Survival In Early-stage Cervical Cancer Research Articles

Preoperative prediction of retroperitoneal lymph node involvement in clinical stage IB and IIA cervical cancer.

Lymph node metastasis (LNM) is the most important factor affecting survival in early-stage cervical cancer (CC). International Federation of Gynecology and Obstetrics revised the staging of CC in 2018 and reported LNM as a staging criterion. We investigated the preoperatively assessable risk factors associated with LNM in surgically treated stage IB1-IIA2 CC patients. This was a retrospective cohort study of women who underwent radical hysterectomy and pelvic lymphadenectomy with or without para-aortic lymphadenectomy for CC stage IB1-IIA2 from 2004 to 2019. All patients included in this study were examined with speculum inspection, parametrial assessment by rectovaginal palpation under general anesthesia, transvaginal ultrasonography, magnetic resonance imaging (MRI), and chest radiography. Clinical staging was done according to the preoperative findings. MRI was used to measure tumor and lymph node dimensions. Out of the 149 women included in the study, 29 (19.4%) had LNM. Univariate analysis revealed that larger tumor size (≥30 mm), lymphovascular space invasion (LVSI) detected with diagnostic biopsy, parametrial involvement, and deep stromal invasion status were significantly different between the group with LNM and the group without LNM. In multivariate analysis, specific preoperative risk factors such as MRI based tumor diameter ≥30 mm and LVSI (+) on the diagnostic biopsy were found to be independent risk factors for LNM in the multivariate analysis. The rate of LNM is high in patients with CC with a tumor size ≥30 mm and preoperative biopsy LVSI status even if they are clinically in early stages. Surgeons can take this into account while deciding between primary surgery and chemoradiotherapy in the treatment of CC.

Sentinel node navigation surgery in cervical cancer: a systematic review and metaanalysis.

Sentinel node navigation surgery (SNNS) is used in clinical practice for the treatment of cervical cancer. This study aimed to elucidate the appropriate sentinel lymph node (SLN) mapping method and assess the safety and benefits of SNNS. We searched the PubMed, Ichushi, and Cochrane Library databases for randomized controlled trials (RCT) and studies on SLN in cervical cancer from January 2012 to December 2020. Two authors independently assessed study quality and extracted data. We quantitatively analyzed the detection rate, sensitivity/specificity, and complications and reviewed information, including the survival data of SLN biopsy (SLNB) without pelvic lymphadenectomy (PLND). The detection rate of SLN mapping in the unilateral pelvis was median 95.7% and 100% and in the bilateral pelvis was median 80.4% and 90% for technetium-99m (Tc) with/without blue dye (Tc w/wo BD) and indocyanine green (ICG) alone, respectively. The sensitivity and specificity of each tracer were high; the area under the curve of each tracer was 0.988 (Tc w/wo BD), 0.931 (BD w/wo Tc), 0.966 (ICG), and 0.977 (carbon nanoparticle). Morbidities including lymphedema, neurological symptoms and blood loss were associated with PLND. One RCT and five studies all showed SNNS without systematic PLND does not impair recurrence or survival in early-stage cervical cancer with a tumor size ≤ 2-4cm. Both Tc w/wo BD and ICG are appropriate SLN tracers. SNNS can reduce the morbidities associated with PLND without affecting disease progression in early-stage cervical cancer.

The Combination of T Stage and the Number of Pathologic Lymph Nodes Provides Better Prognostic Discrimination in Early-Stage Cervical Cancer With Lymph Node Involvement.

ObjectiveStage I and II cervical cancer with pelvic and/or para-aortic lymph node (LN) metastases are upstaged to stage IIIC under the new FIGO 2018 staging system, and radical chemoradiotherapy was recommended. But heterogeneity in outcome existed in this group of patients. We conducted this retrospective analysis to evaluate the heterogeneity of these patients and tried to provide a more detailed classification to reflect the prognosis and guide the treatment. We also evaluated the efficacy and toxicity of surgery followed by sequential chemoradiotherapy in this cohort.MethodsEarly-stage cervical cancer with LN involvement that had radical hysterectomy followed by sequential chemoradiotherapy were retrospectively analyzed. Survival analyses were conducted to identify the prognostic factors.ResultsA total of 242 patients were included in the study; 64 (26.4%) patients had treatment failure, and 51 (21.1%) died. Pathology, T stage, the number of pathologic LN (pLN), and neoadjuvant chemotherapy or not were independent prognostic factors for disease-free survival and overall survival (OS). Patients with T1N < 3 pLN had significantly better survival than T2N < 3 pLN/T1-2 N≥ 3 pLN, with failure rates of 11.6% and 35.8% in each group; and 5 year OS was 92% and 62%, respectively (P = 0.000). About 1.5% of the patients discontinued radiotherapy, and 14.1% had G3-4 hematological toxic effects during radiotherapy; 1.7% developed G2-3 lower limb edema, and 2.9% developed severe urinary toxicity.ConclusionNodal involvement alone is inadequate as the sole pathologic factor to predict survival in early-stage cervical cancer. The combination of tumor and node subcategory provides better prognostic discrimination.

Preoperative Conization May Have a Positive Impact on Survival in Early-Stage Cervical Cancer: A Propensity-Matched Study

Introduction: A recent prospective randomized study demonstrated that minimally invasive surgery (MIS) was inferior to open surgery in disease survival in early-stage cervical cancer. Our aim was to investigate whether there were survival benefits of preoperative conization prior to MIS for early-stage cervical cancer. Methods: We retrospectively analyzed patients who eventually underwent definitive MIS with stage IA2 to IB1 (no >2 cm) squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma. Preoperatively, the patients were separated into 2 groups: one managed with conization and the other undergoing biopsy without conization. Propensity scoring weight and matching were used to reduce the influence of possible allocation biases. The Cox regression model was used for univariate and multivariate analyses of disease recurrence and survival. Results: 227 patients were contained in this study (99 patients in the conization group and 128 patients in the nonconization group). The 5-year DFS of the conization group was statistically better than that of the nonconization group (98.4% vs. 91.8%, p = 0.011). By univariate analysis, conization (HR = 0.11, 95% CI = 0.01–0.87, p = 0.03) and histologic cell type (p = 0.01) were considered as risk factors for recurrence. Multivariate analysis further confirmed conization (HR = 0.04, 95% CI = 0.01–0.51, p = 0.01) and histologic cell type (p < 0.01) correlated with DFS. After propensity score matching (1:1), 84 patients were included in the conization and nonconization groups, respectively, with 5-year DFS still higher in the conization group (98.3% vs. 92.9%, p = 0.037). The results after univariate and multivariate analyses were consistent with those prior to propensity score matching. Conclusion: Preoperative conization in conjunction with MIS seemed to be a safe and feasible approach, with results that may have implications for the reduction of recurrence. Histologic cell type also impacted survival. Therefore, more future prospective studies are warranted.

PIK3CA Mutations Are Not Correlated With Worse Disease-Free Survival in Early-Stage Cervical Cancer Treated With Surgery and Could be a Target for Overcoming Resistance to Chemoradiotherapy in Locally Advanced Cervical Cancer

PIK3CA Mutations Are Not Correlated With Worse Disease-Free Survival in Early-Stage Cervical Cancer Treated With Surgery and Could be a Target for Overcoming Resistance to Chemoradiotherapy in Locally Advanced Cervical Cancer

Does a pre-operative conization improve disease-free survival in early-stage cervical cancer?

Ever since the recent findings showing the lack of benefit of minimally invasive surgery (MIS) versus open surgery in early-stage cervical cancer, gynecologists have tried to explain these results. The primary objective of our study was to assess the impact of pre-operative conization on disease-free survival (DFS) in early-stage cervical cancer. The secondary objective was to analyze the peri-operative morbidity associated with a pre-operative conization. All patients undergoing a surgical management for early-stage squamous carcinoma or adenocarcinoma cervical cancer (IA1, IA2, IB1 and IB2 FIGO 2018) at a French university hospital from 2004 to 2018 were retrospectively included. We examined the association between conization and DFS using a Cox regression model. We also analyzed the morbidity associated with pre-operative conization. 48.4% (44/91) of the patients had a pre-operative conization (defined by a conization up to 90days prior to surgery). 86.8% underwent MIS. There was a non-significant increase in the DFS with one patient presenting a recurrence in the conization group (2.3%) and six (12.8%) in the no conization group (log rank = 0.09). In univariate analysis, conization, definitive FIGO stage and pre-operative tumor size were associated with DFS (p < 0.2). Only pre-operative tumor size was significantly associated with DFS in multivariate analysis. There was a non-significant increase of adverse events in the conization group (43.2% in the conization group versus 23.4%, p = 0.06). Conization, through a reduction of tumor size, could improve DFS. Carefully selected patients could still benefit from minimally invasive surgery.

Wait-time for hysterectomy and survival of women with early-stage cervical cancer: A clinical implication during the coronavirus pandemic

ObjectiveA global pandemic caused by a novel coronavirus (Covid-19) has created unique challenges to providing timely care for cancer patients. In early-stage cervical cancer, postponing hysterectomy for 6–8 weeks is suggested as a possible option in the Covid-19 burdened hospitals. Yet, literature examining the impact of surgery wait-time on survival in early-stage cervical cancer remains scarce. This study examined the association between surgery wait-time of 8 weeks and oncologic outcome in women with early-stage cervical cancer. MethodsThis is a single institution retrospective observational study at a tertiary referral medical center examining women who underwent primary hysterectomy or trachelectomy for clinical stage IA-IIA invasive cervical cancer between 2000 and 2017 (N = 217). Wait-time from the diagnosis of invasive cervical cancer via biopsy to definitive surgery was categorized as: short wait-time (<8 weeks; n = 110) versus long wait-time (≥8 weeks; n = 107). Propensity score inverse probability of treatment weighting was used to balance the measured demographics between the two groups, and disease-free survival (DFS) and overall survival (OS) were assessed. A systematic literature review with meta-analysis was additionally performed. ResultsIn a weighted model (median follow-up, 4.6 years), women in the long wait-time group had DFS (4.5-year rates, 91.2% versus 90.7%, hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.47–2.59, P = 0.818) and OS (95.0% versus 97.4%, HR 1.47, 95%CI 0.50–4.31, P = 0.487) similar to those in the short wait-time group. Three studies were examined for meta-analysis, and a pooled HR for surgery wait-time of ≥8 weeks on DFS was 0.96 (95%CI 0.59–1.55). ConclusionOur study suggests that wait-time of 8 weeks for hysterectomy may not be associated with short-term disease recurrence in women with early-stage cervical cancer.

Significance of Malignant Peritoneal Cytology on the Survival of Women with Early-Stage Cervical Cancer: A Japanese Gynecologic Oncology Group Study

This study examined the association between peritoneal cytology and survival in early-stage cervical cancer. This is a nationwide multicenter retrospective study, examining consecutive women with clinical stage IB1-IIB cervical cancer who underwent radical hysterectomy with available peritoneal cytology results from 2004–2008. Propensity score inverse probability of treatment weighting was used to assess the impact of malignant peritoneal cytology on survival. Among 1409 analyzed cases, 88 (6.2%) had malignant peritoneal cytology. On weighted models, malignant peritoneal cytology was associated with decreased disease-free survival (hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.36–2.32) and overall survival (OS, HR 1.93, 95% CI 1.44–2.59). On sensitivity analyses, malignant peritoneal cytology was associated with decreased OS in adenocarcinoma/adenosquamous carcinoma, high-risk early-stage disease and those who received concurrent chemo-radiotherapy. However, among women who received postoperative systemic chemotherapy, malignant peritoneal cytology was not associated with OS (HR 1.21, 95% CI 0.72–2.04). A systematic review, including our results, showed that malignant peritoneal cytology was associated with decreased OS (HR 4.03, 95% CI 1.81–8.99) and increased recurrence in squamous carcinoma (odds ratio 1.89, 95% CI 1.05–3.39) and adenocarcinoma (odds ratio 4.30, 95% CI 2.30–8.02). In conclusion, the presence of malignant cells in peritoneal cytology is associated with decreased survival in early-stage cervical cancer. The possible benefit of systemic chemotherapy in this subgroup merits further investigation.

The G protein-coupled estrogen receptor (GPER/GPR30) may serve as a prognostic marker in early-stage cervical cancer.

Estrogen signalling is transmitted via various receptors and multiple intracellular signalling pathways. Estrogen receptor alpha (ERα)-mediated transcription of target genes has been demonstrated to be closely linked to human papilloma virus (HPV)-induced carcinogenesis in case of cervical cancer. So far, the role of non-genomic estrogen signals in cervical cancer, e.g. transmitted by the G protein-coupled estrogen receptor (GPER) remains to be rather elusive. Today's knowledge on the role of GPER in cervical cancer is sparse and-to the best of our knowledge-GPER has not been investigated in context with clinicopathological parameters or prognosis of cervical cancer. Therefore, the current study investigated whether GPER is expressed in cervical cancer tissue. Further, GPER was correlated to clinicopathological parameters, tissue markers of cervical carcinogenesis and to patient overall and recurrence-free survival. Cervical cancer tissue was collected from 156 patients during surgery between 1993 and 2002. GPER immunostaining was performed on all the cases and correlated to clinicopathological data. More than half of all patients were diagnosed at advanced stage (FIGO II-IV 93/156; 59.6%) of disease. The large majority of patients presented with tumours of intermediate or high grade (G2-3 140/152, 92.1%). 22 cervical cancer-related deaths (22/156, 14.1%) were documented during the follow-up period. GPER was detected in various subcellular staining patterns. In 129/156 (82.7%) cases GPER was expressed in the tumour cell cytoplasm (GPERcyt). GPER immunopositivity at the cell membrane (GPERmem) was found in 114/156 (73.1%) cases. While co-occurrence of both membrane and cytoplasmic staining (GPERcyt+GPERmem) was detected in the majority of tissue samples (101/156; 64.7%), only few cases (14/156, 9.0%) were classified as not expressing GPER at all. GPERcyt was positively correlated with tumour grade. Statistical associations of GPER and both p16 and p53 were detected. Finally, immunopositivity of GPERcyt was predictive for favourable overall as well as recurrence-free survival in cervical cancer of early stage (FIGO I). This retrospective study reports GPERcyt to be associated with improved overall and recurrence-free survival in early-stage cervical cancer. Further investigations are needed thus to determine whether this observation may be of clinical impact. Interestingly, Raloxifene-a GPER-activating selective estrogen receptor modulator-has recently been demonstrated to be preventive for cervical cancer relapse in mice. Whether this effect is only reliant on raloxifene blocking ERα or may also be related to activation of GPER remains to be determined.

CPE overexpression is correlated with pelvic lymph node metastasis and poor prognosis in patients with early-stage cervical cancer.

Elevated carboxypeptidase E (CPE) levels play crucial roles in tumorigenesis and metastasis. This study investigated the expression and clinicopathological significance of CPE in early-stage cervical cancer. Elevated carboxypeptidase E expression was analyzed using quantitative polymerase chain reaction and western blotting in normal cervical tissue, cervical cancer cell lines, and in cervical cancer tissues and adjacent noncancerous tissues (ANTs) from the same patient. Immunohistochemistry (IHC) was used to examine CPE expression in tissue samples from 112 patients with early-stage cervical cancer (FIGO stages Ia2-IIa2), 60 patients with cervical intraepithelial neoplasia, and 19 patients with normal cervical tissues (NCTs). Associations between CPE expression and prognostic and diagnostic factors were evaluated statistically. CPE expression was significantly higher in cervical cancer cell lines and tissues than in normal tissues and ANTs. Semi-quantitative analysis of IHC indicated that CPE gradually increased from CIN I to cervical cancer, but was absent in NCTs. CPE expression was seen in 40.2% (45/112) of the cervical cancer samples. CPE expression was significantly associated with FIGO stage (P=0.003), tumor size (P=0.012), stromal invasion (P<0.001), lymphovascular space invasion (P=0.016), parametrial infiltration (P=0.027), vaginal involvement (P=0.007), postoperative adjuvant therapy (P=0.024), recurrence (P<0.001), survival (P<0.001), and pelvic lymph node metastasis (PLNM) (P<0.001), and it was significantly higher in tissues from patients with PLNM than without PLNM. Logistic regression analysis identified high-level CPE expression as an independent risk factor for PLNM (P=0.001). Patients with higher CPE expression had shorter overall survival duration than patients with lower CPE expression. Univariate and multivariate Cox-regression analyses suggested that high-level CPE expression is an independent prognostic factor for overall survival in early-stage cervical cancer. High-level CPE expression was associated with a poor prognosis in early-stage cervical cancer. CPE may serve as a biomarker for predicting PLNM and survival in these patients.

Antihormonal agents as a strategy to improve the effect of chemo-radiation in cervical cancer: in vitro and in vivo study.

BackgroundOver the past few years, the concurrent use of cisplatin-based chemotherapy and radiation therapy has dramatically improved the local response and increased overall survival in early-stage cervical cancer. However, for the advanced stages of the disease this standard treatment has proved insufficient. We investigated the capacity of Mifepristone and ICI 182,780, which are anti-progestin and anti-estrogen drugs, respectively, to act as chemo-radiosensitizing agents in cervical cancer cells and cervix xenografts.MethodsThe effect of chemo-radiation alone or combined with Mifepristone or ICI 182,780 was evaluated in HeLa cells and with tumor growth in cervix xenografts. After concomitant chemo-radiotherapy, the effect of each of these antihormonal agents on apoptosis (determined by Annexing V assay) and the cell cycle phases were determined by flow cytometry. The expression of angiogenic factor VEGF in tumor samples was determined using quantitative RT-PCR analysis of VEGF gene expression.ResultsCompared to radiation alone or radiation/cisplatin therapy, there was significantly higher cytotoxicity and a greater antitumoral effect with the combined application of radiation/cisplatin and Mifepristone or ICI 182,780. Analyses of the apoptosis and cell cycle demonstrated changes only with ICI, not with Mifepristone, when was applied in combination with radiation/cisplatin. The analysis of VEGF mRNA expression levels in tumors at the end of the study demonstrated a significant inhibition, compared to radiation only or the radiation/cisplatin treatment, after concurrent chemo-radiotherapy and each one of the antihormonal drugs.ConclusionMifepristone and ICI 182,780 may be potentially promising chemo-radiosensitizing compounds to be used in combination with ionizing irradiation and cisplatin in the treatment of patients with advanced cervical cancer.

The epidermal growth factor receptor pathway in relation to pelvic lymph node metastasis and survival in early-stage cervical cancer

The objective of this study is to correlate the expression of epidermal growth factor receptor (EGFR) components with clinical behavior of early-stage cervical cancer. Tissue samples of 336 consecutive Federation of International Gynecologists and Obstetricians stage IB-IIA cervical cancer patients all treated primarily by radical surgery were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. As representatives for the EGFR pathway, expression of EGFR, pEGFR, PTEN, pAKT, and pERK was assessed by immunohistochemistry on tissue microarrays. Positive immunostaining was observed for EGFR in 32.1%, for pEGFR in 21.0%, for PTEN in 38.3%, for pAKT in 5.3%, and for pERK in 4.3% of tumor samples. Positive EGFR immunostaining was associated with squamous cell carcinoma of the cervix (odds ratio [OR], 7.41; 95% confidence interval [CI], 3.38-16.23, P < .001), negative pEGFR immunostaining with poor differentiation (OR, 0.39; 95% CI, 0.20-0.73, P = .004), and negative PTEN immunostaining with metastatic pelvic lymph nodes (OR, 0.51; 95% CI, 0.30-0.90, P = .019). In multivariate analysis, only pelvic lymph node metastasis (hazard ratio, 6.11; 95% CI, 3.46-10.77, P < .001) and poor differentiation (hazard ratio, 1.91; 95% CI, 1.12-3.26, P = .018) were related to disease-specific survival. In early-stage cervical cancer, loss of PTEN expression is associated with pelvic lymph node metastasis, suggesting PTEN to be one of the tumor suppressor genes affecting pelvic lymph node metastasis. However, expression of EGFR pathway components does not appear to have prognostic impact in surgically treated early-stage cervical cancer.

Nerve Sparing in Radical Surgery for Early-Stage Cervical Cancer: Yes We Should!

Radical hysterectomy with pelvic lymphadenectomy is considered to be the cornerstone in the treatment of early-stage cervical cancer. Although survival in early-stage cervical cancer is up to 95%, long-term morbidity with regard to bladder, bowel, and sexual function is considerable. Damage to the pelvic autonomic nerves may be the cause of these long-term complications following radical hysterectomy. Some authors have presented surgical techniques to preserve the autonomic nerves (ie, the hypogastric nerves and the splanchnic nerves) without compromising radicality. Safety, efficacy, and the surgical techniques of nerve-sparing radical hysterectomy are presented, and data confirm that whenever the decision is made to perform a radical hysterectomy, nerve-sparing techniques should be considered.