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Epidemiologic of epitelial carcinoma of the ovary. Influence of age on prognostic fators and survival
Abstract
Two hundred twenty-seven women diagnosed as epithelial carcinoma of the ovary were studied for the relation between patient age, prognostic factors, and survival. Deficient studies were more frequent in patients over 60 (56% vs. 29.5%, p<0.01). Ascites at surgery was more frequent in older patients, although the positivity of peritoneal fluid was unrelated to age. Infiltration of other organs, FIGO stage, histologic type and tumor differentiation were unrelated to age. "Low-grade malignancy" was diagnosed more frequently in younger patients (p<0.06) Patients under 50 had a high survival rate (Log rank p=0.02).
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Epithelial ovarian cancer is the third most frequent fatal cancer of women in Australia and is one of the leading causes of female cancer deaths in the United States, Northern Europe, Canada and Israel (1,2). There are no identified preventable causes and no reliable means for early diagnosis so that improved survival must lie with the optimal management of patients. While there have undoubtedly been major advances in radiotherapy and chemotherapy over the last 3 decades, the available data suggest that these developments have not improved survival rates for the group of patients with epithelial ovarian cancer. This may be attributed, in part, to a lack of understanding of the multiplicity of prognostic variables that contribute to the outcome of patients with ovarian cancer and perhaps inappropriate selection between treatment options (3).
One of the most characteristic features of epithelial ovarian cancer is its inherent heterogeneity with respect to biological behavior ranging from the relatively indolent nature of borderline tumors to highly aggressive malignant diseases. This can be reflected in a wide variety of prognostic factors, among which the stage of disease is by far the most important, followed by histologic subtype, histologic grade, volume of residual disease, age at diagnosis, and performance status (PS). Within a given stage, histologic grade is the most powerful prognostic factor in stage I disease, followed by dense adherence and large volume of ascites. On the other hand, the main prognostic factor in more advanced stage disease (II-IV) includes an effect of chemotherapy and a volume of residuum, and PS. However, these factors alone cannot always predict patients' survival correctly. A number of new and potentially valuable prognostic factors have emerged as a result of the recent technical advances in molecular genetics, flow cytometric analysis, development of monoclonal antibody, immunohistochemical study, and steroid hormone receptor analysis. This article reviews some of these newly developed "investigational" prognostic variables, as well as the "widely accepted" clinicopathological prognostic factors.
The retrospective analysis of 68 advanced ovarian cancer cases was performed mainly to see whether certain predictive factors were present which might distinguish patients with risk for recurrence or death from those with a good prognosis. Six factors, such as the mode of operation, the site of metastasis, the degree of peritonitis carcinomatosa, the rate of the decline in serum CA125. Performance Status, and pathological type were selected as factors influencing prognosis. We then tried to tally the prognosis estimation score using these factors. The correlation between this score and the survival period was noted in only patients with a survival time up to 3 years. The following formula was obtained: Y = 1.286X -3.429 [X: prognosis estimation score, Y: survival period (months)]. Cases were classified as follows according to the this score. When patients had a value equal to or less than 17.84.2% of patients died within 21 months, while if patients had a value greater than 17.34.7% of cases survived more than 36 months. On the other hand, 89.5% of cases with a survival period longer than 36 months had a prognosis estimation score greater than 18. However, there was little significant correlation between this score and the survival period in patients with survival period longer than 3 years. To conclude, although a low value for this score in advanced ovarian cancer, indicates a poorer prognosis, we cannot make an accurate prognosis for more than 3 years from this score.
Despite recent improvements, the survival of patients with advanced ovarian cancer remains unsatisfactory. In our patients who underwent radical debulking surgery, including systematic pelvic (and, additionally, in about one-third, para-aortic lymphadenectomy), the size of residual tumour volume prior to cytotoxic chemotherapy was the most critical single prognostic determinant. The value of complete tumour removal was reflected in the survival curves. Patients with no residual disease following debulking surgery who underwent complete adjuvant chemotherapy showed a significantly better survival than did women with residual tumour burdens (P less than 0.05). The actuarial 1-year survival rate in patients with no RD, RD less than 2 cm, and RD greater than 2 cm was 96%, 88%, and 83%, the 3-year survival rate was 78%, 56%, and 37%, and the 5-year survival rate was 78%, 40%, and 21%, respectively. Our results agree with previous studies. The data underline the need for aggressive debulking, including systematic lymphadenectomy and subsequent chemotherapy. The smaller the initial cell population the smaller the probability of drug-induced resistance. The greater the diameter of a tumour the greater the number of cells which remain in the G0 phase--and which are thus not susceptible to chemotherapeutic compounds.
In order to forecast the survival of patients, we collected 417 cases of common epithelial carcinoma of the ovary as a population for this study, then selected 141 cases who had survived more than 3 years and 131 cases who had died within 3 years as a sample of statistical inference. The sample was computerized inputting 25 factors which were obtained mainly on the first surgery. We selected 8 factors with 46 items considering their weight to forecast the prognosis on convenience. The selection of factors was carried out by following three basic principles. First, we selected factors that retained high partial correlation coefficients. Second, we selected factors which did not overlap each other in their contents. Third, we selected factors which were not decided intentionally. Accordingly, the score for forecasting the 3-year survival of patients with ovarian carcinoma was framed. The correct discrimination rate of the score when it was judged at the 0 point was 86.8% in the sample group. However, in the sample group outside the population, it was 83.1%.
Flow cytometric analysis of nuclear DNA content was performed on paraffin-embedded tissue from 153 ovarian epithelial carcinomas. The DNA ploidy, DNA index, and S phase fraction were determined without knowing the final outcome of the patients. Fifty-one (38%) of the 134 classifiable histograms were considered to be diploid, 70 (52%) aneuploid, and 13 (10%) multiploid. The DNA index was a better prognostic factor for survival than DNA ploidy; 48% of the patients with a small DNA index (less than 1.3) survived for 5 years after the diagnosis, in contrast to 14% of the patients with a large DNA index (greater than 1.3) (P less than .0001). Carcinomas with a small S phase fraction (less than 11%) were associated with favorable survival (P = .0002). In multivariate analysis, the size of the residual tumor at surgery (P less than .001), the DNA index (P = .001), and the S phase fraction (P = .05) were the only significant independent prognostic factors. The results indicate that flow cytometric nuclear DNA content analysis provides important additional information for the estimation of survival in ovarian carcinoma.
One hundred ten patients with advanced ovarian carcinoma (Stages IIIA, IIIB, and IV) were evaluated for survival. They received as first treatment one of the following regimens: melphalan (L-PAM) (41 patients), cyclophosphamide plus methotrexate plus 5-fluorouracil (CMF) (16 patients), cyclophosphamide plus doxorubicin plus 5-fluorouracil (CAF) (17 patients), cyclophosphamide plus doxorubicin plus hexamethylmelamine plus cisplatin (CHAD) (13 patients, thiotepa plus methotrexate (TM) with fixed rotation with CAF (TM/CAF) (17 patients), and 6 patients received other chemotherapy as first treatment. There was no significant difference in survival time with the various treatment arms despite differences in response rates. Patients with Stage IIIA had significantly longer survival than those with Stages IIIB and IV (P less than 0.01). Patients with good performance status (PS 0) had significantly better survival than those with poor performance status (PS 3-4) (P less than 0.02). At this time the improved response rates on combination chemotherapy has not given improved survival rates, and disease stage and performance status remain of prime importance in survival prediction.