Genomic aberrations relate early and advanced stage ovarian cancer.

BACKGROUND: Because of the distinct clinical presentation of early and advanced stage ovarian cancer, we aim to clarify whether these disease entities are solely separated by time of diagnosis or whether they arise from distinct molecular events. METHODS: Sixteen early and sixteen advanced stage ovarian carcinomas, matched for histological subtype and differentiation grade, were included. Genomic aberrations were compared for each early and advanced stage ovarian cancer by array comparative genomic hybridization. To study how the aberrations correlate to the clinical characteristics of the tumors we clustered tumors based on the genomic aberrations. RESULTS: The genomic aberration patterns in advanced stage cancer equalled those in early stage, but were more frequent in advanced stage (p = 0.012). Unsupervised clustering based on genomic aberrations yielded two clusters that significantly discriminated early from advanced stage (p = 0.001), and that did differ significantly in survival (p = 0.002). These clusters however did give a more accurate prognosis than histological subtype or differentiation grade. CONCLUSION: This study indicates that advanced stage ovarian cancer either progresses from early stage or from a common precursor lesion but that they do not arise from distinct carcinogenic molecular events. Furthermore, we show that array comparative genomic hybridization has the potential to identify clinically distinct patients.

Recurrence rate in vulvar carcinoma in relation to pathological margin distance.

OBJECTIVES: This paper describes the results of a retrospective study of surgical approaches and recurrence rates relating to patients with squamous cell carcinoma (SCC) of the vulva. The aim of this study was to analyze the histological margins in relation to recurrence rate and survival. METHODS: A retrospective chart review of 93 cases of vulvar cancer. The data collected included clinicopathological and surgical characteristics and the following potential risk factors: pathological margin distance, less than 8 mm; stromal invasion depth, more than 2.5 mm; tumor size; and presence of benign or premalignant epithelial disorders. RESULTS: Ninety-three patients (median age, 74 years) underwent modified radical vulvectomy, hemi-vulvectomy, or local wide excision for SCC of the vulva from 2000 to 2005. The tumor was radically removed in 80 patients (86%), although the histopathological margin was less than 8 mm in 50 patients (54%). Eighteen patients (23%) developed a local recurrence. The recurrence rate did not differ between patients in whom the margin distance was 8 mm or more and those in whom the margin distance was less than 8 mm, (23% and 22%, respectively). The median follow-up was 31 months (range, 2-90 months). CONCLUSIONS: Several studies showed that pathological margin distance of more than 8 mm is an important predictor for local recurrence. This finding was not confirmed in the present study.

Surgical staging and treatment of early ovarian cancer: long-term analysis from a randomized trial.

A long-term follow-up analysis of the randomized clinical trial Adjuvant Chemotherapy in Ovarian Neoplasm (ACTION) from the European Organization for Research and Treatment of Cancer was undertaken to determine whether the original results with a median follow-up of 5.5 years could be verified after longer follow-up with more events. In the ACTION trial, 448 patients with early ovarian cancer were randomly assigned, after surgery, to adjuvant chemotherapy or to observation (no further treatment). The original analysis found that adjuvant chemotherapy improved recurrence-free survival but not overall survival and found in a subgroup analysis that completeness of surgical staging was an independent prognostic factor, with better recurrence-free and overall survival among those with complete (optimal) surgical staging. After a median follow-up of 10.1 years, we analyzed the more mature data from the ACTION trial and found support for most of the main conclusions of the original analysis, except that overall survival after optimal surgical staging was improved, even among patients who received adjuvant chemotherapy (hazard ratio of death = 1.89, 95% confidence interval = 0.99 to 3.60; overall two-sided log-rank test P = .05). More cancer-specific deaths were observed among nonoptimally staged patients (40 [27%] of the 147 deaths in the observation arm and 11 [14%] of the 76 deaths in the adjuvant chemotherapy arm) than among optimally staged patients (seven [9%] of the 75 deaths in the observation arm and 11 [14%] of the 76 deaths in the adjuvant chemotherapy arm) (two-sided chi(2) test for heterogeneity, P = .06). Thus, completeness of surgical staging in patients with early ovarian cancer was found to be statistically significantly associated with better outcomes, and the benefit from adjuvant chemotherapy appeared to be restricted to patients with nonoptimal surgical staging.

Lymph node sampling and taking of blind biopsies are important elements of the surgical staging of early ovarian cancer.

BACKGROUND: The purpose of this study was to determine the effect of lymph node sampling and taking of blind biopsies as part of the surgical staging procedure for early ovarian cancer on disease-free survival (DFS) and overall survival (OS) in patients who received no adjuvant chemotherapy. METHODS: In the EORTC ACTION Trial, 448 patients with early ovarian carcinoma were randomized between November 1990 and March 2000-224 patients to observation and 224 to adjuvant platin-based chemotherapy. Only patients allocated to observation were included for the current study. Analyses were performed in a subgroup of 75 optimally staged patients (group A), 46 patients in whom all staging steps were performed except para-aortic or pelvic lymph node sampling (group B), and 14 patients who fulfilled all staging criteria but in whom no blind peritoneal biopsies were taken (group C). The study group did not differ in stage distribution, cell type, or tumor grade. RESULTS: Significantly improved 5-year DFS (P = 0.03) and 5-year OS (P = 0.01) were found in group A (optimally staged) versus group B (no lymph node sampling). A significant difference was also shown in 5-year DFS (P = 0.02) and 5-year OS (P = 0.003) between group A and group C (no blind biopsies). Recurrences occurred in 11 (14.6%) of 75 patients in group A, 16 (34.8%) of 46 patients in group B, and 5 (35.7%) of 14 in group C. The 5-year DFS in group A was 79% versus 61% and 64% in groups B and C, respectively. The 5-year OS decreased from 89% in group A to 71% in group B and 65% in group C. CONCLUSIONS: In this study, statistically significant differences were found in patients in whom para-aortic and pelvic lymph node sampling and taking of blind peritoneal biopsies were undertaken compared with patients in whom these staging steps had been omitted. These findings support the relevance of lymph node sampling and the taking of blind peritoneal biopsies in the surgical staging of early ovarian cancer.

Comparison of CA-125 and standard definitions of progression of ovarian cancer in the intergroup trial of cisplatin and paclitaxel versus cisplatin and cyclophosphamide.

PURPOSE: A definition for progression of ovarian cancer has been proposed based on either a confirmed doubling of CA-125 levels from the upper limit of normal or from the nadir level if levels are persistently elevated. Retrospectively, we determined whether the use of this CA-125 definition in a randomized trial would have shown the same magnitude of difference between the treatment arms as was shown when the standard progression definition was used. PATIENTS AND METHODS: A retrospective analysis was performed on 680 patients in the Taxol Intergroup Trial with advanced epithelial ovarian carcinoma, of whom 628 were assessable according to CA-125. The date of progression according to clinical or radiologic criteria was compared with the date of progression according to CA-125. RESULTS: Of the 628 patients assessable for both definitions, 556 clinical or radiologic progressions were determined compared with 389 according to the CA-125 definition. There was a highly significant difference in the hazard of progression between the paclitaxel and cisplatin arm (TP) compared with the cyclophosphamide and cisplatin arm (CP) when either standard or CA-125 criteria were used to define progression (standard, P = .002; CA-125, P = .011). The hazard ratio of TP/CP over time was similar when comparing the different methods of defining progression. CONCLUSION: The results of this analysis show that the magnitude of the therapeutic benefit was similar whether CA-125 or standard criteria were used to define progression.

Chemotherapy for early ovarian cancer.

PURPOSE OF REVIEW: The treatment of early ovarian cancer has long been based on non-randomized studies and on a small number of randomized studies without sufficient power. Adjuvant chemotherapy is often given to high-risk patients, but the benefit of such an approach has never been proven and the definition of high-risk early ovarian cancer differs widely. Recently, the results of the two largest randomized clinical trials on early ovarian cancer became available. Both trials are discussed, and their results are related to the other relevant literature of the last three years. RECENT FINDINGS: A meta-analysis of over 1500 patients from the year 2001 confirmed tumor grade as a strong prognostic factor but it also demonstrated the adverse effect of capsule rupture before and during surgery. The Adjuvant Chemotherapy in Ovarian Neoplasm trial (European Organization for Research and Treatment of Cancer) randomized 448 patients to either adjuvant chemotherapy following surgery or observation. Adjuvant chemotherapy improved overall survival and disease-free survival in non-optimally staged patients but showed no benefit in optimally staged patients. The Medical Research Council International Collaborative Ovarian Neoplasm 1 trial randomized 477 patients in a similar way. Overall survival and disease-free survival were improved by adjuvant chemotherapy. It was argued that the study population of the International Collaborative Ovarian Neoplasm 1 trial probably represents non-optimally staged patients, and this hypothesis explains why the results of this trial were in accord with those of the Adjuvant Chemotherapy in Ovarian Neoplasm trial. SUMMARY: The implications of these data are that a complete surgical staging is of utmost importance and should be pursued. In cases of non-optimal staging and contraindications for restaging, adjuvant chemotherapy is indicated to deal with unnoticed residual tumor deposits that exist in approximately 25% of cases.

Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial.

BACKGROUND: All randomized trials of adjuvant chemotherapy for early-stage ovarian cancer have lacked the statistical power to show a difference in the effect on survival between adjuvant chemotherapy and no adjuvant chemotherapy. They have also not taken into account the adequacy of surgical staging. We performed a prospective unblinded, randomized phase III trial to test the efficacy of adjuvant chemotherapy in patients with early-stage ovarian cancer, with emphasis on the extent of surgical staging. METHODS: Between November 1990 and January 2000, 448 patients from 40 centers in nine European countries were randomly assigned to either adjuvant platinum-based chemotherapy (n = 224) or observation (n = 224) following surgery. Endpoints were overall survival and recurrence-free survival, and the analysis was on an intention-to-treat basis. The Kaplan-Meier method was used to perform time-to-event analysis, and the log-rank test was used to compare differences between treatment arms. Statistical tests were two-sided. RESULTS: After a median follow-up of 5.5 years, the difference in overall survival between the two trial arms was not statistically significant (hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.44 to 1.08; P =.10). Recurrence-free survival, however, was statistically significantly improved in the adjuvant chemotherapy arm (HR = 0.63, 95% CI = 0.43 to 0.92; P =.02). Approximately one-third of patients (n = 151) had been optimally staged and two-thirds (n = 297) had not. Among patients in the observation arm, optimal staging was associated with a statistically significant improvement in overall and recurrence-free survival (HR = 2.31 [95% CI = 1.08 to 4.96]; P =.03 and HR = 1.82 [95% CI = 1.02 to 3.24] P =.04, respectively). No such association was observed in the chemotherapy arm. In the non-optimally staged patients, adjuvant chemotherapy was associated with statistically significant improvements in overall and recurrence-free survival (HR = 1.75 [95% CI = 1.04 to 2.95]; P =.03 and HR = 1.78 [95% CI = 1.15 to 2.77]; P =.009, respectively). In the optimally staged patients, no benefit of adjuvant chemotherapy was seen. CONCLUSION: Adjuvant chemotherapy was associated with statistically significantly improved recurrence-free survival in patients with early-stage ovarian cancer. The benefit of adjuvant chemotherapy appeared to be limited to patients with non-optimal staging, i.e., patients with more risk of unappreciated residual disease.