Pamela J. Paley

Robotic surgery in gynecologic oncology: program initiation and outcomes after the first year with comparison with laparotomy for endometrial cancer staging

OBJECTIVE The objective of the study was to evaluate outcomes during the first year of a robotic surgery program in gynecologic oncology. STUDY DESIGN We studied the initiation of a robotic surgery program with prospective data collection, including intraoperative times, estimated blood loss (EBL), length of stay (LOS), lymph node yields, and complications. Patients were compared with historical and contemporary open staging surgery for endometrial cancer. RESULTS One hundred eighteen patients underwent robotic surgery (mean age 52.5 years, body mass index of 26.3 kg/m(2), hospital stay of 32.4 hours), with 8 major and 13 minor complications. Compared with open endometrial staging (n = 131), the robotic procedure (n = 25) was longer (283 vs 139 minutes, P < .0001), had less blood loss (66.6 vs 197.6 mL, P < .0001), and had shorter length of stay (40.3 vs 127 hours, P < .0001) with comparable node yields (17.5 vs 13.1, P = .1109). CONCLUSION Robotic surgery is feasible in gynecologic oncology and facilitated a dramatic expansion in our minimally invasive surgical practice. Despite longer operative times, EBL and LOS are reduced and lymph node yields are comparable.

Use of a Symptom Index, CA125, and HE4 to predict ovarian cancer

BACKGROUND Prior studies suggest that combining the Symptom Index (SI) with a serum HE4 test or a CA125 test may improve prediction of ovarian cancer. However, these three tests have not been evaluated in combination. METHODS A prospective case-control study design including 74 women with ovarian cancer and 137 healthy women was used with logistic regression analysis to evaluate the independent contributions of HE4 and CA125, and the SI to predict ovarian cancer status in a multivariate model. The diagnostic performance of various decision rules for combinations of these tests was assessed to evaluate potential use in predicting ovarian cancer. RESULTS The SI, HE4, and CA125 all made significant independent contributions to ovarian cancer prediction. A decision rule based on any one of the three tests being positive had a sensitivity of 95% with specificity of 80%. A rule based on any two of the three tests being positive had a sensitivity of 84% with a specificity of 98.5%. The SI alone had sensitivity of 64% with specificity of 88%. If the SI index is used to select women for CA125 and HE4 testing, specificity is 98.5% and sensitivity is 58% using the 2-of-3-positive decision rule. CONCLUSIONS A 2-of-3-positive decision rule yields acceptable specificity, and higher sensitivity when all 3 tests are performed than when the SI is used to select women for screening by CA125 and HE4. If positive predictive value is a high priority, testing by CA125 and HE4 prior to imaging may be warranted for women with ovarian cancer symptoms.

Surgical outcomes in gynecologic oncology in the era of robotics: analysis of first 1000 cases.

OBJECTIVE We sought to examine outcomes in an expanding robotic surgery (RS) program. STUDY DESIGN In all, 1000 women underwent RS from May 2006 through December 2009. We analyzed patient characteristics and outcomes. A total of 377 women undergoing RS for endometrial cancer staging (ECS) were compared with the historical data of 131 undergoing open ECS. RESULTS For the entire RS cohort of 1000, the conversion rate was 2.9%. Body mass index increased over 3 time intervals: T1 = 26.2, T2 = 29.5, T3 = 30.1 (T1:T2, P = .01; T1:T3, P = .0001; T2:T3, P = .037). Increasing body mass index was not associated with increased major complications: T1 = 8.7%, T2 = 4.3%, T3 = 5.7%. In the ECS cohort, as compared with open ECS, women undergoing RS had lower blood loss (46.9 vs 197.6 mL, P < .0001), shorter hospitalization (1.4 vs 5.3 days, P < .0001), fewer major complications (6.4% vs 20.6%, P < .0001), with higher lymph node counts (15.5 vs 13.1, P = .007). CONCLUSION RS is associated with favorable morbidity and conversion rates in an unselected cohort. Compared to laparotomy, robotic ECS results in improved outcomes.

Influence of ovarian cancer risk status on the diagnostic performance of the serum biomarkers mesothelin, HE4, and CA125.

Objective: To evaluate the effect of ovarian cancer risk on the performance of the serum biomarkers mesothelin, human epididymis protein 4 (HE4), and CA125. Methods: We measured mesothelin, HE4, and CA125 levels from women with invasive ovarian cancer (n = 143), benign gynecologic conditions (n = 124), and controls (n = 344). Demographic, epidemiologic, reproductive, medical, and family history data were collected using a standardized questionnaire. Pedigree and BRCA 1/2 test results were used to stratify women into average and high-risk groups. The diagnostic accuracy of each biomarker was characterized using receiver operating characteristic curve methods. Results: Baseline characteristics did not vary by risk or case status. The distribution of stage and histology was similar in average and high-risk women. All three markers discriminated ovarian cancer cases from risk-matched healthy and benign controls. Marker performance did not vary by risk status. The sensitivity at 95% specificity for discriminating cases from risk-matched healthy control women in the average and high-risk groups, respectively, was 53.9% and 39.0% for mesothelin, 80.4% and 87.8% for HE4, and 79.4% and 82.9% for CA125. The performance of the markers was not as robust when cases were compared with benign controls. Area under the curve values for cases versus healthy and benign controls did not vary by risk status. Conclusions: The ability of serum mesothelin, HE4, and CA 125 levels to discriminate ovarian cancer cases from healthy and benign controls is not influenced by risk status. Our findings support the pursuit of additional studies evaluating the early detection potential of these markers in high-risk populations. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1365–72)

Effects of personal characteristics on serum CA125, mesothelin, and HE4 levels in healthy postmenopausal women at high-risk for ovarian cancer.

Objective: To evaluate if serum levels of candidate ovarian cancer biomarkers vary with individual characteristics of healthy women who are likely candidates for an ovarian cancer screening program. Methods: We analyzed serum CA125, mesothelin, and HE4 levels in a sample of 155 healthy postmenopausal women at increased risk for developing ovarian cancer based on personal and family cancer history. Information on reproductive, family and medical histories, lifestyle factors, and anthropometry was collected by self-report. Twenty-two factors were examined using univariate and multiple linear regression models for the three biomarker levels. Results: In the multivariate models, CA125 levels were significantly higher in women who had used talcum powder (P = 0.02) and were lower in women who were parous (P = 0.05). Mesothelin levels were significantly higher in older women (P = 0.01) and lower in heavier women (P = 0.03). HE4 levels were higher in older women (P = 0.001) and in women who began menstruating at an older age (P = 0.03). Conclusions: CA125, mesothelin, and HE4 levels in healthy, postmenopausal women at increased risk for ovarian cancer are significantly associated with a few ovarian cancer risk factors. Since the effects of these personal characteristics on these serum markers are not large, their incorporation in screening algorithms may be unnecessary. This is true especially if a longitudinal algorithm is used because the marker level at the previous screen reflects personal characteristics such as age, body mass index, and age of menarche. Understanding the influence of personal factors on levels of novel early detection markers in healthy, unaffected women may have clinical utility in interpreting biomarker levels. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2480–7)

Combining a symptoms index with CA 125 to improve detection of ovarian cancer

The current study sought to examine whether an index based on the specific pattern of symptoms commonly reported by women with ovarian cancer could be used in combination with CA 125 to improve the sensitivity or specificity of experimental methods of screening for ovarian cancer.

Serologic analysis of ovarian tumor antigens reveals a bias toward antigens encoded on 17q

We utilized SEREX immunoscreening to identify a set of novel tumor antigens that are associated with human serous ovarian cancer and may prove useful for the early detection and treatment of this disease. Extensive screening with a panel of sera from 25 late‐stage ovarian cancer patients against 3 independent cDNA libraries identified a set of 9 antigens that were immunogenic in more than 1 patient and not in a panel of 20–45 normal female serum donors. These antigens include p53, NY‐ESO‐1, UBQLN1, HOXB6, TOP2A, putative helicase‐RUVBL (RUVBL), HMBA‐inducible (HEXIM1), DDX5 and HDCMA. Ten of 25 ovarian cancer patients (40%) expressed serum IgG to at least 1 of these antigens, while 14% (4/25) had antibodies to 2 or more antigens. Unexpectedly, 4 antigens identified in this screen, DDX5, HEXIM1, TOP2A and HOXB6, are encoded within a region of 17q that also includes the genes for HER2/neu, Homeobox‐B7 and BRCA1. Real‐time RT‐PCR analysis showed that mRNA for HER2/neu and 3 SEREX‐defined antigens, TOP2A, HOXB6 and DDX5, was more abundant in ovarian tumors than most normal tissues, including normal and benign ovarian tissues, suggesting that elevated expression of genes encoded within this region of chromosome 17 is a common event in ovarian tumors. Thus, these abnormal expression patterns combined with the endogenous immune response suggests that these antigens represent potential targets for immunotherapy.

Combined Weekly Topotecan and Biweekly Bevacizumab in Women With Platinum- Resistant Ovarian, Peritoneal, or Fallopian Tube Cancer

A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum‐resistant ovarian, peritoneal, or fallopian tube cancer (OC).

Patterns of Spread and Recurrence of Sex Cord-Stromal Tumors of the Ovary

OBJECTIVE Sex cord-stromal tumors are an uncommon type of ovarian neoplasm and limited data are available in the literature to guide clinical management. Recent published series suggested a lack of lymph node involvement and recommended abandonment of the lymph node dissection as part of the primary surgical staging of these tumors. To confirm these findings, we evaluated pathologic findings in women undergoing surgical management of sex cord-stromal tumors in the Seattle metropolitan area. METHODS A retrospective multi-institutional review of all patients treated with sex cord-stromal tumors at University of Washington Medical Center and Swedish Medical Center in Seattle was conducted. Information was collected on the pathology, evaluation, and treatment of these patients. RESULTS A total of 87 patients were available for analysis, the majority of whom had adult granulosa cell tumors (82%) and Sertoli-Leydig cell tumors (13%). Of these patients, 68% had complete or partial surgical staging procedures, and 47 patients had some nodal tissue examined as part of the initial or restaging procedure. All nodes examined were negative. Tumor size was significantly associated with risk of recurrent disease, with a 20% increase in the hazard of recurrence for each increase of tumor size of 1cm (HR, 1.20; 95% CI, 1.11-1.07). CONCLUSIONS This study confirms the finding that lymph node metastasis are rare in sex-cord stromal tumors. These findings support the hypothesis that routine lymphadenectomy provides limited additional information in the management of these patients and can be omitted from the primary surgical staging procedure or secondary restaging procedures.

Interpretation of Single and Serial Measures of HE4 and CA125 in Asymptomatic Women at High Risk for Ovarian Cancer

Background: Human epididymis protein 4 (HE4) is approved for clinical use with CA125 to predict epithelial ovarian cancer in women with a pelvic mass or in remission after chemotherapy. Previously reported reference ranges for HE4 are inconsistent. Methods: We report positivity thresholds yielding 90%, 95%, 98%, and 99% specificity for age-defined populations of healthy women for HE4, CA125, and Risk of Ovarian Malignancy Algorithm (ROMA), a weighted average of HE4 and CA125. HE4 and CA125 were measured in 1,780 samples from 778 healthy women aged >25 years with a documented deleterious mutation, or aged >35 years with a significant family history. Effects on marker levels of a womans age, ethnicity, and epidemiologic characteristics were estimated, as were the population-specific means, variances, and within- and between-woman variances used to generate longitudinal screening algorithms for these markers. Results: CA125 levels were lower with Black ethnicity (P = 0.008). Smoking was associated with higher HE4 (P = 0.007) and ROMA (P < 0.019). Continuous oral contraceptive use decreased levels of CA125 (P = 0.041), and ROMA (P = 0.12). CA125 was lower in women age ≥55, and HE4 increased with age (P < 0.01), particularly among women age ≥55. Conclusions: Because of the strong effect of age on HE4, thresholds for HE4 are best defined for women of specific ages. Age-specific population thresholds for HE4 for 95% specificity ranged from 41.4 pmol/L for women age 30 to 82.1 pmol/L for women age 80. Impact: Incorporation of serial marker values from screening history reduces personalized thresholds for CA125 and HE4 but is inappropriate for ROMA. Cancer Epidemiol Biomarkers Prev; 21(11); 2087–94. ©2012 AACR.