Optimal cytoreductive surgery is an independent prognostic indicator in stage IV epithelial ovarian cancer with hepatic metastases

OBJECTIVES: The aim of this study was to determine the value of optimal cytoreduction in stage IV epithelial ovarian cancer. METHODS: A retrospective review was performed of 37 women with stage IV epithelial ovarian cancer treated by radical surgery. RESULTS: Optimal surgery to less than 2 cm tumor deposits was performed in 16 of the 37 cases (43%) and tumor debulking to less than 1 cm tumor deposits in 6 cases (16.2%). Twenty-three cases (62%) were designated stage IV because of the presence of liver metastases alone. Although no patients died within 2 weeks of surgery, 7 of the 37 cases (22%) failed to survive more than 50 days after primary surgery. The overall median survival was 11 months with overall 2- and 5-year survivals of 23 and 9%, respectively. On multivariate analysis comparing age, histological type, tumor grade, place of surgery, secondary surgical procedure, performance of bowel surgery, presence of liver metastases, and optimal cytoreduction, only optimal surgery and residual tumor deposits of less than 2 cm, or less than 1 cm, remained highly significant (P = 0.0029 and 0.0086, respectively). Even when assessing only the 27 cases who were designated as having stage IV disease because of the presence of liver metastases, by multivariate analysis, only optimal surgery and residual tumor deposits of less than 2 cm, or less than 1 cm, remained significant (P = 0.023 and 0.036, respectively). Site of metastases designating stage IV status was not associated with a reduced likelihood of achieving optimal debulking (P = 0.18). CONCLUSION: Optimal cytoreduction in women with stage IV epithelial ovarian cancer with or without hepatic metastases is associated with a more favorable outcome survival.     

Ⅲ期上皮性卵巢癌的治疗与预后

目的 探讨影响Ⅲ期上皮性卵巢癌预后的临床病理因素以及手术和化疗对预后的作用。方法对1970年1月～1992年12月我院收拾的Ⅲ期上皮性卵巢癌67例进行回顾性分析。所有患者经初次手术后病理检查诊断并按FIGO标准分期,20例行二次手术,4例行三次手术。63例于术后接受化疗,化疗方案为FCT、FAC、CAP、马法兰等,分别为2-12个疗程不等。结果 Ⅲ期上皮性卵巢癌的2年及5年生存率分别是43.12％和24.17%。分组比较,5年生存率Ⅲa期100%、Ⅲb期14.05%和Ⅲc期23.64%( P<0.005);5年生存率透明细胞癌0.005％,粘液性囊腺癌1.76%,浆液性囊腺癌28.70%和内膜样癌36.27％(P<0.005);G1的5年生存率为87.50% 、G2为48.21%和G3为1.13%(P<0.005);术后残留癌小于2 cm的5年生存率69.50%,大于2 cm的为7.54％(P<0.005);化疗小于8个疗程的5年生存率12.49% ,大于8个疗程的47.55%(P=0.046)。结论Ⅲ期上皮性卵巢癌的预后与临床亚分期、病理类型、组织分级、术后残留癌大小及化疗疗程数相关,与年龄无关。专人、定期、全面的随访监测对提高生存率有重要意义。     

The preoperative albumin level is an independent prognostic factor for optimally debulked epithelial ovarian cancer

Purpose

A low albumin level has been reported to be a prognostic factor for various cancers. The aim of this study was to determine the association between preoperative serum albumin level and survival in patients with epithelial ovarian cancer (EOC).

Methods

Records of 337 patients with EOC that underwent optimal cytoreductive surgery were retrospectively reviewed. Threshold albumin level was planned as 32.5 g L^?1 due to the statistical analyses.

Results

Mean overall survival was 51.5 months. Area under the ROC curve was found statistically significant for the discriminative role of albumin for survival outcome (AUC = 0.857, 95% CI 0.813–0.90, P < 0.001). The best cut-off point for albumin was determined as 32.5 g L^?1. The sensitivity rate, specificity rate, positive and negative predictive values, and accuracy rate for this cut-off level were found 67.2, 91.2, 81.2, 83.1, and 82.5%, respectively. Preoperative hypoalbuminemia was noted in 101 (30.0%) of the patients, of which 6.2% had an albumin level <25 g L^?1. The albumin level was independently and significantly associated with overall survival (HR 2.6; 95% CI 2.1–3.1; P < 0.001). Subgroup analysis showed that patients with an albumin level <32.5 and ≥32.5 g L^?1 had mean estimated overall survival of 40.6 and 96.0 months, respectively. Age, stage, and presence of ascites were the other independent significant factors.

Conclusions

The preoperative albumin level is an independent prognostic factor for overall survival in optimally debulked EOC patients. Further investigations about preoperative albumin level in prognostic models will contribute to the literature.

     

Serum markers as prognostic factors in epithelial ovarian cancer: an overview

A comprehensive review of the literature and the authors' personal experience on serum determination of tumour markers in epithelial ovarian cancer can be summarised as follows: CA 125 is the most reliable marker for monitoring the course of epithelial ovarian cancer; CA 125 assay is not an adequate screening test for this malignancy but it can represent an useful adjunct to clinical examination and ultrasound in the differential diagnosis of ovarian masses in postmenopausal women; Serial measurements of CA 125 are useful in monitoring the response to chemotherapy and follow-up. In patients with preoperative positive CA 125 assay, the concomitant determination of other tumour markers does not add further information when compared to CA 125 alone. Conversely in patients with preoperative negative assay the measurement of one or more of other antigens could be of clinical relevance.     

Preoperative CA 125 levels: an independent prognostic factor for epithelial ovarian cancer

OBJECTIVE:To estimate the association of preoperative CA 125 levels with outcome in primary ovarian cancer patients.METHODS:One hundred forty-two patients with epithelial ovarian cancer, who had a serum CA 125 level drawn before surgery, were retrospectively evaluated. The relationship of preoperative CA 125 levels and various preoperative and postoperative variables was evaluated. CA 125 levels were determined using a solid-phase immunoassay.RESULTS:The median CA 125 value for all patients was 582 U/mL (range 7-52,930 U/mL). Preoperative CA 125 values did not correlate with increasing age (P =.40), but were found to be significantly associated with serous histology compared with other histology (median CA 125 of 870 versus 334 U/mL, P =.02), high-stage (III/IV) compared with low-stage (median CA 125 of 893 versus 174 U/mL, P <.001), high tumor grade (3) compared with grade 1 or 2 (median CA 125 of 928 versus 323 U/mL, P <.001), and the presence of ascites compared with absence of ascites (median CA 125 of 893 versus 220 U/mL, P <.001). Suboptimal cytoreduction (more than 1 cm residual) was associated with significantly higher CA 125 levels (1067 U/mL) compared with individuals with optimal cytoreduction (399 U/mL, P <.001). Preoperative CA 125 values less than 500 U/mL had a positive predictive value for optimal cytoreduction of 82%, but a poor negative predictive value of 48%. After adjusting for covariates, there was a significant association between CA 125 levels and disease-specific survival. As preoperative CA 125 levels increased, the risk of death increased except at the highest values of CA 125.CONCLUSION:Preoperative CA 125 is an independent risk factor for death due to disease in ovarian cancer, but not a reliable predictor of optimal cytoreduction.     

Activation of mTOR signaling pathway associated with adverse prognostic factors of epithelial ovarian cancer

Objective

Activation of the mammalian target of rapamycin (mTOR) pathway enhances cell survival and growth by regulating the efficiency of protein translation. This study was conducted to evaluate the association of activated mTOR signaling molecules with the clinicopathologic characteristics in epithelial ovarian cancer.

Methods

Immunohistochemical staining with antibodies against p-4EBP1, p-mTOR, and p-p70S6K were performed on specimens of 103 patients with ovarian cancer. Tumors were classified as chemoresistant in cases where time to recurrence after the end of chemotherapy was shorter than 6 months.

Results

Expressions of p-mTOR, p-4EBP1, and p-p70S6K were detected in 47.6%, 85.4%, and 64.1% of all patients, respectively. p-4EBP1 overexpression was associated with advanced stage (p = 0.04), histologic grade (p < 0.01), residual mass (p < 0.01), shorter disease-free survival rate (p = 0.01) and chemoresistance (p = 0.02). p-p70S6K was associated with residual mass with marginal significance (p = 0.06). p-4EBP1 expression was correlated with p-p70S6K expression (r = 0.42, p < 0.01), whereas p-mTOR was not associated with expression of its downstream effectors or prognostic factors.

Conclusions

Our findings suggest that p-4EBP1 expression was associated with poor prognostic factors of ovarian cancer and that p-4EBP1 overexpression may be a prognostic biomarker of ovarian cancer.     

Surgery and prognosis in stage III epithelial ovarian cancer

The results of this retrospective case study indicate that a composite of tumor grade, pattern of spread and substage at the time of opening affects the outcome most in the treatment of stage III epithelial tumors of the ovary. The poorest prognosis was associated with grade 3 histology, a pattern of spread requiring extensive and often difficult surgery for removal and a high substage. The best prognosis was usually associated with grade 1, with either very easily removed, isolated spread or low substage.
The extent of tumor defined the degree of primary cytoreduction possible. If the tumor was minimally extensive, primary cytoreduction results were excellent. The same conclusions were reached in the case of secondary cytoreduction at the time of second-look procedure. There was no statistically significant difference ( z = 1.481, P = 0.069) in 5-year survival between patients with microscopic only disease (59%) at second-look, and patients with gross disease not cytoreduced (36%).     

CA 125 measured before second-look laparotomy is an independent prognostic factor for survival in patients with epithelial ovarian cancer

The prognostic significance of serum CA 125 level measured in the week before second-look operation was evaluated in 208 patients with invasive epithelial ovarian cancer. Serum CA 125 level was greater than 35 U/ml in 44.7% of patients. All patients with pathological complete response (PCR) had a serum CA 125 level less than or equal to 35 U/ml except one who developed lung metastases 2 months later. The sensitivity of serum CA 125 for identifying residual tumor at second-look operations was 58%, the specificity was 98%, the predictive value of a positive test was 99%, and the predictive value of a negative test was 43%. By Cox regression analysis, tumor state of second look, serum CA 125 level, histologic type, FIGO stage, and tumor grade were identified as independent prognostic factors for survival. We conclude that measurement of serum CA 125 level after induction chemotherapy represents a noninvasive method to identify patients at high risk for subsequent death from ovarian cancer. As far as we know, this is the first report to identify serum CA 125 level as an independent prognostic factor at the time of second-look laparotomy.     

CA 125 as an independent prognostic factor for survival in patients with epithelial ovarian cancer

Serum CA 125 levels (upper normal value less than 35 U/ml) determined before surgery and 3 months after surgery were evaluated as independent prognostic factors for survival in patients with epithelial ovarian carcinomas. In 163 women preoperative serum levels of CA 125 (p = 0.13) gave no additional information with regard to the relationship of survival prognosis to histologic grade (p = 0.04) and to the diameter of residual tumor mass (p = 0.03). In 132 patients serum CA 125 levels were also determined 3 months after surgery and reflected the effectiveness of the first two cycles of postoperative cytotoxic treatment. At that time CA 125 was the strongest independent prognostic factor for survival (p = 0.0006 Cox model), as compared with histologic grade (p = 0.06), International Federation of Gynecology and Obstetrics stage (p = 0.15), and diameter of residual tumor mass (p = 0.66). Therefore, we concluded that serum CA 125 levels determined 3 months after surgery can identify a high-risk population among patients with epithelial ovarian carcinomas for whom a more aggressive or more intensive treatment might be beneficial.     

Chemotherapy in recurrent epithelial ovarian cancer (EOC): an analysis of prognostic factors

OBJECTIVE: Prognosis of patients with recurrent epithelial ovarian cancer (EOC) is generally poor. Cisplatin is the most effective drug. We used three cisplatin based chemotherapeutic (CT) regimens and retrospectively analyzed the data to determine the response rate, toxicity, survival and the impact of various prognostic factors on the outcome. PATIENTS AND METHODS: Between August, 1989 and September, 1997, 102 patients were diagnosed to have recurrent EOC. Sixty-five of 102 patients received CT every 3 weeks using cisplatin 75 mg/m2 i.v. day 1 plus cyclophosphamide 750 mg/m2 i.v. day 1 (CP, Group A, n = 29), cisplatin 75 mg/m2 i.v. day 1, plus adriamycin 40 mg/m2 i.v. day 1 and cyclophosphamide (CAP, Group B, n = 22) and paclitaxel 135 mg/m2 i.v. day 1 plus cisplatin 75 mg/m2 i.v. day 1 (TP, Group C, n = 14). Twelve patients received single agent CT and were not analyzed. Remaining 25 patients refused CT treatment and were followed for survival. RESULTS: The overall response rate (complete and partial) was 59.2% for patients receiving CP (Group A), 45% for CAP (Group B) and 76.9% for those receiving TP (Group C), p = ns. Response rate was significantly higher for patients with platinum sensitive disease compared to those with platinum resistant disease; 55.76 vs 39%, p < 0.007. CT was generally tolerated well; 2 patients died of CT toxicity, one each in Group A (CP) and C (TP), respectively. The median survival from the date of relapse for patients receiving chemotherapy was 15 months compared to 4 months for those who did not receive chemotherapy, p < 0.001. Chemotherapy responders had a significantly higher median survival than chemotherapy non-responders, 24 months vs 10 months, p < 0.01. The median overall survival was not significantly different in the 3 groups; Group A--15 months, Group B--12 months and 15 months in Group C, p = 0.738. On univariate analysis--time since last CT (< 6 months vs > 6 months, p < 0.037, response to previous CT, p < 0.0183, cisplatinum sensitivity vs resistance, p < 0.032, number of sites (< 2 vs > 2) of recurrence, p < 0.004 and response to salvage CT, p < 0.01 were associated with survival benefit. On multivariate analysis, 2 factors--platinum sensitivity and response to salvage CT attained significance. CONCLUSIONS: Our study confirms the benefit of platinum based chemotherapy in recurrent EOC. Patients with platinum sensitive disease, and those responding to salvage chemotherapy benefit most.     

晚期卵巢上皮性癌的治疗及其对预后的影响

目的:探讨晚期卵巢上皮性癌的治疗及其对预后的影响。方法:回顾分析晚期卵巢上皮性癌患者76例的临床资料,生命统计采用Kaplan-Meier法及Log-rank法检验,利用COX风险比例回归模型判断患者独立的预后影响因素并进行分析。结果:分期、残余灶、腹膜后淋巴结清除术及术后化疗的疗程数是影响预后的重要因素。行和未行腹膜后淋巴结清除术,总的5年存活率分别是52％和22％(P<0.01)。其中残余灶≤2cm者,行与未行腹膜后淋巴结清除术的5年存活率分别是65％、30％(P<0.01)。残余灶>2cm者,行与未行腹膜后淋巴结清除术的5年存活率分别是21％、9％,但差异没有显著性(P>0.05)。结论:理想的肿瘤细胞减灭术、腹膜后淋巴结清除术及术后至少6个疗程的化疗是改善患者预后的重要措施,但如残余灶>2cm,则不必行腹膜后淋巴结清除术。     

A new prognostic model for FIGO stage 1 epithelial ovarian cancer

BACKGROUND: No consensus exists which patients with surgical stage 1 epithelial ovarian should receive postoperative chemotherapy. The purpose of this study was to evaluate the prognostic impact of preoperative CA-125 and to establish a prognostic index to identify patients in different risk categories. METHODS: Data of 600 surgically staged patients with FIGO stage 1 EOC treated in eleven gynecological cancer centers in Australia, the USA and Europe were analyzed. Eligible patients include those with invasive EOC where a preoperative CA-125 was obtained and standard surgical staging performed. Overall survival (OS) was chosen as study endpoint. Preoperative CA-125 values were compared with other prognostic factors, and univariate and multivariate Cox models were calculated. RESULTS: Two hundred and one patients (33.5%) had preoperative CA-125 < or =30 U/ml and CA-125 levels < or =30 U/ml were associated with lower grade, sub-stage 1A and mucinous histologic cell type. Patients with elevated CA-125 levels were more likely to receive chemotherapy. OS probability was 95% and 85% for patients with pretreatment CA-125 < or =30 U/ml and >30 U/ml, respectively (p 0.003). Multivariate analysis confirmed preoperative serum CA-125 >30 U/ml (OR 2.7) and age at diagnosis >70 years (OR 2.6) as the only independent predictors for overall survival. CONCLUSION: Pretreatment of CA-125 < or =30 U/ml dominates over histologic cell type, sub-stage and grade to identify a subgroup of FIGO stage 1 patients with a genuinely good prognosis with extremely good survival and who could possibly be spared with adjuvant chemotherapy.     

Prognostic factors in patients with stage I epithelial ovarian cancer

We analyzed factors predictive of relapse risk in patients with stage I invasive epithelial ovarian cancer: 252 patients from the Princess Margaret Hospital provided a data base for hypothesis generation, and data on 267 patients from the Norwegian Radium Hospital were used for hypothesis testing. The outcomes in most analyses in the two series were very similar, validating the following conclusions. Differentiation (grade) was the most powerful predictor of relapse, followed by dense adherence (which resulted in outcomes equivalent to those in stage II) and, finally, large-volume ascites. When the effects of these three factors were accounted for, then none of the following were prognostic: bilaterality (stage Ib), cyst rupture (stage Ic), capsular penetration (stage Ic), tumor size, histologic subtype, patient age, year of diagnosis, and postoperative therapy. These results allow simplification of stage I substaging, as only differentiation, dense adherence, and large-volume ascites (? peritoneal cytology) need be considered. The 5-year relapse-free rate was 98% in patients with grade 1 tumors in whom both dense adherence and large-volume ascites were absent. These patients are adequately treated by operation alone. Although the relapse risk was high enough in the remaining patients to warrant postoperative treatment, a significant benefit could be shown only for a small subset of patients, namely those with densely adherent tumors treated with abdominopelvic radiotherapy. In grades 2 and 3, none of the therapies used in either series was superior to pelvic radiotherapy or operation alone.     

Reduced retinoblastoma gene protein to Ki-67 ratio is an adverse prognostic indicator for ovarian adenocarcinoma patients

OBJECTIVE: Alterations in the retinoblastoma gene (RB-1) are common in human neoplasia. However, the clinical significance of the deregulated expression of RB-1 in ovarian cancer remains undefined. We therefore conducted a retrospective investigation to clarify the relationships of RB-1 gene protein (pRb) to the percentage of cycling cells, clinicopathologic variables, other G1 interacting proteins and prognosis of nonbenign epithelial ovarian tumors. METHODS: Paraffin-embedded tissue from 127 nonbenign epithelial ovarian tumors, including 44 of low malignant potential (LMP) and 83 primary ovarian adenocarcinomas, was stained immunohistochemically for pRb, p21(Cip1), p27(Kip1), p53, and Ki-67 antigen (a cell proliferation associated marker). Expression of these markers was correlated with clinicopathologic features and with overall survival of patients with adenocarcinomas. RESULTS: pRb levels were significantly lower in LMP tumors than in carcinomas (P = 0.027). In the latter group, pRb expression decreased with increasing grade (I-II vs III) (P = 0.010), advancing stage (I-II vs III) (P < 0.001), and bulk residual disease (P = 0.014). pRb was not related to Ki-67 expression (P > 0.10) or to overall survival (P > 0.10) but a low pRb to Ki-67 ratio emerged as an important indicator of poor survival in univariate analysis in the entire cohort (P = 0.0076) and in the platinum-treated patients (P = 0.0162) as well as in multivariate analysis, along with histologic type and FIGO stage. CONCLUSIONS: Diminished pRb levels are related to several clinicopathologic indicators of aggressiveness in ovarian adenocarcinomas. More importantly, pRb expression coupled with the percentage of Ki-67 positive cells is a better prognostic marker than pRb, Ki-67, or other G1 interacting proteins and supplements the information gained from traditional prognosticators.     

Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer

OBJECTIVE: Currently available clinical and molecular factors provide still an insufficient prognostic and predictive assessment for patients with epithelial ovarian cancer (EOC). To identify a potential molecular target and prognostic/predictive factor for EOC, we investigated in a retrospective study the prognostic value of Ep-CAM overexpression in EOC. METHODS: We assessed by immunohistochemistry the expression of the Ep-CAM antigen on tissue microarrays containing paraffin-embedded tissue samples of 199 patients with documented EOC. Patients were operated for ovarian cancer in the period between June 1980 and January 2000. RESULTS: We observed a rate of Ep-CAM overexpression of 68.8%. Ep-CAM overexpression was significantly related to a decreased overall survival (P = 0.036). The prognostic power of Ep-CAM overexpression was particularly strong in patients with stage III and IV disease. In fact, in this subgroup, median overall survival was twofold higher in patients without as compared to patients with Ep-CAM overexpression (46 vs. 23 months, P < 0.01). Univariate analysis revealed a correlation with histologic grade. We observed a significantly higher rate of Ep-CAM overexpression (83.5%) in grade 3 tumors. Histologic subtypes associated with a higher rate of Ep-CAM overexpression were serous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, clear cell carcinoma, and endometrioid carcinoma. Cox regression analysis showed Ep-CAM overexpression to be an independent prognostic marker (P = 0.037, RR = 1.64). CONCLUSIONS: This retrospective analysis demonstrates for the first time an independent prognostic value of Ep-CAM overexpression in patients with EOC. Ovarian cancer patients with Ep-CAM overexpressing tumors are frequent and would qualify for treatment with Ep-CAM-specific immunotherapeutic approaches.     

Long-term results and prognostic factors in patients with epithelial ovarian cancer

OBJECTIVES: The aim of this study was to evaluate long-term results and to assess prognostic factors which have an impact on overall survival in patients with epithelial ovarian cancer. METHODS: A retrospective analysis of 287 patients treated between 1975 and 1995 was performed. All operations were performed by senior surgeons. Histologic sections were reviewed by the same pathologist. Successive adjuvant chemotherapy regimens are described. Survival was evaluated in 1997. Follow-up lasted 25-260 months (median 90). Statistical methods included Kaplan-Meier survival curves, log-rank test, and multivariate analysis. RESULTS: The 5-year survival rates were 76, 42, 21, and 6% for patients with stage I, II, III, and IV disease, respectively. Age, FIGO stage, cytology of ascites, histologic type and grade, extent of surgery, and number of residual tumors were significant prognostic indicators in univariate analysis. Multivariate analysis showed that the risk of mortality according to FIGO stage was 2.8, 95% CI [1.2-6.3], P = 0.01 for FIGO II, 5.6, 95% CI [2.9-10.8], P < 0.001 for FIGO III, and 10.5, 95% CI [4.9-22. 1], P < 0.001 for FIGO IV in comparison with FIGO I. Patients with a serous epithelial carcinoma had a 1.7-fold higher risk of mortality than patients with other histologic types: RR = 1.7, 95% CI [1.1-2. 8], P < 0.001. Patients whose tumors distribution permitted optimal surgery had a 2.3-fold lower risk of mortality than patients treated with sub- or nonoptimal surgery: RR = 0.43, 95% CI [0.29-0.64], P < 0.001. The risk of mortality for patients treated with alkylating agents, platinum-based combination chemotherapy without taxanes, or carboplatin plus paclitaxel regimens compared with patients who did not receive treatment was reduced by 47%, 95% CI [8-69%], P = 0.025, 55%, 95% CI [22-74%], P = 0.005, and 70%, 95% CI [35-86%], P = 0.002, respectively. CONCLUSION: Our study confirms the benefit of cytoreductive surgery and the efficacy of platinum plus paclitaxel first-line chemotherapy which has recently been recognized as the standard treatment for advanced epithelial ovarian cancer.