Advanced-stage Ovarian Carcinoma Research Articles

Prognostic significance of cell cycle proteins and genomic instability in borderline, early and advanced stage ovarian carcinomas.

Disturbed cell cycle-regulating checkpoints and impairment of genomic stability are key events during the genesis and progression of malignant tumors. We analyzed 80 epithelial ovarian tumors of benign (n = 10) and borderline type (n = 18) in addition to carcinomas of early (n = 26) and advanced (n = 26) stages for the expression of Ki67, cyclin A and cyclin E, p21WAF-1, p27KIP-1 and p53 and correlated the results with the clinical course. Genomic instability was assessed by DNA ploidy measurements and, in 35 cases, by comparative genomic hybridization. Overexpression of cyclin A and cyclin E was observed in the majority of invasive carcinomas, only rarely in borderline tumors and in none of the benign tumors. Similarly, high expression of p53 together with undetectable p21 or loss of chromosome arm 17p were frequent events only in adenocarcinomas. Both borderline tumors and adenocarcinomas revealed a high number of chromosomal gains and losses. However, regional chromosomal amplifications were found to occur 13 times more frequently in the adenocarcinomas than in the borderline tumors. The expression pattern of low p27 together with high Ki67 was found to be an independent predictor of poor outcome in invasive carcinomas. The results provide a link between disturbed cell cycle regulatory proteins, chromosomal aberrations and survival in ovarian carcinomas.

The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma.

The prognostic significance and nature of p53 dysfunction in ovarian carcinoma is unclear. The relation between p53 overexpression, p53 mutations, and their effects on overall survival in primary ovarian carcinoma is explored. Tumor specimens from 171 consecutive epithelial ovarian carcinomas were examined for overexpression of p53 protein with DO7 antibody. P53 mutations were determined by direct sequencing. The influences of conventional histopathologic prognostic factors and various p53 molecular alterations on overall survival were assessed. Overall, 48.5% and 57.3% of the samples showed p53 overexpression and p53 mutation, respectively. Although neither p53 overexpression nor the mere presence of a p53 mutation impacted overall survival, the combination did prognosticate survival both in univariate and multivariate models. The authors' results suggest 4 mechanisms that may affect p53 dysfunction in nearly 100% of advanced stage ovarian carcinomas. These include null mutation, nonresponsive p53 (wild-type [wt] p53 sequence, DO7 negative), sequestration (wt p53 sequence, DO7 positive), and missense mutation. Median survival for these groups that constitute sequentially 21.3%, 20.5%, 12.3%, and 45.9% of the 122 Stage III or IV (International Federation of Gynecology and Obstetrics) cancers was 1.49, 1.31, 3.09, and 3.6 years, respectively. The nonresponsive p53 and null sequence tumors grouped together as functionally null convey the worst prognosis relative to missense mutations in a univariate model (P = 0.006). Functionally null p53 (P = 0.002), stage (P = 0.008), and optimal cytoreduction (P = 0.008) were independent prognostic factors by multivariate analysis. Sequestration of wt p53 is unique to advanced stage ovarian carcinoma. Functionally null p53 represents an independent molecular predictor of compromised survival.

The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma

BACKGROUND The prognostic significance and nature of p53 dysfunction in ovarian carcinoma is unclear. The relation between p53 overexpression, p53 mutations, and their effects on overall survival in primary ovarian carcinoma is explored. METHODS Tumor specimens from 171 consecutive epithelial ovarian carcinomas were examined for overexpression of p53 protein with DO7 antibody. P53 mutations were determined by direct sequencing. The influences of conventional histopathologic prognostic factors and various p53 molecular alterations on overall survival were assessed. RESULTS Overall, 48.5% and 57.3% of the samples showed p53 overexpression and p53 mutation, respectively. Although neither p53 overexpression nor the mere presence of a p53 mutation impacted overall survival, the combination did prognosticate survival both in univariate and multivariate models. The authors' results suggest 4 mechanisms that may affect p53 dysfunction in nearly 100% of advanced stage ovarian carcinomas. These include null mutation, nonresponsive p53 (wild-type [wt] p53 sequence, DO7 negative), sequestration (wt p53 sequence, DO7 positive), and missense mutation. Median survival for these groups that constitute sequentially 21.3%, 20.5%, 12.3%, and 45.9% of the 122 Stage III or IV (International Federation of Gynecology and Obstetrics) cancers was 1.49, 1.31, 3.09, and 3.6 years, respectively. The nonresponsive p53 and null sequence tumors grouped together as functionally null convey the worst prognosis relative to missense mutations in a univariate model (P = 0.006). Functionally null p53 (P = 0.002), stage (P = 0.008), and optimal cytoreduction (P = 0.008) were independent prognostic factors by multivariate analysis. CONCLUSIONS Sequestration of wt p53 is unique to advanced stage ovarian carcinoma. Functionally null p53 represents an independent molecular predictor of compromised survival. Cancer 2000;89:2006–17. © 2000 American Cancer Society.

Primary Appendiceal Malignancy Mimicking Advanced Stage Ovarian Carcinoma: A Case Series

Background. Primary appendiceal malignancy metastatic to the ovaries is a rare condition that may mimic late stage ovarian cancer. This condition is rarely diagnosed preoperatively.Cases. Three patients referred to our institution from 1994 to 1999 for presumed late stage ovarian cancer were found to have primary appendiceal adenocarcinoma, adenocarcinoid, and mucinous cystadenocarcinoma metastatic to the ovaries at laparotomy. We describe the clinical course of these patients and review the relevant literature.Conclusion. It is important for the gynecologic oncologist to be aware of the clinicopathological features and surgical management of these malignancies, as the incidence, prognosis, and recommended treatment vary with histological subtype.

Expression of Carbohydrate Antigens in Advanced-Stage Ovarian Carcinomas and Their Metastases—A Clinicopathologic Study

Objective. Up-regulated expression or loss of expression of various carbohydrate antigens on the surface of cancer cells has been associated with a metastatic phenotype and poor survival in epithelial malignancies of different origins. The object of this study was to investigate the expression of carbohydrate antigens in two groups of patients diagnosed with advanced-stage ovarian carcinoma—one with an extremely favorable outcome and the other with a uniformly poor survival.Methods. Sections from 76 paraffin-embedded blocks (primary ovarian carcinomas and metastatic lesions) from 45 patients diagnosed with advanced-stage ovarian carcinomas (FIGO stages III–IV) were immunohistochemically stained using five monoclonal antibodies for Lewisy (Ley)(two antibodies), Sialyl Lewisx (Slex), Tn, and Sialyl Tn (STn) antigens. Patients were divided in two groups based on outcome. Long-term survivors (21 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Staining results for primary tumors and metastases were analyzed separately.Results. Mean follow-up period was 70 months. The mean values for DFS and OS were 109 and 125 months for long-term survivors and 3 and 25 months for short-term survivors. Staining for all four antigens was seen in the majority of cases (range = 72–96%) and tended to be comparable in primary tumors and their metastases. However, absence of immunoreactivity for STn was seen in 9/38 (24%) metastatic lesions and only 1/38 (3%) primary tumors. This finding did not reach statistical significance (P > 0.05). A combined pattern of membranous and cytoplasmic staining was predominant in the majority of cases. Enhanced staining for Ley and STn was detected in the invasive front of some tumors, while Slex and Tn immunoreactivity did not relate to cell location. Primary tumors and metastatic lesions of long-term survivors displayed immunoreactivity patterns that were comparable to those of short-term survivors. In the evaluation of survival curves, more diffuse staining for Slex showed marginal correlation with poor survival (P = 0.05), while a trend toward poorer survival was seen in tumors that were more extensively stained for Ley and Tn (P > 0.05).Conclusions. Ley, Slex, STn, and Tn antigens are widely expressed in primary ovarian carcinomas and their metastases. Altered expression of Sialyl Tn is observed with tumor progression in a fraction of ovarian carcinomas. Expression of membrane carbohydrate residues is prevalent in tumors of both long-term and short-term survivors and does not appear to be a strong predictor of disease outcome. However, larger studies are needed to further elucidate the role of these molecules in ovarian carcinogenesis.

Expression of angiogenesis-related genes in ovarian carcinoma--a clinicopathologic study.

Angiogenic factors play a role in tumor growth and spread. The object of this study was to analyze the correlation between mRNA expression of angiogenesis-related genes and disease outcome in advanced-stage ovarian carcinomas. Sections from 66 primary ovarian carcinomas and metastatic lesions from 41 patients diagnosed with advanced stage ovarian carcinoma (FIGO stages III-IV) 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). Patients were divided in two groups based on disease outcome. Long-term survivors (17 patients) and short-term survivors (24 patients) were defined using a double cut-off of 36 months for disease-free survival (DFS) and 60 months for overall survival (OS). Mean follow-up period was 70 months. The mean values for DFS and OS were 116 and 133 months for long-term survivors, as compared to 3 and 21 months for short-term survivors, respectively. Expression of bFGF mRNA, most often intense, was detected in tumor and stromal cells in the majority of cases. Weak expression of IL-8 mRNA was detected in both cell compartments, while VEGF mRNA expression was limited to few cases. Primary tumors displayed higher bFGF and IL-8 mRNA expression. However, these differences did not reach statistical significance (P > 0.05). bFGF, IL-8 and VEGF mRNA expression in both tumor and stromal cells was comparable in tumors of long-term and short-term survivors, and showed no correlation with disease outcome in survival analysis (P > 0.05). bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. mRNA expression of VEGF, bFGF, and IL-8 does not appear to be a predictor of disease outcome in advanced-stage ovarian carcinoma.

Primary appendiceal malignancy mimicking advanced stage ovarian carcinoma: a case series

International Journal of Gynecology & ObstetricsVolume 70, Issue S4 p. D72-D72 Ovarian cancer: Chemotherapy and advanced disease Primary appendiceal malignancy mimicking advanced stage ovarian carcinoma: a case series J. McBroom, J. McBroomSearch for more papers by this authorM. Parker, M. ParkerSearch for more papers by this authorT. Krivak, T. KrivakSearch for more papers by this authorG.S. Rose, G.S. RoseSearch for more papers by this author J. McBroom, J. McBroomSearch for more papers by this authorM. Parker, M. ParkerSearch for more papers by this authorT. Krivak, T. KrivakSearch for more papers by this authorG.S. Rose, G.S. RoseSearch for more papers by this author First published: 11 December 2003 https://doi.org/10.1016/S0020-7292(00)81915-3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume70, IssueS42000Pages D72-D72 RelatedInformation

Platinum-Based Chemotherapy for Advanced-Stage Serous Ovarian Carcinoma of Low Malignant Potential

Purpose: To evaluate the effect of platinum-based chemotherapy on tumor response in patients with advanced-stage serous ovarian carcinoma of low malignant potential. Patients and methods: We conducted a retrospective review of hospital records, pathology slides, and office charts of patients identified as having Stage III or IV serous ovarian cancer of low malignant potential. Results: Between November 1979 and April 1993, 21 patients with advanced-stage serous ovarian carcinoma of low malignant potential received platinum-based chemotherapy following initial cytoreductive surgery. The amount of residual disease was recorded in 20 patients; 8 (40%) had macroscopic residual tumor <2 cm in largest diameter, and 12 (60%) had only microscopic disease. Sixteen patients underwent a second-look laparotomy following chemotherapy; 10 (62.5%) had no evidence of disease, 1 (6%) had a partial response, 2 (12.5%) had stable disease, and 3 (19%) had progressive disease. During a mean follow-up of 64 months, only 1 patient had died of disease. She had progressive disease noted at second-look laparotomy. Five of 6 patients who did not have a complete response to initial chemotherapy underwent further therapy with oral etoposide (1), intraperitoneal platinum (2), intraperitoneal mitoxantrone (1), or both (1). The sixth patient received no further therapy. Three of the patients subsequently receiving salvage intraperitoneal therapy underwent a third-look laparotomy. Two had partial responses noted, while the third patient had stable disease. Conclusions: Platinum-based chemotherapy is effective in achieving surgically documented responses in patients with advanced-stage serous ovarian tumors of low malignant potential. The benefit of this therapy in improving survival is unproven.

504 Phase I study with paclitaxel in combination with ifosfamide in pretreated patients with advanced ovarian carcinoma

Introduction Patients (pts) with advanced ovarian carcinoma and an inadequate response to first line platinum based combination chemotherapy have a very poor prognosis. Salvage regimens were clearly needed. In order to determine the maximal tolerable dose (MTD) of the combination paclitaxel (P) and ifosfamide (IFO), we performed this ongoing phase I study. Treatment Pts were treated with P 3 h i. v. infusion after standard premedication on day (d) I, IFO was given as I h i. v. infusion with the standard use of Mesna i.v. on d.2-5. The next cycle was given on d.22. Number of cycles depending on response and toxicity. We chose the following dose levels (dl): [mg/m2] d11: P 135/IFO 1500; d12: P135/IFO 2000; d13: P 175/IFO 2000; d14: PI75/IFO 1500. MTD was defined: neutropenia 4° longer than 5 days or febrile neutropenia, thrombopenia ≥3°, other organ toxicity >2° according to WHO criteria. Patient Characteristics 14 pts entered this ongoing trial. 13 pts entered d11-3 and so far 1 pt d14; age 52 yrs (37–66), WHO PS 1 (0-2). Pretreatment All pts had had a platinum based combination chemotherapy for advanced stage ovarian carcinoma prior to study entry. 10/14 pts had cisplatinum refractory disease with disease progression while receiving prestudy treatment. Number of prior treatment regimens 1.5 (1–3). Toxicity and Results With regard to P treatment, after standard premedication neither mild nor severe HSR's occurred. The following toxicities could be observed in 10 pts and 51 treatment cycles at dl's 1 + 2 [grade WHO (number of cycles)]: neutropenia 2° (6), 3° (21), 4° (24); anemia 2° (24), 3° (6); thrombocytopenia 1° (7), 2° (6); nausea/vomiting 1° (33),2° (18); myalgia 1° (33); peripheral neuropathy 1° (36), 2° (12); mucositis 1° (39), 2° (8); diarrhea 1° (13), 2° (3). After we performed dose escalation of IFO up to 2000 mg/m2 during dl 2 and 3 in 2 out of 8 pts treatment interruptions have to be performed because of CNS toxicity 3° WHO and in one additional patient suffering from nephrotoxicity grade 3 WHO. The MTD of IFO used in the combination with P and given over 4 days is 1500 mg/m2. In order to enhance the efficacy of P we escalated the dose up to 175 mg/m2 and intend to treat the following pts according to d14. At all dl's responses could be observed. d11 (5 pts): PR 2, SD 3; d12 (5 pts): CR1, SD3, PO 1; d13 (3 pts): CRI, PR2; d14 (I pt): not evaluable for response and toxicity so far. Conclusions The combination of P and IFO is leasable and active in the treatment of pretreated advanced ovarain carcinoma pts. 014 will be further evaluated during this ongoing study.

Value of P-glycoprotein, glutathione S-transferase pi, c-erbB-2, and p53 as prognostic factors in ovarian carcinomas.

To determine the prognostic value of immunostaining of P-glycoprotein (P-gp), glutathione S-transferase (GST) pi, c-erbB-2, and p53 in patients with advanced-stage ovarian carcinoma. Immunostaining of P-gp, GST pi, c-erbB-2, and p53 was performed on 89 primary tumors and 38 residual tumors after chemotherapy (P-gp and GST pi) in patients with advanced ovarian carcinoma treated with platinum- and doxorubicin-containing chemotherapy. The results of immunostaining were related to clinicopathologic prognostic factors, response to chemotherapy, and progression-free survival (PFS) and overall survival. P-gp and GST pi immunoreactivity were present in 13 (15%) and 79 cases (89%), respectively, and were not associated with any other prognostic factor or PFS or overall survival. C-erbB-2 immunoreactivity was present in 18 cases (20%) and was associated with undifferentiated histiotype (P < .05), but not with PFS or overall survival. p53 immunoreactivity was present in the nuclei of 31 cases (35%) and cytoplasm of nine cases (10%). Nuclear p53 staining was associated with grade III tumors, presence of more than 1-L ascites, and residual tumor after first laparotomy more than 2 cm. Nuclear p53 staining was associated with shorter PFS (relative risk [RR], 3.3; 95% confidence interval [CI], 2.0 to 5.6) and overall survival (RR, 2.6; 95% CI, 1.7 to 3.8). After adjustment for presence of more than 1-L ascites or age more than 50 years, nuclear p53 staining did not retain independent prognostic significance in stage III/IV tumors. The frequency of P-gp staining in residual tumors after chemotherapy (18 of 38 cases) was higher in comparison to untreated tumors (13 of 89 cases) (P < .001). No combination of prognostic parameters was able to predict response to chemotherapy adequately. Nuclear immunoreactivity of p53 in ovarian carcinomas is associated with shorter PFS and overall survival and determinants of more aggressive tumor growth. The higher frequency of P-gp immunoreactivity in residual tumors after chemotherapy points to induction of P-gp in ovarian carcinomas by doxorubicin-containing combination chemotherapy. The determination of P-gp, GST pi, c-erbB-2, and p53 does not permit more adequate prediction of response to chemotherapy.

Advanced-stage ovarian carcinoma presenting during infertility evaluation

Fecundity has been extended to the menopause by advances in assisted reproductive techniques. The incidence of ovarian cancer increases with age, and an increased risk of ovarian cancer has been associated with incessant ovulation and infertility. The increased risk of ovarian cancer in older infertility patients must be kept in mind when evaluating these patients so that this diagnosis is not overlooked or delayed.

Cisplatin, carboplatin, and cyclophosphamide combination chemotherapy in advanced-stage ovarian carcinoma: an Eastern Cooperative Oncology Group pilot study.

Cyclophosphamide (CTX) 600 mg/m2, carboplatin 280 mg/m2, and cisplatin 50 mg/m2 were administered on day 1 every 4 weeks to 41 previously untreated ovarian cancer patients with residual disease greater than 2.0 cm after primary laparotomy. Of 22 patients with measurable disease treated with up to eight cycles of therapy, the overall clinical response rate was 73% (exact 95% confidence interval [CI], 50% to 89%), with 50% complete response (CR). Six of 11 clinical CR (cCR) patients underwent surgical restaging; three pathologic CRs (pCRs) and three pathologic partial responses (pPRs) with residual disease less than 2.0 cm were documented. Fourteen patients had nonmeasurable but assessable disease; the clinical response rate was 57% (Cl, 29% to 82%) with two (14%) CRs. Second-look surgery was performed in one of the two cCR patients; a pPR was documented. Five patients with nonassessable disease were stable during chemotherapy; two underwent surgery and had pCRs. The median time to treatment failure (TTF) was 14.8 months, and median survival for the 41 patients is 26.7 months. Overall, 37% of the patients had progression-free intervals of at least 2 years, and 27% have survival times in excess of 3 years. Hematologic toxicity was substantial but manageable, with 58% and 66% experiencing a granulocyte nadir less than 500/microL and a platelet nadir less than 50,000/microL, respectively. One treatment-associated fatality occurred as a result of leukopenic sepsis and renal failure in the setting of progressive disease and ureteral obstruction. Mild to moderate nausea and vomiting occurred in most patients, but none experienced severe ototoxicity or peripheral neuropathy. Over all courses, 73% of the projected dose intensity of CTX and carboplatin and 86% of cisplatin were delivered. Since granulocytopenia and thrombocytopenia were dose-limiting, the addition of colony-stimulating factors that support both myeloid and megakaryocyte precursors may permit further dose intensification.

A Role for Tumor Markers in Therapeutic Decisions after Chemotherapy Induction of Objective Remission in Stage III Epithelial Ovarian Neoplasms

The management of advanced stage ovarian carcinomas is presently based on initial surgical debulking, multiple drug chemotherapy including cisplatinum, second-look laparotomy. Such an aggressive approach has improved objective response rates and expected survival time, but no dramatic change has been demonstrated as for definitive cure percentages. Many Authors have attempted to turn an optimal objective response to chemotherapy (no residual or minimal residual disease at second-look) into a definitive cure with irradiation. Some reports show satisfactory results, but a high incidence of bowel obstructive complications has been demonstrated, probably due to multiple surgical manipulations before radiotherapy. A reliable diagnostic tool, that could help to avoid the second-look laparotomy (whose inherent role in improving survival is not assessed) should be therefore useful. The possible role of serum tumor markers determinations, for this purpose, is here discussed on the ground of a series of 20 patients affected by stage III ovarian carcinoma. Following this experience, a valuable role seems attributable to CA 125 in monitoring tumor response. Patients achieving values under 35 U/ml before second-look laparotomy showed tumor residuals in the range O-microscopic- less than 1 cm., that is, neoplastic localizations reliable for consolidation radiation therapy.

Brain metastases in epithelial ovarian carcinoma; two case reports

The cases of two patients with epithelial ovarian carcinoma who had been treated with surgery and cisplatin-containing combination chemotherapy and had developed brain metastases are described. Modern protocols for management of advanced-stage epithelial ovarian carcinoma have resulted in prolonging the lives of the patients sufficiently for central nervous system metastases to become apparent and possible resistence of the ‘blood brain’ barrier to the currently used chemotherapeutic agents may have left the CNS ‘unprotected’ from metastases.

Optimal debulking following chemotherapy of advanced-stage epithelial ovarian carcinoma.

We reviewed the records of 110 consecutive patients with advanced-stage epithelial ovarian carcinoma treated at the Soroka Medical Center, Beer-Sheva, Israel, from 1961-1987. Twenty patients (18.1%) had optimal debulking at initial laparotomy, 30 patients (27.2%) had nonoptimal debulking at initial laparotomy, 20 patients (18.1%) had an "inoperable" disease at initial laparotomy, and 40 patients (36.3%) had such poorly written records that no information about the degree of resectability at initial laparotomy could be obtained. Four patients, in whom the residual tumor left at initial laparotomy had responded to chemotherapy, had a second laparotomy. In all four patients optimal debulking surgery at second laparotomy was easy to perform and was successful. The value of a second laparotomy after a few cycles of chemotherapy in order to optimally debulk the residual tumor left at initial laparotomy is discussed. It is concluded that a second attempt of debulking surgery after chemotherapy has a respectable place in the management of patients with advanced-state epithelial ovarian carcinoma, but further research is needed.

The treatment of advanced stage ovarian carcinoma with a combination of chemotherapy, radiotherapy, and radiosensitizer: Report of a pilot study from the National Cancer Institute

Twenty-eight patients with Stage III or IV ovarian carcinoma were treated with combined chemotherapy-radiotherapy employing a unique protocol. Four cycles of cyclophosphamide and hexamethylmeamine alternated with four cycles of concurrent cisplatin, whole abdominal radiotherapy, and intraperitoneal misonidazole. The entire treatment program lasted six months. Clinical complete responses were seen in 50% of the patients with an overall response rate of 61% Pathologic complete response (PCR) confirmed at second look surgery occurred in 18% of the group (5 patients). Median survival of the entire group was 15.2 months with all PCB's alive NED. This outcome was no different than our previous experience with combination chemotherapy alone. Toxicities seen included leukopenia, thrombocytopenia, nausea, vomiting, and weight loss. However, these side effects were manageable. Two non-tumor deaths occurred. This study demonstrates the feasibility of combining drug and radiation therapy concurrently in the treatment of ovarian cancer, further research is needed to explore different sequencing and dose levels that could improve the outcome.