able to identify a clear prognostic cut-off value for GGT in patients with cervical cancer., Conclusions: High GGT--a marker for apoptosis and cervical cancer risk--is associated with advanced tumor stage in patients with cervical cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT)±chemotherapy (ChT)., Methods: Treatment schedule was EBRT with 45-50.4Gy±concomitant cisplatin chemotherapy plus 4×7Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the "protocol period" (2001-2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90>85Gy), often with inserting additional interstitial needles. Dose volume constraints (D(2cc)) were 70-75Gy for rectum and sigmoid and 90Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis., Findings: One hundred and fifty-six consecutive patients (median age 58years) with cervix cancer FIGO stages IB-IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93±13Gy, D(2cc) 86±17Gy for bladder, 65±9Gy for rectum and 64±9Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3years was 95%; 98% for tumours 2-5cm, and 92% for tumours >5cm (p=0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3years was overall 74%, 83% for tumours 2-5cm, 70% for tumours >5cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3years was in total 68%, 72% for tumours 2-5cm, 65% for tumours >5cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1+2 and 11 grade 3+4 late events were observed in 143 patients. G1+2/G3+4 events for bladder were n=32/3, for rectum n=14/5, for bowel (including sigmoid) n=3/0, for vagina n=128/2, respectively., Interpretation: 3D conformal radiotherapy±chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95-100% at 3years in limited/favourable (IB/IIB) and 85-90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65-70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the association between five interleukin-1 (IL-1) and -6 gene polymorphisms and risk of high grade cervical intraepithelial neoplasia (CIN 2-3)., Methods: This case-control study investigates five common IL-1 and IL-6 gene polymorphisms in 131 women with CIN 2-3 and 209 controls by pyrosequencing and polymerase chain reaction. Associations between gene polymorphisms and risk of CIN 2-3 are analysed by univariate and multivariable models. Their combined effect on the risk of CIN is evaluated by haplotype analysis., Results: In a multivariable regression model IL1A -889 (odds ratio 0.3 [95% confidence interval 0.1-0.8], p=0.01) and smoking (4.0 [1.7-9.1], p=0.001) are independently associated with the risk of high grade CIN. Haplotype analysis does not reveal any high-risk combinations for the susceptibility of CIN., Conclusion: The single nucleotide polymorphism IL1A -889 is independently associated with risk of high grade CIN., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: C-reactive protein (CRP) is the prototypical biomarker of inflammation. Genetic variations within the CRP gene have been shown to be associated with alterations of CRP expression and prognosis in cancer patients. The purpose of this study was to evaluate the association between four polymorphisms of the CRP gene, CRP serum levels, clinicopathological parameters of cervical cancer and survival in patients with cervical cancer., Materials and Methods: The four most common single nucleotide gene polymorphisms CRP1919 (rs1417938), CRP2667 (rs1800947), CRP3872 (rs1205), and CRP5237 (rs2808630) were evaluated in 178 patients with cervical cancer. DNA was extracted from blood samples and CRP gene polymorphisms were investigated, using pyrosequencing. Findings were correlated with CRP serum levels, clinico-pathological parameters of cervical cancer, and disease-free and overall survival. Furthermore, the association between haplotype combinations and survival was investigated., Results: Presence of the CRP gene polymorphism CRP5237A>G was associated with lower CRP serum levels (p=0.04). Univariate survival analysis revealed that CRP1919T>A polymorphism (p=0.02), International Federation of Gynecology and Obstetrics stage (p<0.001), lymph node involvement (p=0.004), histological grade (p=0.01), and serum CRP levels (p<0.001) correlate with overall survival. In the multivariable Cox regression model, CRP1919T>A (p=0.02), tumor stage (p<0.001), lymph node involvement (p=0.03), patients' age (p=0.02), and serum CRP levels (p<0.001) were found to be independently associated with overall survival. None of the haplotype combinations were associated with prognosis of patients with cervical cancer., Conclusion: Presence of the CRP1919T>A polymorphism was associated with impaired overall survival in patients with cervical cancer. The CRP gene polymorphism CRP5237A>G was associated with decreased serum CRP levels.

Objective: To evaluate the association between 3 vascular endothelial growth factor (VEGF) gene polymorphisms and susceptibility of cervical intraepithelial neoplasia (CIN)., Materials and Methods: This prospectively collected case-control study investigates three common VEGF gene polymorphisms (ie, VEGF -460 [rs833061], VEGF +405 [rs2010963], and VEGF +936 [rs3025039]) in 203 women with CIN and 209 healthy women by DNA pyrosequencing. Associations between polymorphisms and CIN risk are evaluated with univariate and multivariable models and haplotype analysis., Results: In a multivariable regression model, the variant VEGF +405C allele was associated (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.2-5.1], P = 0.02) with increased susceptibility of CIN independent of number of sexual partners (OR, 2.2; 95% CI, 1.1-4.6; P = 0.03) and smoking (OR, 3.3; 95% CI, 1.6-6.6; P = 0.001). The haplotype VEGF -460C - +405C - +936C was associated with an OR of 5.2 (95% CI, 1.2-52.7) for the susceptibility of CIN., Conclusions: The presence of the variant VEGF +405C allele and the haplotype VEGF -460C - +405C - +936C are independently associated with higher susceptibility of CIN.

Objectives: The Glasgow Prognostic Score (GPS) is known to reflect the degree of tumor-associated cachexia and inflammation and is associated with survival in various malignancies. We investigated the value of the GPS in patients with cervical cancer., Methods: We included 244 consecutive patients with cervical cancer in our study. The pretherapeutic GPS was calculated as follows: patients with elevated C-reactive protein serum levels (>10 mg/L) and hypoalbuminemia (<35 g/L) were allocated a score of 2, and patients with 1 or no abnormal value were allocated a score of 1 or 0, respectively. The association between GPS and survival was evaluated by univariate log-rank tests and multivariate Cox regression models. The GPS was correlated with clinicopathologic parameters as shown by performing chi2 tests., Results: In univariate analyses, GPS (P < 0.001, P < 0.001), International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.001, P < 0.001), and lymph node involvement (P < 0.001, P < 0.001), but not patients' age (P = 0.2, P = 0.07), histological grade (P = 0.08, P = 0.1), and histological type (P = 0.8, P = 0.9), were associated with disease-free and overall survival, respectively. In a multivariate analysis GPS (P = 0.03, P = 0.04), FIGO stage (P = 0.006, P = 0.006), and lymph node involvement (P = 0.003, P = 0.002), but not patients' age (P = 0.5, P = 0.5), histological grade (P = 0.7, P = 0.6), and histological type (P = 0.4, P = 0.6) were associated with disease-free and overall survival, respectively. The GPS was associated with FIGO stage (P < 0.001) and histological grade (P = 0.02)., Conclusions: The GPS can be used as an inflammation-based predictor for survival in patients with cervical cancer.

Background: The development of low-grade cervical dysplasia (CIN I) has been linked to a decrease of apoptosis and Langerhans cell (LC) count in the cervical epithelium and to an increase in the expression of various adhesion molecules. Vaginally administered progesterone locally increases apoptosis and the number of LCs, and reduces the expression of various adhesion molecules. We hypothesized that vaginal progesterone would increase the regression rate in women with CIN I., Materials and Methods: A non-randomized, open phase II trial with vaginal progesterone as treatment of CIN I was performed. Forty women were treated with vaginal micronized progesterone at 400 mg daily for 10 days/month from menstrual cycle day 16-25 for 6 months. The control group consisted of 96 consecutive women with CIN I treated prior and after the study period. After 3 and 6 months, all women were examined for regression, persistence, or progression of disease. Women were treated according to standard clinical protocols. In cases of progressive disease, a large loop excision of the transformation zone (LLETZ) was performed., Results: The mean (standard deviation) age of women in the treatment and control groups was 32.0 (7.6) and 32.6 (8.5) years, respectively. A total of 30% and 38.3% of CIN I regressed in the treatment and control group, respectively. In a multivariate model, a higher number of children, a higher lifetime number of sexual partners, a lower age at first intercourse, non-use of condoms as contraception, current smoking, and treatment with vaginal progesterone were associated with a higher probability of having persistent or progressive CIN. Current smoking and treatment with vaginal progesterone were associated with a higher probability of undergoing LLETZ., Conclusion: Treatment with vaginal progesterone is associated with a lower rate of disease regression and a higher rate of surgical interventions in women with CIN I. We suggest that vaginal progesterone treatment should not be applied in women with known dysplasia.

Background: Many physicians advocate repeat surgery after cervical conization with a diagnosis of cervical cancer stage FIGO IA1. In a multicenter trial, whether repeat surgery is a necessary therapeutic procedure in the treatment of cervical cancer stage FIGO IA1 was evaluated and a literature review performed., Patients and Methods: From 1997 to 2006, 156 patients with squamous cell cervical cancer, stage FIGO IA1, were primarily treated with conization in three different institutions; 102 of these patients underwent repeat surgery, comprising the study group for the present trial., Results: In the conization specimen, 22 patients had clear resection margins, none of whom had residual dysplasia in the repeat conization/hysterectomy specimen. Sixty-four patients had cervical intraepithelial neoplasia (CIN) I-III at the conization resection margin; of these, 29, 9, 24, and 2 patients had no sign of residual dysplasia, CIN I, CIN II/III, or multifocal cervical cancer FIGO IA1 in the repeat conization/hysterectomy specimen, respectively. Sixteen patients had invasive cancer at the resection margin of the conization specimen; no sign of dysplasia, CIN I, CIN II/III, or residual cervical cancer were found in the repeat conization/hysterectomy specimen in 4, 1, 5, and 6 cases, respectively. In a multivariate analysis, risk factors for residual CIN II/III or multifocal invasive carcinoma in patients with CIN at the resection margin were advanced patient age and presence of multifocal invasive cervical cancer, but not depth of invasion, lymphovascular space involvement (LVSI), nor positive endocervical curettage., Conclusion: The risk of residual dysplasia after conization of FIGO IA1 cervical cancer with clear margins is minimal. A considerable number of patients with locally resected FIGO IA1 cervical cancer, who had CIN I-III at the resection margin, showed signs of residual high-grade CIN or multifocal cervical cancer. The need for repeat surgery when signs of invasive carcinoma are present at the resection margins after conization is clear.

Objective: The purpose of this study was to evaluate the association between fibrinogen plasma levels on disease-free patients and overall survival in patients with cervical cancer., Study Design: Pretherapeutic fibrinogen plasma levels were examined in 313 patients with cervical cancer who were treated at the Department of Obstetrics and Gynecology, Medical University of Vienna. Fibrinogen plasma levels were correlated with clinical-pathologic findings and patient survival., Results: Mean (+/- SD) pretherapeutic fibrinogen plasma levels were 417.4 mg/dL (+/- 130.3 mg/dL). Elevated fibrinogen plasma levels were associated with advanced tumor stage (P < .001) and patient age (P < .001), but not with histologic type (P = .4), histologic grade (P = .1), and pelvic lymph node involvement (P = .9). In a multivariate survival analysis, fibrinogen plasma levels (P < .001 and < .001) and lymph node involvement (P < .001 and = .001), but not patients' age (P = .8 and .4) and histologic type (P = .7 and .5) were associated with overall or disease-free survival, respectively. Histologic grade was associated with disease-free (P = .01), but not with overall, survival (P = .2)., Conclusion: Fibrinogen plasma levels are an independent prognostic parameter in patients with cervical cancer.

Background: We aimed to identify the number of histologically verified cervical intraepithelial neoplasia (CIN)/cervical cancer lesions detected by endocervical cytobrush (EC) which have been missed by repeat PAP smear and colposcopy before large loop excision of the transformation zone (LLETZ)., Patients and Methods: A retrospective cohort study of 1,676 consecutive patients in a colposcopy clinic undergoing repeat PAP smear, colposcopy, biopsy, and subsequent LLETZ., Results: Data were available for 1,421 patients. EC identified 31/1,367 (2.2%) cases of CIN and/or cervical cancer missed by repeat PAP smear and colposcopy. Compared to repeat PAP smear and colposcopy, the combination of repeat PAP smear, colposcopy and EC increased the positive predictive value (PPV) (89.6% vs. 98.9%, p=0.07), but this difference was not statistically significant. Sensitivity (93.1% vs. 93.9%; p=0.8), specificity (27.7% vs. 27.7%; p=1.0), and negative predictive value (NPV) (11.9% vs. 13.1%, p=0.9) were also not significantly different. The number needed to screen (NNS) for identifying one additional case of CIN and/or invasive cancer by EC was 45. In a multivariate analysis, presence of CIN/cervical cancer in the LLETZ specimen and human papilloma virus infection, but not age, visibility of the transformation zone or presence of an endovcervical lesion were independently associated with the likelihood of CIN and/or invasive cancer detected by EC., Conclusion: Adding EC to repeat PAP smear and colposcopy identifies 2.2% more cases of CIN and/or cervical cancer, but does not significantly increase the sensitivity, specificity, PPV or NPV of repeat PAP smear and colposcopy.

Background: Laparoscopic pelvic lymph node staging is widely used in patients with cervical cancer prior to the initiation of primary chemoradiation therapy. Data on the morbidity of this procedure are sparse., Patients and Methods: Between 1995 and 2007, 71 patients with locally advanced cervical cancer (FIGO stage IB2-IIIB) underwent laparoscopic pelvic lymph node staging prior to primary chemoradiation therapy. Surgical outcome and perioperative morbidity were evaluated., Results: The median operation time, number of resected lymph nodes and time between surgery and the initiation of chemoradiation therapy was 100 minutes, 15 lymph nodes and 18 days, respectively. Intraoperatively, one laceration of the obturatoric artery and one bladder injury occurred. One procedure was converted to a laparotomy. Three short-term postoperative complications including one hematoma in the port side area, one umbilical suture insufficiency requiring a hernia reposition, and one postoperative bleeding that required rehospitalization were noted. Two patients with intraabdominal abscesses required repeat laparoscopy. Of note, three patients developed port site metastases during followup., Conclusion: Although patients experienced perioperative morbidity, the present study provides further evidence that, overall, laparoscopic pelvic lymph node staging is a relatively safe procedure for patients with cervical cancer.

Background: The clinical value of colposcopy and biopsy prior to large loop excision of the cervical transformation zone (LLETZ) with respect to negative histology and positive specimen margin rates, was evaluated., Patients and Methods: A total of 2,050 consecutive patients who had undergone LLETZ from 1997 to 2005, were included. As diagnostic workup prior to LLETZ, 290 patients underwent repeat PAP test only and 1,760 patients had undergone colposcopy/biopsy., Results: The diagnostic approach using colposcopy/biopsy reduced the rates of negative histology and positive margins from 6.0% to 1.9% (p < 0.001) and from 28.2% to 21.7% (p = 0.002), respectively. The rates of invasive carcinomas were not different between the groups (6.6% vs. 6.5%; p = 0.9)., Conclusion: Performing colposcopy and biopsy prior to LLETZ reduces unnecessary surgical procedures and decreases positive margin rates.

Objective: To evaluate whether C-reactive protein (CRP) serum levels can be used as a prognostic parameter in patients with cervical cancer., Methods: In the present study, CRP serum levels were measured in 215 patients with cervical cancer. CRP serum levels were measured prior to therapy for cervical cancer and were correlated to clinical data., Results: The median CRP serum level in patients with cervical cancer was 0.5 mg/dl (interquartile range 0.5-0.9 mg/dl). CRP serum levels were significantly associated with advanced tumor stage (p<0.001), lymph node involvement (p=0.01) and patients' age (p=0.01), but not with histological grade (p=0.1) and histological type (p=0.9). In a univariate and multivariate analysis CRP serum levels, tumor stage, and lymph node involvement, but not histological grade, histological type and patients' age were associated with overall and disease-free survival., Conclusion: CRP serum levels can be used as additional prognostic parameter in patients with cervical cancer.

Background: To investigate the clinical impact of MRI based cervix cancer brachytherapy combined with external beam radiochemotherapy applying dose volume adaptation and dose escalation in a consecutive group of patients with locally advanced cervix cancer., Methods: In the period 1998-2003, 145 patients with cervix cancer stages IB-IVA were treated with definitive radiotherapy +/- cisplatin chemotherapy. Median age was 60 years. In 67 patients, the tumour size was 2-5 cm, in 78 patients it was >5 cm. In 29 cases the standard intracavitary technique was combined with interstitial brachytherapy. Total prescribed dose was 80-85 Gy (total biologically equivalent dose in 2 Gy fractions). Since 2001, MRI based treatment planning integrated systematic concepts for High Risk Clinical Target Volume (HR CTV) and organs at risk (OAR), biological modelling, Dose-Volume-Histogram analysis, dose-volume-adaptation (D90, D 2 cm(3)), and dose escalation, if appropriate and feasible., Findings: Dose volume adaptation was performed in 130/145 patients. The mean D90 during the whole period was 86 Gy, with a mean D90 of 81 Gy and 90 Gy during the first and second period, respectively (p<<0.01). Median follow-up was 51 months. Complete remission at 3 months was achieved in 138/145 patients (95%). Actuarial continuous complete remission for true pelvis (CCRtp) was 88% at 3 years. For tumours 2-5 cm, CCRtp was 96% both in 1998-2000 and 2001-2003. For tumours >5 cm it was 71% in 1998-2000 and 90% in 2001-2003 (p=0.05). Progression free survival (PFS) for true pelvis (local control) was 85%, PFS for distant metastases was 80%, both at 3 years. Local control for tumours >5 cm was 64% in 1998-2000 and 82% in 2001-2003 (p=0.09) and 100% and 96%, respectively, for tumours 2-5 cm. PFS for distant metastases remained the same during the two treatment periods with 79% and 80%. Overall survival (OS) was 58%, and cancer-specific survival (CSS) was 68% at 3 years. In the two different periods improvement in OS was from 53% to 64% (p=0.03) and in CSS from 62% to 74% (p=0.13). Improvement occurred only in tumours >5 cm: OS 28% versus 58% (p=0.003); CSS 40% versus 62% (p=0.07). Actuarial late morbidity rate (LENT SOMA, grades 3 and 4) at 3 years was gastrointestinal 4%, urinary 4% and vaginal 5% (stage IIA/IIIA). Gastrointestinal and urinary late morbidity (G3,G4) was 10% in 1998-2000 and 2% in 2001-2003., Interpretation: In locally advanced extensive cervix cancer, local control of > or = 85% can be achieved with low treatment related morbidity (G3/G4), when exploiting the potential of MRI based 3D treatment planning including dose volume adaptation and dose escalation and a combined intracavitary/interstitial brachytherapy, if appropriate. A significant impact of this improvement of local control on survival is to be expected. For locally advanced limited disease the MRI based approach will likely result in assuring excellent local control (> or = 95%) and in minimizing treatment related morbidity.