Outcome of Epithelial Ovarian Cancer: Time for Strategy Trials to Resolve the Problem of Optimal Timing of Surgery.

INTRODUCTION: The standard treatment of ovarian cancer is the combination of debulking surgery and chemotherapy. There is an ongoing discussion on which treatment is best: primary debulking surgery (PDS) or neoadjuvant chemotherapy with interval debulking (NACT-IDS). Even a large randomized trial has not settled this issue. We examined whether comparing a specified treatment protocol would not be a more logical approach to answer this type of discussions. METHODS: A retrospective study of 142 consecutively treated patients according to a fixed protocol between 2000 and 2012 was conducted. Disease-free survival and overall survival were calculated by univariate and multivariate analyses for the whole group and for advanced stages separately. Specific differences between PDS and NACT-IDS were studied. Comparison of results from large databases was made. RESULTS: Disease-free survival and overall 5-year survival for the whole group were 35% and 50%. For the advanced stages, disease-free survival and overall 5-year survival were 14% and 36%, with a median disease-free and overall survival of 16 and 44 months. Of the 98 women with advanced ovarian carcinoma, 54% of operable patients underwent PDS and 44% underwent NACT-IDS. More patients in the PDS group were optimally (<1 cm) debulked: 80% vs 71%. There was no significant difference in survival between PDS or NACT-IDS. Optimally debulked patients had a significant better overall survival in multivariate analysis with a hazard ratio of 2.1. DISCUSSION: Outcome of treatment according to a fixed protocol with a mixture of PDS and NACT-IDS was similar to results from large databases. We hypothesize that comparison of a specific strategy may yield more useful results than awaiting the perfect randomized trial.

A novel approach to predict the likelihood of specific ovarian tumor pathology based on serum CA-125: a multicenter observational study.

BACKGROUND: The CA-125 tumor marker has limitations when used to distinguish between benign and malignant ovarian masses. We therefore establish likelihood curves of six subgroups of ovarian pathology based on CA-125 and menopausal status. METHODS: This cross-sectional study conducted by the International Ovarian Tumor Analysis group involved 3,511 patients presenting with a persistent adnexal mass that underwent surgical intervention. CA-125 distributions for six tumor subgroups (endometriomas and abscesses, other benign tumors, borderline tumors, stage I invasive cancers, stage II-IV invasive cancers, and metastatic tumors) were estimated using kernel density estimation with stratification for menopausal status. Likelihood curves for the tumor subgroups were derived from the distributions. RESULTS: Endometriomas and abscesses were the only benign pathologies with median CA-125 levels above 20 U/mL (43 and 45, respectively). Borderline and invasive stage I tumors had relatively low median CA-125 levels (29 and 81 U/mL, respectively). The CA-125 distributions of stage II-IV invasive cancers and benign tumors other than endometriomas or abscesses were well separated; the distributions of the other subgroups overlapped substantially. This held for premenopausal and postmenopausal patients. Likelihood curves and reference tables comprehensibly show how subgroup likelihoods change with CA-125 and menopausal status. CONCLUSIONS AND IMPACT: Our results confirm the limited clinical value of CA-125 for preoperative discrimination between benign and malignant ovarian pathology. We have shown that CA-125 may be used in a different way. By using likelihood reference tables, we believe clinicians will be better able to interpret preoperative serum CA-125 results in patients with adnexal masses.

Uterine and quality of life changes in postmenopausal women with an asymptomatic tamoxifen-thickened endometrium randomized to continuation of tamoxifen or switching to anastrozole.

OBJECTIVE: Before the knowledge that 5 years of adjuvant tamoxifen is less efficacious than 2 to 3 years of tamoxifen followed by 2 to 3 years of anastrozole/exemestane, we designed a multicenter double-blind randomized controlled trial in women taking tamoxifen with a thickened endometrium to compare uterine and quality-of-life parameters between those switching to anastrozole and those continuing tamoxifen. METHODS: Asymptomatic postmenopausal women who took adjuvant tamoxifen for 2 to 3 years for operable breast cancer with a double endometrial thickness greater than 7 mm were randomized to 20 mg tamoxifen or 1 mg anastrozole for the remaining duration, totaling 5 years. Tablets were unrecognizable for drug assignment. The primary endpoints were the differences in double endometrial thickness and uterine volume after 1 year. Uterine and quality-of-life data were analyzed using regression methods, and missing values were handled using multiple imputation. RESULTS: Seventy-two women (median age, 60 y) were randomized in five hospitals. Relative to women continuing tamoxifen, women switching to anastrozole experienced a decrease of 53% (95% CI, 41%-63%) in double endometrial thickness and a decrease of 51% (95% CI, 39%-60%) in uterine volume. Vaginal dryness (b = 0.064; 95% CI, 0.016-0.112) and sexual problems (b = 0.054; 95% CI, 0.007-0.102) increased in women taking anastrozole compared with women taking tamoxifen. Treatment arms did not differ regarding withdrawal rate and the experience of (serious) adverse events. CONCLUSIONS: Despite premature trial closure, our data provided valuable insights. Switching to anastrozole strongly decreased the endometrial thickness and uterine volume but increased sexual disturbances. Safe and effective interventions are needed to alleviate sexual dysfunction.

Risk grouping in stage IB squamous cell cervical carcinoma.

OBJECTIVES: To test the Gynecologic Oncology Group (GOG) prognostic criteria (based on stromal invasion, tumor size and vascular invasion) for early squamous cervical carcinoma (SCC) in an independent population and to evaluate the prognostic value of a simpler model. METHODS: We studied 221 patients who underwent radical hysterectomy and bilateral lymphadenectomy for stage IB SCC between 1987 and 1993. Adjuvant treatment consisting of radiotherapy and/or chemotherapy was given in case of large tumor size, positive lymph nodes or invasion into the parametria. Histological slides from all patients were reviewed by one pathologist. RESULTS: The GOG criteria divided the patients from our population in a small low risk group (3-year relapse-free rate (RFR) of 100%), a small high risk group (RFR of 57%) and a bigger intermediate risk group (RFR of 80-90%). These results are in good agreement with those of the original publication. A risk model based on 2 of the 3 factors used by the GOG may perform as well as the 3-factor model, especially when allowing interaction. Tumors measuring >2 cm and invading into the outer third of the cervical wall had a 5-year DFS of 56% compared to 93% for tumors measuring < or =2 cm or invading to less then the outer third of the cervical wall. CONCLUSION: The GOG criteria could be validated in this independent population. A model based on 2 of the 3 factors may perform as good.

E-cadherin and catenins in early squamous cervical carcinoma.

OBJECTIVES: To examine the prognostic significance of the protein expression of E-cadherin, alpha-, beta-, and gamma-catenin in early squamous cervical carcinoma (SCC). METHODS: We studied 219 patients who underwent radical hysterectomy and bilateral lymphadenectomy at our institution for stage IB SCC between 1987 and 1993. Immunohistochemistry using monoclonal antibodies against E-cadherin, alpha-, beta-, and gamma-catenin was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolapse served as controls. RESULTS: Membrane expression for E-cadherin, alpha-, beta-, and gamma-catenin was decreased and low expression (< or =50% positive cells) was found in 198/219 (90%), 154/219 (70%), 157/219 (72%), and 181/219 (83%) tumors, respectively, and high (>50% positive cells) in 21/219 (10%), 65/219 (30%), 62/219 (28%), and 38/219 (17%) tumors, respectively. In univariate analysis, all classical clinicopathological parameters but none of the investigated proteins were associated with prognosis. In multivariate analysis, only deep stromal invasion was independently related to survival. CONCLUSION: E-cadherin, alpha-, beta-, and gamma-catenin were not independently associated with prognosis in stage IB SCC.

Cyclins and proliferation markers in early squamous cervical carcinoma.

OBJECTIVES: To examine the prognostic significance of the protein expression of cyclin E, cyclin A and cyclin D3, and of the proliferation markers Ki-67 and BM28 in early squamous cervical carcinoma (SCC). METHODS: Tissue blocks from 221 patients who underwent radical hysterectomy and bilateral lymphadenectomy at our institution for stage IB SCC between 1987 and 1993 were available for this study. Immunohistochemistry using monoclonal antibodies against cyclin E, cyclin A, cyclin D3, Ki-67 and BM28 was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolapse served as controls. RESULTS: Cyclin E, cyclin A, Ki-67 and BM28 expression was increased in SCC and high expression was observed in 81.5% (180/221), 35% (78/221), 25.5% (56/221) and 92% (204/221) of tumors, respectively. Cyclin D3 was decreased in SCC and low expression was found in 50.5% (111/220) of tumors. In univariate analysis, all classical clinicopathological parameters but none of the investigated proteins were associated with prognosis. In multivariate analysis, only deep stromal invasion was independently related to survival. CONCLUSION: Cyclin E, cyclin A and cyclin D3 and the proliferation markers Ki-67 and BM28 are not independently associated with prognosis in stage IB SCC.

Expression of the 67 kDa laminin receptor and the alpha6 integrin subunit in serous ovarian carcinoma.

The aim of this study was to analyze the expression of two laminin receptors, the 67 kDa laminin receptor (LBP) precursor and the alpha6 integrin subunit, in effusions and solid tumors of patients diagnosed with serous ovarian carcinoma and to evaluate their predictive role. Eighty-eight effusions and one hundred sixteen primary (= forty-one) and metastatic (= seventy-five) ovarian carcinomas were evaluated for expression of the above-mentioned mRNAs using in situ hybridization (ISH). LBP protein expression was studied in 24 effusions and 43 solid tumors using immunohistochemistry (IHC). Alpha6 integrin subunit protein expression was studied in 27 effusions using flow cytometry (FCM). Expression of LBP mRNA was frequently detected in both carcinoma (92 of 116 cases, 79%) and stromal (79 of 116 cases, 68%) cells in solid tumors. Expression was still higher in cancer cells in effusions (85 of 88 specimens, 96%). In contrast, alpha6 integrin subunit was less frequently detected in both solid tumors (33 of 116; 28% in carcinoma cells, 23 of 116; 20% in stromal cells) and effusions (36 of 88; 41%). LBP protein expression was found in 19 of 24 (79%) effusions and 40 of 43 (93%) solid tumors, and was higher in effusions of patients who received chemotherapy prior to tapping (P = 0.024). FCM showed protein expression of the alpha6 integrin subunit in 17 of 27 (63%) effusions. Expression of the alpha6 integrin subunit mRNA in tumor cells of solid lesions was significantly lower in solid tumors of FIGO stage-IV patients compared to those of patients diagnosed with stage-III-disease (P = 0.004), and its absence predicted significantly shorter overall survival (OS) in univariate analysis (P = 0.018). Absence of alpha6 integrin subunit protein expression using FCM predicted median OS of 12 months compared to 26 months for patients with tumors expressing the protein, although this finding did not reach significance (P = 0.27). In conclusion, as opposed to previous reports, both mRNA and protein expression of the alpha6 integrin subunit do not appear to be down-regulated in effusions compared to solid tumors. Loss of alpha6 integrin subunit mRNA (and possibly protein) expression is a novel prognostic marker in advanced-stage ovarian carcinoma. LBP mRNA and protein expression is independent of that of the alpha6 integrin subunit in both solid tumors and effusions of serous ovarian carcinoma.

Expression of p27, p21, and p16 protein in early squamous cervical cancer and its relation to prognosis.

OBJECTIVE: To examine the prognostic significance of the protein expression of the cyclin-dependent kinase (cdk) inhibitors p27, p21, and p16 in early squamous cervical cancer (SCC). METHODS: From 221 [corrected] patients who underwent radical hysterectomy and bilateral lymphadenectomy at our institution for stage IB SCC between 1987 and 1993, tissue blocks were available for this study. Immunohistochemistry using monoclonal antibodies against p27, p21, and p16 was used to examine protein expression. Ten patients who underwent hysterectomy for uterine prolaps served as controls. RESULTS: p21 and p16 expression were increased in SCC and high expression was observed in 20% (44/221) and 43% (94/220) of tumors, respectively. p27 was decreased in SCC and low expression was found in 80% (177/221) of tumors. In univariate analysis all classical clinicopathological parameters were associated with prognosis. Low p16 expression was significantly related to decreased overall (P = 0.036) but not disease-free survival (P = 0.103). In multivariate analysis, deep stromal invasion but none of the cdk inhibitors was independently related to survival. CONCLUSION: The cdk inhibitors p27, p21, and p16 are not independently associated with prognosis in stage IB SCC.

Interleukin-8 and vascular endothelial growth factor mRNA and protein levels are down-regulated in ovarian carcinoma cells in serous effusions.

Angiogenic factors are involved in tumor growth and spread. The aim of this study was to evaluate the expression of angiogenesis-related genes in malignant serous effusions of patients with advanced-stage (FIGO stage III and IV) ovarian carcinoma. In addition, to compare the results for carcinoma cells in effusions with corresponding primary tumors and metastatic lesions, and analyze their prognostic role. Sections from 66 effusions and 90 primary and metastatic lesions from 62 ovarian and primary peritoneal carcinoma patients, were evaluated for expression of basic fibroblast factor (bFGF), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) using mRNA in situ hybridization (ISH). Protein expression was evaluated in a subset of specimens using immunohistochemistry (IHC). ISH results were correlated with clinical parameters. In both effusions and solid tumors, bFGF mRNA was the most commonly expressed factor (93% of effusions and 95% of solid tumors) followed by IL-8, while VEGF was expressed in a minority of the specimens (P < 0.001 for bFGF vs. IL-8 and VEGF). In solid tumors, angiogenic mRNA expression was seen in both tumor and stromal cells in the majority of positive cases. ISH results did not differ in primary and metastatic tumors. However, carcinoma cells in effusions showed down-regulated expression of VEGF, when compared with both primary tumors (P = 0.029) and metastases (P = 0.015). IL-8 showed a similar down-regulation in effusions, when compared with metastases (P = 0.005). IHC showed excellent agreement with mRNA findings on protein level. In the study of clinico-pathologic parameters, IL-8 mRNA expression in effusions was associated with higher tumor grade (P = 0.044). Angiogenic gene expression in effusions showed no correlation with patient age, previous treatment, residual tumor size, FIGO stage or disease outcome in survival analysis (P > 0.05). Peritoneal and pleural effusions showed similar expression patterns. In conclusion, bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. It is highly expressed in both solid tumors and serous effusions, while IL-8 and VEGF are down regulated in carcinoma cells in effusions, possibly due to the lack of interaction with stromal cells. mRNA expression of VEGF, bFGF, and IL-8 does not appear to be a predictor of disease outcome in advanced-stage ovarian carcinoma. Carcinoma cells in pleural and peritoneal effusions show a similar metastatic expression profile, in agreement with our previous findings, supporting the true metastatic nature of ovarian carcinoma cells in ascites.

Caveolin-1 expression in ovarian carcinoma is MDR1 independent.

We studied the role of caveolin-1 in tumor progression and prognosis in serous ovarian carcinoma and the association between caveolin-1 and MDR1 expression. The study involved immunohistochemical analysis for caveolin-1 and P-glycoprotein (P-gp) expression in 75 effusions and 90 solid lesions from ovarian and primary peritoneal carcinoma; in situ hybridization for MDR1 messenger RNA (mRNA) expression in 62 effusions and all 90 tumors; and reverse transcription-polymerase chain reaction (RT-PCR) for caveolin-1 mRNA expression in 23 effusions. Immunohistochemical analysis localized caveolin-1 to the cell membrane in 43 effusions and 24 tumors. P-gp membrane expression was detected in 14 effusions and 11 tumors; MDR1 mRNA, in 20 effusions and 30 tumors. Caveolin-1 mRNA was expressed in 19 effusions. Caveolin-1 protein expression showed no association with that of P-gp protein or MDR1 mRNA. The expression of all markers was similar in carcinoma cells in pleural and peritoneal effusions. Caveolin-1 is a novel diagnostic marker for effusions; expression is moderately elevated in tumor cells in effusions, possibly owing to altered signal transduction and metabolism in cancer cells at this site. Expression seems MDR1 independent.