Overall Survival In Cervical Cancer Research Articles

Systematic review and meta-analysis of the prognostic significance of microRNAs in cervical cancer.

In this meta-analysis, we analyzed case-control studies that assessed the prognostic potential of miRNAs in cervical cancer. We comprehensively searched EMBASE and PubMed databases and enrolled seven studies with 445 cervical cancer cases. A fixed effects model was used to calculate pooled hazard ratios (HRs) and associated 95% confidence intervals (95% CIs) from the overall survival (OS) data. Our analysis showed that poor OS in cervical cancer was associated with low miR-125 expression (HR = 1.61, 95% CI: 1.02–2.55, P = 0.042; I2 = 10.1%, P = 0.292; n = 99), low miR-145 expression (HR = 1.70, 95% CI: 1.29–2.24, P < 0.001; I2 = 0%, P = 0.560; n = 193) and high miR-196 expression (HR = 0.28, 95% CI: 0.15–0.52, P < 0.001; I2 = 0%, P = 0.950, n = 197). This makes microRNAs such as miR-125, miR-145 and miR-196 potential prognostic biomarkers in cervical cancer.

Marital Status and Survival in Locally Advanced Cervical Cancer Treated With Radiation and Brachytherapy

Several studies have shown a positive association between marital status and enhanced survival among cancer patients. Improving cervical cancer outcomes requires a better understanding of social and biologic factors to develop effective targeted intervention and therapeutics. We explored the association of martial status on survival of locally advanced cervical cancer patients treated with brachytherapy in California. All residents of California diagnosed with cancer are reported to the California Cancer Registry (CCR). Using data from the CCR, we identified patients with a new diagnosis of cervical cancer stage FIGO stage IB2- IVA from 2004-2014 treated with external beam radiotherapy (EBRT). We examined the patient and tumor characteristics including marital status: married vs. single/widowed/divorced (single), the use of brachytherapy, age, race, socioeconomic status (SES), histology, stageand treatment year. Using Cox proportional hazards, we examined the impact of martial status on overall survival in cervical cancer. We identified 4,481 patients with complete radiation boost information (brachytherapy vs. EBRT). Distribution by FIGO stage was 11% IB2; 32% II, 54% III, 4% IVA. The majority of patients (57%) were single/widowed/divorced, 41% married, and 2% unknown marital status. Over a third of patients (36%) were white, 6% black, 41% Hispanic, and 16% Asian. Nearly half of patients (45%) of the single and married patients were treated with a brachytherapy boost. There was no association between the receipt of a brachytherapy boost and marital status. Single patients had a worse overall survival compared to married patients, HR 1.152 95% CI (1.0. 1.3), p<0.037, after controlling variables such as stage, histology, tumor grade, age, race, SES, treatment year, and brachytherapy boost receipt. The majority of locally advanced cervical cancer patients presenting in California are single. Despite the equity in brachytherapy treatment, single patients had worse survival outcomes compared to those that are married. Clarification of causes and evaluation of social support networks could illuminate novel interventions to improve survival in this vulnerable population.

Bcl-2-like Protein 11 (BIM) Expression Is Associated with Favorable Prognosis for Patients with Cervical Cancer.

Bcl-2-like protein 11 (BIM) is a pro-apoptotic member of the Bcl-2 protein family. BIM elicits cell death by binding to pro-survival Bcl-2 proteins. Even though the association of BIM expression with cell death has been investigated, its clinical survival significance in cervical cancer has not. In the current study, the prognostic significance of BIM in cervical cancer was investigated. The study included normal cervical tissues (n=254), cervical intraepithelial neoplasia (CIN) tissues (n=275), and invasive cervical cancer (n=164). In order to identify BIM expression, immunohistochemistry (IHC) was performed, and IHC scoring by quantitative digital image analysis was determined. Then, the association of BIM with prognostic factors was investigated. BIM expression was higher in cervical cancer than normal cervical tissues (p<0.001). Well and moderate differentiation indicated higher BIM expression than did poor differentiation (p=0.001). Also, BIM expression was high in radiation-sensitive cervical cancer relative to radiation-resistant cancer (p=0.049). High BIM expression showed better 5-year disease-free survival (DFS) and overall survival (OS) rates (p=0.049 and π=0.030, respectively) than did low expression. In a multivariate analysis, BIM was shown to be an independent risk factor for DFS and OS in cervical cancer, with hazard ratios of 0.22 (p=0.006) and 0.46 (p=0.046), respectively. BIM is associated with favorable prognostic markers for prediction of DFS and OS in cervical cancer. High BIM expression is a potential prognostic marker as well as a chemotherapeutic target for cervical cancer.

The prognostic value of long non coding RNAs in cervical cancer: A meta-analysis

Cervical cancer is one of the most common malignancies in women worldwide. Numerous literatures demonstrate that aberrantly expressed lncRNAs are involved in tumorigenesis and development, and may have the potential to be prognostic markers. However, their prognostic functions in cervical remain controversial. Therefore, we performed this meta-analysis to evaluate the prognostic significance of lncRNAs in cervical cancer. We searched databases to identify relevant articles. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. 15 studies involving 1868 patients with cervical cancer and 12 lncRNAs were included. Our results indicated that the levels of lncRNAs were associated with the overall survival ((HR = 1.56, 95%CI = 1.02–2.38, P < 0.001, random-effect) and event free survival (HR = 1.33, 95%CI = 0.77–2.28, P < 0.01, random-effect). High HOTAIR expression was associated with shorter overall survival in cervical cancer (HR = 3.93, 95% CI = 2.34–6.62, P < 0.001, fixed-effect). In conclusion, our meta-analysis suggested that lncRNAs may serve as novel predictive factors for prognosis of cervical and high expression HOTAIR was associated with shorter overall survival in cervical cancer.

Incorporation of the number of positive lymph nodes leads to better prognostic discrimination of node-positive early stage cervical cancer.

To determine the prognostic value of the number of positive lymph nodes (LNs) in cervical cancer and further stratify patients with positive LNs into multiple risk groups based on analysis of Surveillance Epidemiology and End Results (SEER) program. Patients with cervical cancer who undergo hysterectomy and had pathologically-confirmed positive LNs after lymphadenectomy were identified using the SEER database (1988-2012). Kaplan–Meier survival methods and Cox proportional hazards regression were performed. We included 2,222 patients with the median number of removed LNs and positive LNs was 22 and 2, respectively. Multivariable Cox analysis showed patients with > 2 positive LNs had poorer cause-specific survival (CSS) (hazard ratio [HR] 1.631, 95% confidence interval [CI] 1.382–1.926, P < 0.001) and overall survival (OS) (HR 1.570, 95% CI 1.346–1.832, P < 0.001) than patients with 1–2 positive LNs. Five-year CSS and OS were 78.9% vs. 65.5% (P < 0.001) and 76.7% vs. 62.7% (P < 0.001) for 1–2 positive LNs and > 2 positive LNs, respectively. The number of positive LNs had prognostic value in cervical squamous cell carcinoma or adenosquamous carcinoma, but not in cervical adenocarcinoma. The number of positive LNs is an independent risk factor for CSS and OS in cervical cancer. This new category might be helpful in better prognostic discrimination of node-positive early stage cervical cancer after hysterectomy.

Epidemiology and survival of cervical cancer in the French West-Indies: data from the Martinique Cancer Registry (2002–2011)

ABSTRACT Background: The Caribbean ranks seventh among world regions most affected by cervical cancer. Social health inequalities, such as differences in access to screening services, engender disparities in incidence and mortality between low- and middle-income countries and industrialized countries. The French National Cancer Plan 2014–2019 focuses on reducing inequalities in cervical cancer. Objective: The aim of this study was to describe the geographical distribution and overall survival of cervical cancer, based on data from a population-based cancer registry in Martinique (French West-Indies). Methods: We included all cases of cervical cancer diagnosed between 2002 and 2011. The geographical distribution was described by zone of residence and by aggregated units for statistical information (IRIS). Based on the results of the model, standardized incidence rates (SIRs) were calculated using a Gamma Poisson model. Survival rates were calculated using the Kaplan–Meier method. Cox proportional hazards models were used to investigate the risk factors for cervical cancer mortality. Results: A total of 1253 cases were analyzed (947 in situ tumors and 306 invasive cancers). 1230 cases with geolocalization were used to map the distribution of the incidence of in situ and invasive cervical cancers. Five IRIS were significantly over-incident. The 5-year overall survival rate was 55%, with a median survival of 6.5 years [95% CI: 4.9–10.1]. Multivariate analysis confirmed age at diagnosis (HR = 2.15 [1.50–3.09]; p < 0.0001), FIGO stage (HR = 3.53 [2.50–4.99]; p < 0.0001) and zone of residence (HR = 1.51 [1.06–2.13]; p = 0.02) as risk factors. Conclusions: Prognostic factors suggest that cervical cancer needs to be diagnosed at an early stage. Our results could allow cervical cancer screening programs to clearly identify geographical areas that would benefit from targeted interventions with a view to reducing incidence and mortality of cervical cancer in the Caribbean.

Loss of ARID1A/BAF250a expression is linked to tumor progression and adverse prognosis in cervical cancer

The tumor suppressor gene ARID1A encodes BAF250a, a component of human SWI/SNF chromatin-remodeling complexes. Loss of BAF250a expression has recently been reported in several tumor types. To investigate the potential correlation between BAF250a and various clinicopathologic parameters, we assessed the expression of BAF250a in archival tumor tissue specimens from 147 patients with cervical cancer and 191 with cervical intraepithelial neoplasia as well as 376 matched nonadjacent normal tissues by immunohistochemical staining. Messenger RNA expression level for BAF250a was decreased in cervical cancer cell lines (P = .013) and tissues (P = .010), when compared with normal cervical epithelial tissue using SYBR Green real-time polymerase chain reaction. BAF250a was also detected in nuclear fractions of HeLa cells and in nuclei of cervical cancer tissue samples by Western blotting and immunohistochemistry, respectively. BAF250a expression gradually decreased in transitioning from normal to cervical carcinoma (P < .001), and this loss of expression was significantly associated with tumor stage (P = .005), tumor grade (P = .029), tumor size (P = .003), and lymph node metastasis (P = .020). In multivariate analysis, overall survival in cervical cancer was significantly reduced in cases with BAF250a loss (hazard ratio, 2.78 [1.01-7.63]; P = .047). Our findings suggest a potential role for BAF250a in providing valuable prognostic information to clinicians for risk assessment in cervical cancer.

Role of the RAD51 G172T polymorphism in the clinical outcome of cervical cancer patients under concomitant chemoradiotherapy

IntroductionCervical cancer is one of the most common cancers diagnosed in women worldwide. Mammalian cells are constantly exposed to a wide variety of genotoxic agents from both endogenous and exogenous sources. The RAD51 protein is required for meiotic and mitotic recombination and plays a central role in homology-dependent recombinational repair of double-strand breaks (DSBs). Given the functional relevance of the DNA repair system on carcinogenesis, potential associations between genetic polymorphisms of DNA repair genes, cancer risk and response to therapy have been intensively evaluated. This is the first study evaluating the role of the RAD51 G172T genetic variants in cancer prognosis and clinical outcome of cervical cancer patients. Material and methodsWe analyzed RAD51 G172T polymorphism genotypes in cervical cancer patients who underwent a platinum-based chemotherapy in combination with radiotherapy. Genotyping was performed by Taqman™ Allelic Discrimination methodology. Results and discussionConcerning the overall survival rates found using Kaplan–Meier method and Log Rank Test, we observed that the mean survival rates were statistically different according to the patients RAD51 genotypes. The group of patients carrying the T allele present a higher mean survival rate than the other patients (102.3months vs. 86.4months, P=0.020). Using the Cox regression analysis, we found an increased overall survival time for T-carrier patients, when compared with GG genotype, with tumor stage, age and presence of lymph nodes as covariates [hazard ratio (HR), 0.373; 95% CI, 0.181–0.770; P=0.008]. Among patients (n=193), RAD51 genotype frequency distributions were not under the influence of clinicopathologic characteristics, namely, treatment response (P=0.508), recurrence (P=0.150) and tumor stage (P=0.250). ConclusionsThis is the first study evaluating the role of the RAD51 G172T genetic variants in cancer prognosis and clinical outcome of cervical cancer patients. Our results indicate an influence of the RAD51 genetic variants in overall survival of cervical cancer. Thereby, RAD51 G172T genotypes may provide additional prognostic information in cervical cancer patients who underwent cisplatin-based chemotherapy in combination with radiotherapy.

Ploidy and S-phase fraction as predictive markers of response to radiotherapy in cervical cancer

The aim of this study was to investigate the potential clinical utility of DNA flow cytometry biomarkers, ploidy, and S-phase fraction (SPF) in predicting overall survival in cervical cancer. This prospective study involved 159 patients with cervical carcinoma (median follow-up, 48 months). Pretreatment clinical staging was done according to the FIGO 2009 update classification. Biopsy tumor samples were used for flow cytometry analysis and histological examination. A prognostic study was performed using both Cox and Bayesian Weibull regression models. Eighty (50.3%) tumors presented DNA aneuploidy, mostly observed in adenosquamous (AS) cell carcinoma (8 of 9 cases) and adenocarcinoma (AC) (12 of 17 cases). The median SPF value (8.6%) was used for discriminating low vs. high tumor cell proliferation. High SPF significantly correlated with aneuploidy ( p < 0.001). All AS carcinomas had SPF > 15%, while all ACs presented SPF < 10% ( p < 0.001). Forty-three (27%) patients died of the disease during follow-up. Log-rank tests revealed significant differences between survival curves for older patients (≥44 years) ( p = 0.029), advanced clinical staging ( p < 0.001), and DNA diploidy in stage IIB of disease ( p = 0.039). Both regression analyses showed that advanced clinical staging and low SPF independently predict worse overall survival of patients. The results suggest that DNA flow cytometry parameters can provide additional predictive information in cervical cancer management.

Erlotinib (E) combined with cisplatin (C) and radiotherapy (RT) for patients with locally advanced squamous cell cervical cancer: A phase II trial

5511 Background: New strategies beyond standard chemoradiation (CRT) are needed in locally advanced squamous cell cervical carcinoma. Combinations that increase the complete response rates (CR) may lead to longer progression-free and overall survival in cervical cancer. Pre-clinical data indicates that inhibition of epidermal growth factor receptor (EGFR) enhances the effect of C and RT. We previously reported the results of the phase I of E when administered concurrently with standard CRT for locally advanced cervical cancer that defined the safety and the maximal tolerated dose of 150mg/day for the combination. Methods: Eligibility criteria included histologically proven squamous cell cervical carcinoma, stage IIB to IIIB; no prior therapy; ECOG PS<3 and adequate end-organ functions. Patients (pts) received E 150mg/day one week before and combined with C (40mg/m2, weekly, 5 cycles) and RT (external beam RT - 4500cGy in 25 fractions, followed by 4 fractions/600cGy/weekly of brachytherapy). Results: Between 02/2006 and 10/2007, 37 pts were enrolled. Two pts did not complete the planned schedule (one presented Raynaud’s Syndrome and had C interrupted and one presented grade 4 hepatotoxicity). Twelve pts are still under treatment, 25 pts are available for toxicity and 23 for response evaluation. Within the 23 pts who received through E+CRT, median duration of treatment was 77(64–106) days. Pts presented median age 43(28–68), stage IIB 11(47.8%), IIIA 1(4.3%) and IIIB 11(47.8%). Overall E+CRT was well tolerated. Significant grade 3 toxicities were diarrhea and skin rash in 3(12%) and 5 (20%) pts, respectively. Twenty-one pts (91.3%; IC 95% 70.5 - 98.5) presented CR and 2 (8.7%) presented partial response. With a median follow-up of 9(3–25) months, none of the 23 pts progressed. Conclusions: Our data indicate that the combination of E+CRT is feasible and leads to high CR (91.3%) compared to historical CRT data (38–75%). To our knowledge this is the first report of E+CRT in cervical cancer pts. The trial has finished accrual and final results will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche

Markers of angiogenesis in cervical cancer: A Gynecologic Oncology Group study

5536 Background: Extensive tumor angiogenesis has correlated with poorer progression-free and overall survival in cervical cancer; however, specific markers of angiogenesis have not been studied prospectively. Methods: Cervical cancer patients with high-risk features on radical hysterectomy were eligible for randomization to adjuvant pelvic irradiation ± radiosensitizing platinum. Following central pathology review, formalin-fixed, paraffin-embedded tumors were sectioned into 4-micron specimens. Semi-quantitative immunohistochemisty (IHC) was performed using previously validated antibodies against mutant p53 (mp53), vascular endothelial growth factor (VEGF), thrombospondin-1 (TSP-1), and endothelial markers CD 31 and CD 105. Tumoral histoscores (HS) were calculated for mp53 and VEGF using the formula: [% cells positive × (intensity +1)], with a 5% threshold for positivity and intensity ranging 1–4+ (3+ = intensity of positive control). Intensity scores (0–4+) were assigned to TSP-1 specimens referencing the positive control (3+). MVD “hotspots” were counted in a 20X high-power field. HS and MVD counts were considered as continuous variables and TSP-1 intensity as an ordinal variable. Associations between markers were determined by Pearson’s and Spearman’s correlation tests, between markers and clinico-pathologic variables by Wilcoxon rank test, and between markers and survival by Cox regression modeling. Results: One hundred seventy-six specimens were analyzed. Acquisition of mp53 and increased VEGF expression were associated with increased MVD assessed by both CD31 (p=0.08 and p=0.002, respectively) and CD105 (p=0.02 and p=0.012, respectively). Statistically significant associations between markers and high-risk pathologic factors included: low-level TSP-1 and high CD-105 counts with lymph node metastases; high VEGF scores with advanced stage, non-squamous histologic subtype, and depth of tumor invasion; and high CD 31 counts with parametrial metastases. Survival analysis is currently being performed. Conclusions: Angiogenesis occurs early in cervical carcinogenesis, and may be a rational target for biologic therapy in cervical cancer. No significant financial relationships to disclose.

Impact of Adoption of Chemoradiotherapy on the Outcome of Cervical Cancer in Ontario: Results of a Population-Based Cohort Study

To describe the adoption of concurrent cisplatin-based chemoradiotherapy (C-CRT), and to evaluate its impact on the outcome of cervical cancer in Ontario. We used a population-based cancer registry to identify the 4,069 patients with invasive carcinoma of the cervix diagnosed in Ontario between 1992 and 2001. We linked electronic records of treatment to the registry. We described time trends in the use of C-CRT, and we compared survival before and after widespread adoption of C-CRT. Over the study period, the proportion of patients treated with primary radical radiotherapy (RT) remained constant at approximately 42%. Between 1992 and 1998, less than 10% of RT cases received chemotherapy. Early in 1999, there was rapid adoption of C-CRT. Between 1999 and 2001, more than 60% of RT cases received C-CRT. There was a contemporaneous increase in overall 3-year survival from 71.1% in the 1995 to 1998 cohort to 75.9% in the 1999 to 2001 cohort (P = .03). There was no change in survival in patients treated with surgery alone. However, there was a significant increase in 3-year survival from 58.6% in the 1995 to 1998 cohort to 69.8% in the 1999 to 2001 cohort (P < .01) in the subpopulation of patients treated with primary RT +/- chemotherapy. The adoption of C-CRT was associated with a significant improvement in overall survival of cervical cancer at the population level. The magnitude of the benefit of C-CRT in the general population was consistent with the results of the relevant clinical trials.