Changes in the demographics and perioperative care of stage IA(2)/IB(1) cervical cancer over the past 16 years

OBJECTIVES: The aim of this study was to determine whether there have been any significant changes in the demographics and perioperative care of FIGO stage IA(2)/IB(1) cervical cancer over the past 16 years and, if so, to quantify them. METHODS: Since July 1984, all patients with FIGO stage IA(2)/IB(1) cervical cancer undergoing radical surgery by members of our division have been entered into a prospective database. Selection for surgery has been unchanged over the past 16 years. Since March 1994 and November 1996, one surgeon has performed radical vaginal trachelectomy and laparoscopic assisted radical vaginal hysterectomy, respectively. Statistical analysis used Spearman's correlation analysis, the proportional hazards regression model of Cox, and the Mantel-Hanzel test was performed. Due to the number of statistical analyses, statistical significance was defined as P < 0.01. RESULTS: Eight hundred sixty-four patients have undergone radical surgery (784 radical hysterectomy, 42 radical vaginal trachelectomy, 32 radical vaginal hysterectomy, 6 radical abdominal trachelectomy) for FIGO stage IA(2)/IB(1) carcinoma of the cervix by members of our division since 1984. There have been no changes in the median age (40 years), tumor size (2.0 cm), incidence of capillary lymphatic space involvement (47%), or positive pelvic lymph nodes (6%) over the past 16 years. The median Quetelet index (24.6), depth of tumor invasion (squamous cell carcinomas only) (6.0 mm), and proportion of patients with comorbid conditions (17%) have increased over time (P = 0.001, P = 0.003, and P < 0.001, respectively). Pathologically, there has been an increase in the proportion of adenocarcinomas (28%) and a decrease in the proportion of grade 3 tumors (28%) (P < 0.001 and P < 0.001, respectively). The median operating time (2.8 h), hospital stay (7.0 days), blood loss (600 cc), allogeneic blood transfusion (23%), postoperative infections (13%), and noninfectious complications (6%) have all decreased (P < 0.001, P < 0.001, P < 0.001, P < 0.001, P < 0.001, and P = 0.002, respectively). There has been no change in the incidence of positive surgical margins (3%), adjuvant radiation (13%), or recurrence-free survival (2 and 5 years, 94 and 90%, respectively) after a median follow-up of 45 months. CONCLUSION: Despite no substantive changes in the selection criteria for surgery and the small time interval studied (16 years), almost all indices of operative and postoperative morbidity analyzed have decreased significantly. These changes have occurred without an increase in the use of adjuvant radiation or decrease in recurrence-free survival. Although little progress has been made in the cure rates associated with surgical management of FIGO stage IA(2)/IB(1) cervical cancer during this time interval, it appears that the morbidity of surgery has decreased.     

Treatment of stage IB2, IIA bulky cervical cancer: a single-institution experience of neoadjuvant chemotherapy followed by radical hysterectomy and primary radical hysterectomy

Introduction  

The aim of this study was to compare the efficacy and safety of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy (NAC group) with primary radical hysterectomy (RH group).     

Ovarian metastases in early-stage cervical cancer (IA2–IIA): a multicenter retrospective study of 1965 patients (a Cooperative Task Force study)

This is a retrospective study of patients treated for early-stage cervical cancer to identify pathologic risk factors associated with ovarian metastases and, therefore, to establish when ovarian preservation can be performed without increasing the risk of relapse in order to improve the quality of life in premenopausal patients. Between 1982 and 2004, 1965 patients with FIGO stage IA2-IB-IIA cervical squamous cell carcinoma and nonsquamous histology types were surgically treated; 1695 (86%) patients underwent primary radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic node dissection, the remaining 270 patients (14%) had their ovaries preserved. The clinical records were reviewed for all patients and clinical features at presentation, the histopathology and follow-up data were recorded. Overall, ovarian metastases were diagnosed in 16 of 1695 patients, for an incidence rate of 0.9%. Univariate analysis shows age (45 years: P = 0.0079), FIGO stage (IB1-IIA 4 cm: P = 0.0133), histology (squamous vs nonsquamous, P = 0.0014), noninvolved peripheral stromal thickness (<3 vs >3 mm: P = 0.0001), lymphvascular space involvement (present vs absent, P = 0.0007), lymph node status (positive vs negative, P = 0.00009) to be statistically associated with the presence of ovarian metastases. Multivariate analysis shows only age (P = 0.0119), FIGO stage (P = 0.011), histology (P = 0.001), and unaffected peripheral stromal thickness (<3 mm: P = 0.037) to be independent risk factors for ovarian metastases. Based on the present data and on the data available in the literature, ovarian preservation could be safely performed in young patients with early-stage squamous cell carcinoma (histology as the most significant risk factor), with macroscopically normal ovaries, and with preserved peripheral unaffected cervical stroma.     

Efficacy of different types of treatment in FIGO stage IB2 cervical cancer in Korea: results of a multicenter retrospective Korean study (KGOG-1005)

The purpose of this study is to review FIGO stage IB2 cervical cancers in Korea for the past 10 years, and evaluate the most frequently employed and appropriate management strategy, and also assess the survival benefits of neoadjuvant chemotherapy (NAC). This is a retrospective chart review of 727 FIGO stage IB2 patients from 1995 to 2005. Six hundred ninety-two patients were enrolled, and all dates on which the patients died were double checked through the "National Registry of Death Statistics" of the Korea National Statistical Office. Management strategies were divided into five groups according to the primary treatment modality. The most frequently employed primary treatment modality for stage IB2 cervical cancer in Korea during the past 10 years was radical hysterectomy (RH). The next was NAC, followed by radiotherapy (RT) and/or extrafascial hysterectomy, concurrent chemoradiotherapy (CCRT) and/or extrafascial hysterectomy, in descending order. The surgery group showed the best results, with an 89% 5-year disease-free survival rate. However, there was no statistical difference between the surgery, NAC, and CCRT groups. For FIGO stage IB2 cervical cancer during the past 10 years in Korea, RH and adjuvant RT or CCRT was the most frequently employed treatment strategy. As a primary modality, RH, NAC, and CCRT showed similar survival rates. However, RH demonstrated the best survival rate among the above treatment strategies.     

Flow cytometric DNA analysis and neoadjuvant chemotherapy of cervix cancer (stage IB2-IIIB)

The purpose of the present study is to determine the predictive role of the data of flowcytometric DNA-analysis--aneuploidity DNA-index, proliferative index in patients with squamous cervical cancer who was given chemotherapy as a initial treatment. The data of 12 patients in stage IB2-IIIB, who were divided into two groups according to the second-line treatment--surgery of definitive radiotherapy, were analysed. These data were correlated with the respond of the tumor to neoadjuvant chemotherapy (clinical and histopathological) as well as other factors such as stage, size of tumor lesion, grading disease free survival. The method of flowcytometric DNA-analysis was presented briefly. The results we have obtained, although in quiete limited number of patients, are interesting and justify prospective studies of the problem.     

Neoadjuvant chemotherapy and vaginal radical trachelectomy for fertility-sparing treatment in women affected by cervical cancer (FIGO stage IB-IIA1)

Objectives

The aim of the present report is to support the feasibility and the safety of a new fertility-sparing treatment in young women affected by bulky cervical cancer.

Methods

Between February 2007 and October 2010, seven patients presenting large IB-IIA1 tumors (30-45 mm) were scheduled for conservative treatment. All patients underwent neoadjuvant chemotherapy (NACT) followed by laparoscopic pelvic lymphadenectomy and vaginal radical trachelectomy (VRT).

Results

One patient presented hematological toxicity during NACT (grade 3). All patients showed complete disappearance of tumor (n = 4/7) or partial response (a 50% or more decrease in total tumor size, n = 3/7) to neoadjuvant treatment, and they were all treated with pelvic lymphadenectomy and VRT. Additional treatment (interstitial brachytherapy) was offered to only one woman because of a persistent parametrial tumoral lesion.After a mean follow up of 22 months (range 5-49), no relapse was observed. To date, only one woman in our study attempted to conceive and she is currently pregnant.

Conclusions

Neoadjuvant chemotherapy for fertility sparing treatment is an innovative approach which is potentially quite interesting for many young women affected by bulky cervical cancer. These women, i.e. those with tumors larger than 2 cm (2-5 cm), are traditionally not offered fertility sparing treatment, thus the preliminary data we report here might have a promising impact. Nevertheless, for these patients it may be suitable to use the more radical, and time-tested, conservative surgical approach to allow for a complete and conservative excision of the residual tumor after neoadjuvant treatment.Studies with a larger number of patients and adequate follow-up are required to validate this conservative approach and to define clearly the good indications for this treatment.     

The prognostic significance of p53, mdm2, c-erbB-2, cathepsin D, and thrombocytosis in stage IB cervical cancer treated by primary radical hysterectomy

de Jonge ETM, Viljoen E, Amant F, Nesland JM, Holm R. The prognostic significance of p53, mdm2, c-erbB-2, cathepsin D, and thrombocytosis in stage IB cervical cancer treated by primary radical hysterectomy. Int J Gynecol Cancer 1999; 9: 198–205.
The objective of this study was to evaluate the value of platelet count, p53, MDM2, c-erbB-2, and cathepsin D immunoreactivity as predictors of lymph node metastasis (LNM) as well as their prognostic significance in patients with stage IB cervical cancer treated by radical hysterectomy between 1991 through 1995. We also report on the outcome of a protocol considering lymph-vascular space invasion (LVSI) in addition to LNM as a strong motivation for adjuvant radiotherapy. A total of 93 patients were the subject of this retrospective study. The incidence of positive nodes was high (30.1%). Thrombocytosis (≥ 400.000/mm³) was present in 6.7% of patients. Positive immunostaining was found for p53 (50.6%), MDM2 (21.7%), c-erbB-2 (14.5%), and cathepsin D (45.8%), but none of them was able to predict LNM. Only thrombocytosis was associated with an unfavorable prognosis: a statistically significant association was shown with relapse-free and overall survival in an univariate analysis ( P = 0.0431 and P = 0.0012, respectively) with a tendency to significance in multivariate analysis ( P = 0.079 and P = 0.0882, respectively). We postulate that thrombocytosis in early stage cervical cancer could be a marker for subclinical tumor burden. LVSI, regarded as an indication for adjuvant radiotherapy, was no longer associated with poor relapse-free or overall survival, but resulted in a 41% postoperative irradiation rate. Further research is needed to establish the value of LVSI in postoperative radiotherapy decision making.     

Overexpression of cystic fibrosis transmembrane conductance regulator (CFTR) is associated with human cervical cancer malignancy, progression and prognosis

Objective

To investigate the correlation of cystic fibrosis transmembrane conductance regulator (CFTR) to cervical cancer progression and prognosis by examining CFTR expression levels in different cervical tissues and cell lines.

Methods

Paraffin-embedded cervical tissue samples (n = 192) were collected for immunohistochemistry (IHC), while fresh cervical tissue samples (n = 165) and human cervical cell lines were collected for protein and mRNA detection by quantitative real-time PCR and western blot, respectively. Correlations between CFTR expression levels to cancer clinicopathologic features and prognosis were statistically analyzed.

Results

Both CFTR mRNA and protein expression gradually increased from normal to precancerous (LSIL, HSIL) and cervical cancer tissues (p < 0.05). Furthermore, CFTR expression level was well-correlated to tumor stage (p < 0.001), histological grades (p < 0.001), lymphatic metastasis (p < 0.001), vascular invasion (p < 0.05), interstitial invasive depth (p < 0.05), tumor size (p < 0.05) and HPV infection (p < 0.05). In vitro, CFTR mRNA and protein were expressed strongly both in SiHa and HeLa, but little was seen in Caski and H8 (p < 0.05). More importantly, overexpression of CFTR conferred significantly poorer survival in cervical carcinoma (Log rank p = 0.028), although it was not an independent predictor for prognosis according to multivariate analysis (p > 0.05).

Conclusions

These results suggest that higher CFTR expression is closely associated with cervical cancer progression, aggressive behaviors and poorer prognosis, indicating that CFTR may function as a novel tumor marker, a prospective prognostic indicator and a potential therapeutic target for cervical cancer.     

Phase II study of neoadjuvant chemotherapy with mitomycin-c, vincristine and cisplatin (MVC) in patients with stages IB2-IIB cervical carcinoma

OBJECTIVE: The efficacy and toxicity of neoadjuvant chemotherapy (NAC) with mitomycin-C, vincristine and cisplatin (MVC) were assessed in bulky cervical carcinoma patients. METHODS: Forty-six patients with stage IB2 to IIB cervical cancer were treated with intravenous combination of mitomycin-C 10 mg/m(2), vincristine 1 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks. After three cycles of NAC, the patients either underwent surgery or radiation therapy, depending on their suitability for radical hysterectomy. RESULTS: All 46 patients enrolled in this study were suitable for surgery after NAC. Twenty (44%) patients had risk factors after surgery and received postoperative radiation. Toxic nonhematologic reactions consisted primarily of grades 1-2 nausea and vomiting (87%) and the most common hematologic toxicity was anemia (60%). Clinical responses occurred in 83% (38/46) of patients, including 24% (11/46) with a complete response (CR) and 13% (6/46) with a pathologically determined complete response. For a median follow up period of 28 months, the 3-year disease-free and overall survival rates were 74% and 80%, respectively. Pathologically confirmed lymph node metastasis or parametrial involvement and an initial tumor size > or =4 cm were associated with shorter disease-free survival (P=0.040, P=0.000, P=0.025, respectively). CONCLUSION: Intravenous administration of MVC as a NAC seems to be well tolerated and beneficial in patients with stage IB2 to IIB cervical cancer.     

Confirmation of the prognostic value of the ECPI-1 score (myometrial invasion, DNA-ploidy and mean shortest nuclear axis) in FIGO stage I endometrial cancer patients with long follow-up

In FIGO stage I endometrial cancer patients, histologic type and grade are correlated with prognosis and used for therapeutic decision making. However, assessment of these histologic features is subjective, and the results are not always perfectly reproducible. Contrarily, previous studies have shown that DNA-ploidy and morphometric features are highly reproducible and have a strong prognostic value in these cancers. Multivariate analysis has demonstrated that a combination of mean shortest nuclear axis (MSNA), DNA-ploidy and depth of myometrial invasion (the so-called ECPI-1 score) overshadowed the value of all other features investigated. The present study was set up to evaluate further and compare the prognostic power of the ECPI-1 score in 77 FIGO I patients with long follow-up (10–15 years). Grade (revised), invasion depth, MSNA and ploidy were all highly significant. However, the ECPI-1 score (with exactly the same threshold as in the previous study, 0.87) greatly exceeded the prognostic value of these single features. Only two (3%) of the 64 patients with ECPI-1 0.87 died (at 14 and 62 months), in contrast to 11 (84.6%) of the 13 cases with ECPI-1> 0.87 (10 died within 42 months) ( P < 0.0001, Mantel-Cox value = 51.1). These results confirm the prognostic strength of the ECPI-1 score in stage I endometrial carcinoma.     

The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early stage (FIGO I-II) epithelial ovarian carcinoma

Abstract. Skirnisdóttir I, Sorbe B, Seidal T. The growth factor receptors HER-2/neu and EGFR, their relationship, and their effects on the prognosis in early stage (FIGO I–II) epithelial ovarian carcinoma.
Epithelial ovarian cancer is a heterogeneous disease and many biologic and molecular factors are important for its development and progression, including growth rate, metastatic potential, chemo- and radiosensitivity, and prognosis. Even in the early stages (FIGO I–II), many questions persist about the biologic behavior, optimal treatment, and prognosis.
In a series of 106 patients with epithelial ovarian cancers in FIGO stages IA-IIC, a number of known prognostic factors (age, FIGO stage, histopathologic type, and tumor grade) were studied in relation to two important growth factor receptors for oncogenesis (HER-2/neu and EGFR). Immunohistochemical techniques were used. All patients received adjuvant radiotherapy 4–6 weeks after the primary surgery. In a univariate analysis, the expression of the HER-2/neu receptor was not associated with any of the clinicopathologic factors studied or survival status. Positive EGFR staining was associated with poor survival in a univariate analysis. Co-expression of HER-2/neu and EGFR was most frequently seen in serous tumors and positive staining for HER-2/neu alone was associated with mucinous tumors. Both endometrioid and clear cell tumors belonged to the largest subgroup with concomitant negativity for both HER-2/neu and EGFR. In a multivariate Cox analysis, the tumor grade and EGFR status of the tumors were independent and significant prognostic factors. A therapeutic strategy for epithelial ovarian cancer might be to decrease EGFR expression by gene therapy in combination with adjuvant radiotherapy or chemotherapy.     

Expression of HER2neu (c-erbB-2) and epidermal growth factor receptor in cervical cancer: prognostic correlation with clinical characteristics, and comparison of manual and automated imaging analysis

OBJECTIVES: To evaluate HER2neu and epidermal growth factor receptor (EGFR) expression with respect to overall survival and disease-free survival (DFS), and correlate expression with pretreatment factors. Comparative evaluations of manual and automated immunohistochemical imaging systems for HER2neu and EGFR expression were made. METHODS: Fifty-five patients with stages I-IVA carcinoma of the cervix were treated with definitive radiation therapy. Immunohistochemistry was performed for HER2neu and EGFR, and scored by both manual and automated methods. Univariate and multivariate analyses were performed with disease-free survival (DFS) and overall survival (OS) as primary endpoints, and biomarkers were evaluated for correlation between prognostic factors. RESULTS: Strong correlations in HER2neu and EGFR protein expression were observed between digitally and manually analyzed staining (P <== 0.0001). Increased FIGO stage and decreased HER2neu expression were significant for reduced DFS on univariate analysis (P <== 0.001 and P = 0.03, respectively). Increased FIGO stage, decreased HER2neu expression, and increased membranous staining of EGFR were significant for diminished OS on univariate analysis (P <== 0.0001, P = 0.002, and P = 0.043, respectively). Multivariate analysis revealed only increased membranous staining of EGFR associated with diminished DFS and OS (P = 0.046 and P = 0.012, respectively). Overexpression of HER2neu correlated significantly with adenocarcinoma, and overexpression of EGFR correlated significantly with squamous cell carcinoma histology (P = 0.038 and P = 0.035). Inverse correlations were observed between HER2neu expression and clinical stage, EGFR membranous staining, and EGFR distribution (P = 0.007, P = 0.006, and P = 0.034, respectively). CONCLUSIONS: Increased expression of HER2neu and decreased EGFR membranous staining identified patients with improved DFS and OS on univariate analysis, although only decreased EGFR membranous staining was significant on multivariate analysis. We also found strong correlation of results between manually and automated imaging methods.     

The importance of biological factors (bcl-2, bax, p53, PCNA, MI, HPV and angiogenesis) in invasive cervical cancer.

OBJECTIVE: The present study was designed to analyse the relationship between apoptosis related proteins (bcl-2 and bax), tumour suppressor protein p53, proliferation markers (PCNA and mitotic index), human papillomavirus (HPV) and angiogenesis in cervical cancer and their impact on clinical outcome. STUDY DESIGN: Tumours from 111 patients were assessed by immunohistochemistry for the expression of bcl-2, bax, p53 and PCNA, by PCR for the presence of HPV-DNA, for the quantification of the mitotic index and the microvessel density (CD 31). The results were correlated with various histopathologic characteristics and survival. RESULTS: The multiple Cox's regression analysis for overall survival of all prognostic variables gave as best model: bcl-2 (P<0.001), lymphovascular permeation (P=0.004), mitotic index (P=0.019), tumour grade (P=0.048) and FIGO stage (P=0.070). Subanalysis was performed for the patients where the lymph node status was known (n=79). Adding the lymph node status gave as best model for overall survival bcl-2 (P=0.001), lymphovascular permeation (P=0.003) and mitotic index (P=0.044). However, they hardly influenced the association. CONCLUSION: In the apoptotic pathway of cervical cancer, bcl-2 is one of most important proteins. It can probably not only mediate cell death but also regulate cell growth. A better understanding of their relations will probably provide the basis for more rational cancer therapies in the future.