Janne Kærn

Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma

BACKGROUND Previous studies on prognostic factors in stage I invasive epithelial ovarian carcinoma have been too small for robust conclusions to be reached. We undertook a retrospective study in a large international database to identify the most important prognostic variables. METHODS 1545 patients with invasive epithelial ovarian cancer (International Federation of Gynaecology and Obstetrics [FIGO] stage I) were included. The records of these patients were examined and data extracted for univariate and multivariate analysis of disease-free survival in relation to various clinical and pathological variables. FINDINGS The multivariate analyses identified degree of differentiation as the most powerful prognostic indicator of disease-free survival (moderately vs well differentiated hazard ratio 3.13 [95% CI 1.68-5.85], poorly vs well differentiated 8.89 [4.96-15.9]), followed by rupture before surgery (2.65 [1.53-4.56]), rupture during surgery (1.64 [1.07-2.51]), FIGO 1973 stage Ib vs Ia 1.70 [1.01-2.85]) and age (per year 1.02 [1.00-1.03]). When the effects of these factors were accounted for, none of the following were of prognostic value: histological type, dense adhesions, extracapsular growth, ascites, FIGO stage 1988, and size of tumour. INTERPRETATION Degree of differentiation, the most powerful prognostic indicator in stage I ovarian cancer, should be used in decisions on therapy in clinical practice and in the FIGO classification of stage I ovarian cancer. Rupture should be avoided during primary surgery of malignant ovarian tumours confined to the ovaries.

Analysis of prognostic factors in stage I epithelial ovarian carcinoma : importance of degree of differentiation and deoxyribonucleic acid ploidy in predicting relapse

OBJECTIVES Our purpose was to identify prognostic factors in stage I epithelial invasive ovarian carcinoma. STUDY DESIGN The traditional clinical and pathologic prognostic variables and deoxyribonucleic acid ploidy were analyzed in a group of 290 patients. RESULTS A multivariate analysis identified degree of differentiation as the most powerful prognostic indicator of disease-free survival, followed by deoxyribonucleic acid ploidy and, finally, International Federation of Gynecology and Obstetrics (1986) stage. Tumors with clear cell carcinoma elements were not graded, and in this subgroup International Federation of Gynecology and Obstetrics (1986) stage was the most important prognostic characteristic. When the effects of the three most important factors were accounted for in graded tumors, then none of the following were prognostic: histologic type, dense adhesion, extracapsular growth, ascites, rupture during surgery, International Federation of Gynecology and Obstetrics (1973) stage, size of tumor, and age and type of adjuvant treatment. None of 77 patients with well differentiated deoxyribonucleic acid diploid tumors had relapses. CONCLUSION Deoxyribonucleic acid ploidy is an important new independent prognostic factor in stage I ovarian carcinoma.

Randomized study on adjuvant chemotherapy in stage I high-risk ovarian cancer with evaluation of DNA-ploidy as prognostic instrument

Summary Purpose: Adjuvant chemotherapy versus observation and chemotherapy at progression was evaluated in 162 patients in a prospective randomized multicenter study. We also evaluated DNA-measurements as an additional prognostic factor. Patients and methods: Patients received adjuvant carboplatin AUC 7 every 28 days for six courses (n - 81) or no adjuvant treatment (n = 81). Eligibility included surgically staged and treated patients with FIGO stage I disease, grade 1 aneuploid or grade 2 or 3 non-clear cell carcinomas or clear cell carcinomas. Disease-free (DFS) and disease-specific (DSS) survival were end-points. Results: Median follow-up time was 46 months and progression was observed in 20 patients in the treatment group and 19 in the control group. Estimated five-year DFS and DSS were 70% and 86% in the treatment group and 71% and 85% in the control group. The hazard ratio was 0.98 (95% confidence interval (95% CI): 0.52-1.83) regarding DFS and 0.94 (95% CI: 0.37-2.36) regarding DSS. No significant differences in DFS or DSS could be seen when the log-rank test was stratified for prognostic variables. Therefore, data from both groups were pooled for the analysis of prognostic factors. DNAploidy (P = 0.003), extracapsular growth (P = 0.005), tumor rupture (P = 0.04), and WHO histologic grade (P = 0.04) were significant independent prognostic factors for DFS with P < 0.0001 for the model in the multivariate Cox analysis. FIGO substage (P = 0.01), DNA ploidy (P < 0.05), and histologic grade (P = 0.05) were prognostic for DSS with a P-value for the model < 0.0001. Conclusions: Due to the small number of patients the study was inconclusive as regards the question of adjuvant chemotherapy. The survival curves were superimposable, but with wide confidence intervals. DNA-ploidy adds objective independent prognostic information regarding both DFS and DSS in early ovarian cancer.

Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients

Background:The CALYPSO phase III trial compared CD (carboplatin-pegylated liposomal doxorubicin (PLD)) with CP (carboplatin-paclitaxel) in patients with platinum-sensitive recurrent ovarian cancer (ROC). Overall survival (OS) data are now mature.Methods:Women with ROC relapsing >6 months after first- or second-line therapy were randomised to CD or CP for six cycles in this international, open-label, non-inferiority trial. The primary endpoint was progression-free survival. The OS analysis is presented here.Results:A total of 976 patients were randomised (467 to CD and 509 to CP). With a median follow-up of 49 months, no statistically significant difference was observed between arms in OS (hazard ratio=0.99 (95% confidence interval 0.85, 1.16); log-rank P=0.94). Median survival times were 30.7 months (CD) and 33.0 months (CP). No statistically significant difference in OS was observed between arms in predetermined subgroups according to age, body mass index, treatment-free interval, measurable disease, number of lines of prior chemotherapy, or performance status. Post-study cross-over was imbalanced between arms, with a greater proportion of patients randomised to CP receiving post-study PLD (68%) than patients randomised to CD receiving post-study paclitaxel (43%; P<0.001).Conclusion:Carboplatin-PLD led to delayed progression and similar OS compared with carboplatin-paclitaxel in platinum-sensitive ROC.

miRNA profiling along tumour progression in ovarian carcinoma

MicroRNAs (miRNAs) are small non‐coding RNAs that exert a regulatory effect post‐transcriptionally by binding target mRNAs and inhibiting gene translation. miRNA expression is deregulated in cancer. The aim of this study was to characterize the differences in miRNA expression pattern and the miRNA‐regulating machinery between ovarian carcinoma (OC) cells in primary tumours versus effusions. Using miRNA array platforms, we analysed a set of 21 tumours (13 effusions, 8 primary carcinomas) and identified three sets of miRNAs, one that is highly expressed in both primary carcinomas and effusions, one overexpressed in primary carcinomas and one overexpressed in effusions. Levels of selected miRNAs were analysed using quantitative PCR in an independent set of 45 additional tumours (30 effusions, 15 primary carcinomas). Reduced miR‐145 and miR‐214 and elevated let‐7f, miR‐182, miR‐210, miR‐200c, miR‐222 and miR‐23a levels were found in effusions in both sets. In silico target prediction programs identified potential target genes for some of the differentially expressed miRNAs. Expression of zinc finger E‐box binding homeobox (ZEB)1 and c‐Myc, targets of miR‐200c, as well as of p21 protein (Cdc42/Rac)‐activated kinase (PAK)1 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN), predicted targets of miR‐222, were analysed. Inverse correlations between expression levels of the indicated miRNAs and of the predicted target genes were found. In addition, higher expression of the miRNA‐processing molecules Ago1, Ago2 and Dicer was observed in effusions compared to primary carcinomas. In conclusion, our data are the first to document different miRNA expression and regulation profiles in primary and metastatic OC, suggesting a role for these molecules in tumour progression.

Circulating tumor cells in the peripheral blood and bone marrow of patients with ovarian carcinoma do not predict prognosis.

Ovarian carcinoma is apparently restricted for a long time to the peritoneal cavity. However, about 50% of patients with a surgically documented complete intraabdominal response experience later recurrence. Occult hematogenous micrometastases are common to most epithelial malignancies and have recently been found in 30% of bone marrow samples of ovarian carcinoma patients, as examined by immunocytochemistry. Moreover, these findings were associated with poor progression‐free and overall survival. The aim of the current study was to evaluate the possible prognostic significance of tumor cells detected in the peripheral blood and bone marrow of ovarian carcinoma patients by an immunomagnetic method.

Adjuvant Chemotherapy for Early-Stage Ovarian Cancer: Review of the Literature

PURPOSE This overview summarizes studies with acceptable quality and validity and presents a synthesis of the effectiveness on adjuvant therapy after surgery for early ovarian cancer (EOC) patients. METHODS The literature published between 1970 and 2006 was identified systematically by computer-based searches in MEDLINE and Cochrane library. RESULTS Twenty-two prospective randomized studies were analyzed, which included 4,626 patients. No difference between adjuvant chemotherapy (AC) and radiotherapy was found. There is agreement on that patients with stage IA, grade 1 tumors have excellent survival and do not need postsurgical therapy. The International Collaborative Ovarian Neoplasm 1/Adjuvant Chemotherapy in Ovarian Neoplasm trials were the first to show an effect on survival of AC, but in patients with adequate surgical staging, there was no additional effect of AC. For patients who are staged incompletely at the time of initial surgery, completion of the staging procedure with either laparoscopy or laparotomy is a reasonable approach before a final decision is made regarding the need for AC. If full staging cannot be performed due to medical contraindication or patient refusal, consideration of AC is reasonable in selected patients. Using prognostic variables such as grade, International Federation of Gynecology and Obstetrics substage, pretreatment of CA-125 < or = 30 U/mL, and DNA ploidy, it is possible to divide patients into risk groups to avoid overtreatment. Gynecologic Oncology Group study 157 suggests that it may be possible to minimize chemotherapy-induced toxicity by using three instead of six cycles of AC, although it is not known fully whether this will compromise effectiveness. CONCLUSION Future randomized studies in EOC will include the investigation of new targeted therapies and new prognostic factors in adequately staged patients.

Therapy effect of either paclitaxel or cyclophosphamide combination treatment in patients with epithelial ovarian cancer and relation to TP53 gene status

Cell death after treatment with chemotherapy is exerted by activation of apoptosis, and the p53 protein has been shown to actively participate in this process. This recent focus on TP53 status as a possible determinant of cancer therapy response has raised the question of whether or not mutations in the TP53 gene have an influence on paclitaxel therapy. The TP53 status has been analysed at the DNA level in tumours from 45 ovarian cancer patients randomized to treatment with paclitaxel and cisplatin or cyclophosphamide and cisplatin. Therapy response was obtained for 38 patients with clinically evaluable disease after initial surgery. The positive response rate to the paclitaxel/cisplatin therapy was 85% vs 61% for the patients who received the cyclophosphamide/cisplatin regimen. A significant difference in relapse-free survival in favour of paclitaxel/cisplatin chemotherapy was found (P = 0.001). A total of 33 tumour samples (73%) had detectable sequence alterations in the TP53 gene. When relapse-free survival was estimated for all patients with TP53 alterations in their tumours, a significant better outcome for the paclitaxel/cisplatin group was found compared with the patient group receiving cyclophosphamide and cisplatin therapy (P = 0.002). We did not observe an association between TP53 tumour status and prognosis for patients who received paclitaxel/cisplatin combination treatment, indicating that the effect of this therapy is not influenced by this parameter.

Borderline ovarian tumours.

Borderline ovarian tumours account for 10-20% of all epithelial ovarian cancer. Historically, standard primary surgery has included borderline ovarian tumours, omentectomy, peritoneal washing and multiple biopsies. As one-third of borderline ovarian tumours are diagnosed in women under the age of 40 years, fertility-sparing treatment has been more frequently used in the past 10 years. Fertility drugs are well tolerated in women with infertility after fertility-sparing surgery. Careful selection of candidates is necessary. Laparoscopic techniques can be used, but should be reserved for oncologic surgeons. This conservative treatment increases the rate of recurrence, albeit with no effect on survival. The pregnancy rate is nearly 50%, and most are achieved spontaneously. These women should be closely followed up. The question is whether this is acceptable from a gynaecologic oncologic point of view. For this reason, we will discuss recently published studies and gynaecologic oncologic concerns about the mode of fertility-sparing surgery and its consequences.

Class III β-tubulin expression in advanced-stage serous ovarian carcinoma effusions is associated with poor survival and primary chemoresistance

The objective of this study was to analyze the clinical role of nestin, a stem cell marker, and class III β-tubulin in advanced-stage serous ovarian carcinoma. Nestin and class III β-tubulin protein expression were investigated in 217 effusions using immunohistochemistry. Results were analyzed for association with clinicopathologic parameters including chemotherapy response and survival. Class III β-tubulin and nestin were expressed in tumor cells in 98.6% and 95.6% of specimens, respectively. Staining extent was comparable in prechemotherapy and postchemotherapy effusions. No association was found with patient age, histologic grade, International Federation of Gynecology and Obstetrics stage, primary surgery versus secondary debulking, or residual disease volume. High class III β-tubulin expression in prechemotherapy effusions was significantly associated with primary chemoresistance (progression-free survival <6 months; P = .036) and with a trend for less favorable response to first-line treatment (P = .054). In univariate survival analysis, high class III β-tubulin expression in prechemotherapy effusions was significantly associated with poor overall survival (P = .021), with a trend for poor progression-free survival (P = .067). These associations did not have independent prognostic value in Cox multivariate analysis. Nestin expression was unrelated to chemoresistance or survival. Both class III β-tubulin and nestin are frequently expressed in serous ovarian carcinoma cells in effusions. Nestin does not provide predictive or prognostic data in this patient group, whereas class III β-tubulin expression in prechemotherapy effusions is associated with poor chemoresponse and shorter survival, suggesting that it may be a therapeutic target in ovarian cancer.