Concordance of BRCA mutation detection in tumor versus blood, and frequency of bi-allelic loss of BRCA in tumors from patients in the phase III SOLO2 trial.

OBJECTIVE: Maintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2 in the tumor. METHODS: Blood and tumor samples were analyzed. A concordance analysis of germline BRCAm status (BRACAnalysis® CLIA test) and tumor BRCAm status (myChoice® CDx test) was conducted (Myriad Genetic Laboratories, Inc.). Bi-allelic loss of BRCA1 and BRCA2 and a genomic instability score (GIS) (myChoice® CDx test) were also determined. RESULTS: 289 of 295 enrolled patients had a germline BRCAm confirmed centrally and tumor BRCAm status was evaluable in 241 patients. There was 98% and 100% concordance between tumor and germline testing for BRCA1m and BRCA2m, respectively, with discordance found in four cases. Of 210 tumor samples evaluable for BRCA zygosity, 100% of germline BRCA1-mutated tumors (n = 144) and 98% of germline BRCA2-mutated tumors (n = 66) had bi-allelic loss of BRCA. One patient with a heterozygous BRCA2m had a GIS of 53, was progression free for 911 days and remained on olaparib at data cut-off. CONCLUSIONS: Very high concordance was demonstrated between tumor and germline BRCA testing, supporting wider implementation of tumor BRCA testing in ovarian cancer. Near 100% rates of bi-allelic loss of BRCA in platinum-sensitive relapsed ovarian tumors suggest routine testing for BRCA zygosity is not required in this population and reflects BRCA loss being a driver of tumorigenesis.

Prognostic value of serum HE4 in patients with advanced ovarian, fallopian tube, and peritoneal carcinoma.

PURPOSE: In this study, the prognostic value of serum HE4 was investigated in patients with advanced ovarian, fallopian tube, and peritoneal carcinoma. METHODS: Serum HE4 and CA125 levels were measured in both patients and controls, and the response of treatment and the detection of recurrence were evaluated by serum HE4 and CA125 levels in the patients. RESULTS: The results showed that the levels of serum HE4 and CA125 were significantly higher in advanced patients than those seen in benign disease controls (p < 0.001). Compared with CA125, HE4 had higher specificity, but lower sensitivity. Furthermore, serum HE4 was closely associated with the response of treatment and recurrence, the effective response rate for therapy treatment showed by HE4 was higher than CA125, and a serum HE4 level was correlated with a sensitivity of 82.8% and a specificity of 99%, a positive predictive value (PPV) of 97.7%, and a negative predictive value (NPV) of 77.9% to show the presence of recurrence; the accuracy of HE4 for recurrence prediction after treatment was 88.6%. CONCLUSIONS: Our study indicated that serum HE4 levels are effective for diagnosis, evaluating the response of treatment and predicting recurrence in patients with advanced ovarian, fallopian tube, and peritoneal carcinoma.

Phase II trial of nintedanib in patients with bevacizumab-resistant recurrent epithelial ovarian, tubal, and peritoneal cancer.

BACKGROUND: Bevacizumab provides benefit in epithelial ovarian cancer (EOC), yet resistance to bevacizumab often occurs. We determined if nintedanib, a tyrosine kinase inhibitor of VEGF, FGF, and PDGF receptors has antitumor activity in bevacizumab-resistant recurrent EOC, tubal, and peritoneal cancer. METHODS: This phase II study evaluated nintedanib 200 mg/day until disease progression or unacceptable toxicity. The primary objective was 6-month progression free survival (PFS6m). Secondary objectives were response rate and toxicity. Simon two-stage optimal design was used. Baseline angiogenic plasma biomarkers were measured. RESULTS: 27 patients were enrolled evaluable for PFS; 26 were evaluable for PFS6m. The median age was 65 years (range 44-73); 89.9% had high-grade serous EOC; 70% received at least >2 prior chemotherapies; and 81% (22/27) had chemoresistant disease. With median follow up of 15.6 months (range 2-38) the PFS6m rate was 11.5% (3/26). Three participants had long duration of disease control (8-16 months). Median PFS and overall survival were 1.8 and 16 months, respectively. Response rate was 7.4% (2/27 PR). Thirty-seven percent (10/27) had stable disease, while 56% (15/27) had progressive disease. Adverse events included Grade 3 liver enzyme elevation (15%), Grade 3 diarrhea (7%), Grade 2 fatigue (7%), and Grade 2 nausea/vomiting (15%). PD patients exhibited higher levels of CD73, IL6, and VEGFD (p < 0.05) compared to PR/SD patients. IL6 was associated with worse PFS (p = 0.03). CONCLUSIONS: Single-agent nintedanib has minimal activity in an unselected bevacizumab-resistant EOC population. Nintedanib was tolerable and toxicities were manageable. Plasma CD73, IL6, and VEGFD were identified as prognostic markers for progressive disease, and IL6 was associated with worse PFS confirming similar observations made in patients treated with other anti-angiogenic agents.

Beyond prophylaxis: Extended risk of venous thromboembolism following primary debulking surgery for ovarian cancer.

OBJECTIVE: To determine the incidence and risk factors for venous thromboembolism (VTE) within six months after primary debulking surgery (PDS) for epithelial ovarian cancer (EOC). METHODS: In a historical cohort, we estimated the cumulative incidence of clinically diagnosed VTE within 6 months among consecutive women who underwent PDS for EOC at a single institution from 1/1/2003 to 12/31/2011. We evaluated perioperative variables as potential risk factors of VTE within 6 months during the postoperative period using univariate and multivariable Cox proportional hazards models. RESULTS: Among 860 women without an immediate history (past 30 days) of a VTE, the cumulative incidence of VTE was 7.5% (95% CI, 5.7-9.3) by 30 days and 13.8% (95% CI, 11.4-16.2) by 6 months following surgery. Macroscopic residual disease (adjusted HR 1.99 [95% CI 1.35-2.94] vs microscopic), increasing estimated blood loss (1.25 [1.05-1.49] per doubling), longer hospital length of stay (3.00 [1.57-5.75]), and experiencing a cardiac event within 30 postoperative days (2.72 [1.55-4.80]) were independently associated with subsequent VTE within 6 months. In-hospital VTE prophylaxis included heterogeneous approaches; dual prophylaxis did not impact 30-day or 6-month VTE rates. CONCLUSIONS: VTE occurred in 1 in 7 women with EOC within 6 months of PDS-a substantial risk of VTE that extends into the adjuvant chemotherapy period. Novel prophylactic measures should be explored in these women at high risk for VTE.

Combining a symptom index, CA125 and HE4 (triple screen) to detect ovarian cancer in women with a pelvic mass.

OBJECTIVES: To assess a simple algorithm of CA125, HE4 and Symptom Index to predict ovarian cancer in women with a pelvic mass. METHODS: This was a prospective study of women referred to a gynecologic oncology clinic for surgical evaluation of a pelvic mass. Preoperatively, women completed a SI and had serum markers drawn. Results were correlated with pathology. A triple screen was considered positive if at least 2 of the 3 markers were abnormal (positive SI, CA125≥35U/mL, HE4≥140pmol/L). RESULTS: 218 patients enrolled in the study. 66 patients (30%) had ovarian or fallopian tube cancer (97% epithelial), 124 (57%) had benign masses, 17 (8%) had borderline tumors, and 11 (5%) had metastatic disease. The SI, CA125 and HE4 were positive in 87.9%, 74.2% and 60.6% of ovarian cancer patients, respectively. Of the 112 women with a positive SI 58 (52%) had ovarian cancer and 75 (67%) had non-benign masses. Excluding borderline and metastatic cancers the sensitivity of the triple screen was 79%; specificity 91%, PPV 83% and NPV 89%. CA125 alone had a sensitivity, specificity, PPV and NPV of 79%, 76%, 63% and 87% respectively. Requiring only one of the three tests to be abnormal resulted in a sensitivity of 97% but specificity dropped to 50%. CONCLUSIONS: An algorithm using SI, CA125 and HE4 has good performance statistics for predicting cancer in women with pelvic masses. The triple screen has higher specificity and PPV than CA125 alone but similar sensitivity and NPV for predicting ovarian cancer.

Evaluation of Transvaginal Ultrasound plus CA-125 Measurement and Prophylactic Salpingo-Oophorectomy in Women at Different Risk Levels of Ovarian Cancer: The Modena Study Group Cohort Study.

OBJECTIVE: To evaluate the effectiveness of transvaginal ultrasound (TVU) and serum CA-125 measurement in women at different risk of developing ovarian cancer/fallopian tube cancer (OC/FTC) and the incidence of primary peritoneal cancer (PPC) after risk-reducing salpingo-oophorectomy (RRSO). METHODS: Between 2002 and 2014, 661 women at different risk of OC/FTC/PPC due to a family history or BRCA1/2 gene mutation were offered TVU and CA-125 measurement or RRSO as prevention strategies. The detection rate of OC/FTC/PPC was evaluated, and the sensitivity and specificity for CA-125 measurement and TVU were calculated. Survival and event analysis was performed for diagnosed patients. RESULTS: After a median follow-up of 112 months, 12 OC/FTC/PPC cases were detected (2.6/1,000 persons/year). The screening sensitivity was 70%, with 73% for BRCA carriers. Six (50%) of 12 cancers were stage I or II. Among 41 women who underwent RRSO, 2 BRCA1 carriers developed a PPC (4.9%). At 61-month follow-up, overall and event-free survival were 75 and 64%, respectively. CONCLUSIONS: The cancer detection rate in women with BRCA mutation or a strong family history supports the effectiveness of our surveillance program for early diagnosis. Screening for women at lower risk of OC/FTC is not recommended. A residual risk of PPC after RRSO remains for BRCA1 carriers.

A randomised, open-label, phase 2 study of the IDO1 inhibitor epacadostat (INCB024360) versus tamoxifen as therapy for biochemically recurrent (CA-125 relapse)-only epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer.

OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months). The primary endpoint was investigator-assessed progression-free survival (PFS; RECIST v1.1). Secondary endpoints included CA-125 response (Gynecologic Cancer InterGroup criteria), overall survival, safety, and tolerability. RESULTS: The study was terminated primarily due to slow accrual and lack of evidence of superiority. Median PFS was 3.75months for epacadostat (n=22) versus 5.56months for tamoxifen (n=20; HR, 1.34 [95% CI, 0.58-3.14]; P=0.54). Of evaluable patients, 1 (5.0%) epacadostat and 3 (15.8%) tamoxifen patients had confirmed CA-125 responses. The most common treatment-emergent adverse event was fatigue (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%). Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known mechanism of action. IDO1 expression was observed in 94% of archival tumour samples. CONCLUSIONS: This first report of immunotherapy evaluation in biochemical-only relapse ovarian cancer and of IDO1 inhibitor monotherapy in ovarian cancer found no significant difference in efficacy between epacadostat and tamoxifen. Epacadostat was generally well tolerated.

The expression of asparaginyl endopeptidase promotes growth potential in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common and lethal cancer-related death among females in the world. Asparaginyl endopeptidase (AEP) is a member of C13 family peptidases and expressed in the extracellular matrix and tumor cells. The aim of this article is to explore the function of asparaginyl endopeptidase in epithelial ovarian cancer. The expression of AEP was examined in 20 EOC samples, 3 EOC metastasis samples, 6 fallopian tube metastasis samples, 4 peritoneum metastasis samples and 20 benign ovarian tumor samples by immunohistochemistry. The expression of AEP was also evaluated in serum and ascites of EOC patients by elisa. And we used a lentiviral vector to overexpress AEP in human epithelial ovarian cancer cell lines SKOV3ip and detected the function of AEP-SKOV3ip cells both in vitro and in vivo. The growth of AEP-SKOV3ip cells was observed by MTT, migration and tube formation assays in vitro. Additionally, the subcutaneous mice model was used to identify the tumor growth and metastasis in vivo. Mice tumors were stained for CD31 to determine the microvessel density (MVD). We demonstrated that AEP was highly expressed in the EOC patient tissues and ascites. The AEP transfected SKOV3ip cells could both promote tumor growth in vitro and in vivo. The MVD in AEP-SKOV3ip group was higher than that in NC-SKOV3ip group. Therefore, our results demonstrated that AEP could induce EOC growth and progressionboth in vitro and in vivo.

Evidence of Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom Familial Ovarian Cancer Screening Study.

Purpose To establish the performance of screening with serum cancer antigen 125 (CA-125), interpreted using the risk of ovarian cancer algorithm (ROCA), and transvaginal sonography (TVS) for women at high risk of ovarian cancer (OC) or fallopian tube cancer (FTC). Patients and Methods Women whose estimated lifetime risk of OC/FTC was ≥ 10% were recruited at 42 centers in the United Kingdom and underwent ROCA screening every 4 months. TVS occurred annually if ROCA results were normal or within 2 months of an abnormal ROCA result. Risk-reducing salpingo-oophorectomy (RRSO) was encouraged throughout the study. Participants were observed via cancer registries, questionnaires, and notification by centers. Performance was calculated after censoring 365 days after prior screen, with modeling of occult cancers detected at RRSO. Results Between June 14, 2007, and May 15, 2012, 4,348 women underwent 13,728 women-years of screening. The median follow-up time was 4.8 years. Nineteen patients were diagnosed with invasive OC/FTC within 1 year of prior screening (13 diagnoses were screen-detected and six were occult at RRSO). No symptomatic interval cancers occurred. Ten (52.6%) of the total 19 diagnoses were stage I to II OC/FTC (CI, 28.9% to 75.6%). Of the 13 screen-detected cancers, five (38.5%) were stage I to II (CI, 13.9% to 68.4%). Of the six occult cancers, five (83.3%) were stage I to II (CI, 35.9% to 99.6%). Modeled sensitivity, positive predictive value, and negative predictive value for OC/FTC detection within 1 year were 94.7% (CI, 74.0% to 99.9%), 10.8% (6.5% to 16.5%), and 100% (CI, 100% to 100%), respectively. Seven (36.8%) of the 19 cancers diagnosed < 1 year after prior screen were stage IIIb to IV (CI, 16.3% to 61.6%) compared with 17 (94.4%) of 18 cancers diagnosed > 1 year after screening ended (CI, 72.7% to 99.9%; P < .001). Eighteen (94.8%) of 19 cancers diagnosed < 1 year after prior screen had zero residual disease (with lower surgical complexity, P = .16) (CI, 74.0% to 99.9%) compared with 13 (72.2%) of 18 cancers subsequently diagnosed (CI, 46.5% to 90.3%; P = .09). Conclusion ROCA-based screening is an option for women at high risk of OC/FTC who defer or decline RRSO, given its high sensitivity and significant stage shift. However, it remains unknown whether this strategy would improve survival in screened high-risk women.

Thresholds and timing of pre-operative thrombocytosis and ovarian cancer survival: analysis of laboratory measures from electronic medical records.

BACKGROUND: Thrombocytosis has been associated with poor ovarian cancer prognosis. However, comparisons of thresholds to define thrombocytosis and evaluation of relevant timing of platelet measurement has not been previously conducted. METHODS: We selected Tumor Registry confirmed ovarian, primary peritoneal, and fallopian tube cancer cases diagnosed between 1995-2013 from the Vanderbilt University Medical Center. Laboratory measured platelet values from electronic medical records (EMR) were used to determine thrombocytosis at three thresholds: a platelet count greater than 350, 400, or 450 × 10(9)/liter. Timing was evaluated with 5 intervals: on the date of diagnosis, and up to 1, 2, 4, and 8 weeks prior to the date of diagnosis. Cox regression was used to calculate hazard ratios (HR) and confidence intervals (CI) for association with overall survival; adjustment included age, stage, grade, and histologic subtype of disease. RESULTS: Pre-diagnosis platelet measures were available for 136, 241, 280, 297, and 304 cases in the five intervals. The prevalence of thrombocytosis decreased with increasing thresholds and was generally consistent across the five time intervals, ranging from 44.8-53.2 %, 31.6-39.4 %, and 19.9-26.1 % across the three thresholds. Associations with higher grade and stage of disease gained significance as the threshold increased. With the exception of the lowest threshold on the date of diagnosis (HR350: 1.55, 95 % CI: 0.97-2.47), all other survival associations were significant, with the highest reaching twice the risk of death for thrombocytosis on the date of diagnosis (HR400: 2.01, 95 % CI: 1.25-3.23). CONCLUSIONS: Our EMR approach yielded associations comparable to published findings from medical record abstraction approaches. In addition, our results indicate that lower thrombocytosis thresholds and platelet measures up to 8 weeks before diagnosis may inform ovarian cancer characteristics and prognosis.

Diagnostic and prognostic value of serum human epididymis protein 4 in patients with primary fallopian tube carcinoma.

AIM: The aim of our study was to assess the levels of human epididymis protein 4 (HE4) with the common tumor marker carbohydrate antigen 125 (CA125) in the diagnosis and monitoring of therapy for primary fallopian tube carcinoma (PFTC). METHODS: Serum HE4 and CA125 levels from 82 PFTC patients and 154 patients with benign pelvic masses as the control were measured by Roche electrochemiluminescent immunoassay. HE4 determinations for surgery response and recurrence monitoring were assessed in PFTC patients. RESULTS: Serum HE4 and CA125 concentrations were significantly higher in PFTC patients compared with those seen in patients with benign pelvic masses (P < 0.001). Compared with CA125, HE4 had higher specificity, but lower sensitivity whether at early or advanced stage, and the combination of HE4 + CA125 led to higher sensitivity and specificity. HE4 + CA125 performed significantly better than CA125 or HE4 alone in early stage patients. In early stage the sensitivity was 35.7% for HE4 and 64.3% for CA125, while sensitivity for the combination of HE4 and CA125 could reach 71.4%. Furthermore, the two markers were associated with the progression and histology of PFTC. Serum HE4 level was closely correlated with surgical therapy. PFTC patients displayed a greater decline in the level of HE4 compared with CA125 (76.4% vs 55.7%). Combined with CA125, HE4 elevation better predicted recurrence in PFTC patients. CONCLUSIONS: This study indicated that serum HE4 levels are closely associated with PFTC and the outcome of surgical therapy and recurrence in Chinese patients.

Rare primary fallopian tube carcinoma; a gynaecologist's dilemma.

Primary fallopian tube carcinoma is rare and accounts for 0.14-1.8% of all malignancies of the female genital tract. It has been found to be associated with nulliparity and subfertility, as well as with pelvic inflammatory disease. High parity has been reported to be protective but not in our 3 cases. History of pregnancy and the use of oral contraceptives decrease the PFTC risk significantly in literature. PFTC has been described in high-risk breast-ovarian cancer families with germ-line BRCA-1 and BRCA-2 mutations. Symptoms are nonspecific and include abdominal pelvic pain, vaginal bleeding and watery discharge. However, diagnosis is rarely achieved pre-operative because of misleading imaging. In many cases, the diagnosis is made incidentally on histopathology after surgery for an un-related condition commonly being an ovarian carcinoma.

Risk factors for readmission in patients with ovarian, fallopian tube, and primary peritoneal carcinoma who are receiving front-line chemotherapy on a clinical trial (GOG 218): an NRG oncology/gynecologic oncology group study (ADS-1236).

BACKGROUND: Readmission within 30days is a measure of care quality. Ovarian cancer patients are at high risk for readmission, but specific risk factors are not defined. This study was designed to determine risk factors in patients with ovarian cancer receiving upfront surgery and chemotherapy. METHODS: The study population was enrolled to GOG 0218. Factors predictive of admission within 30days of a previous admission or 40days of cytoreductive surgery were investigated. Categorical variables were compared by Pearson chi-square test, continuous variables by Wilcoxon-Mann-Whitney test. A logistic regression model was used to evaluate independent prognostic factors and to estimate covariate-adjusted odds. All tests were two-tailed, α=0.05. RESULTS: Of 1873 patients, 197 (10.5%) were readmitted, with 59 experiencing >1 readmission. One-hundred-forty-four (73%) readmissions were post-operative (readmission rate 7.7%). Significant risk factors include: disease stage (stage 3 vs 4, p=0.008), suboptimal cytoreduction (36% vs 64%, p=0.001), ascites, (p=0.018), BMI (25.4 vs 27.6, p<0.001), poor PS (p<0.001), and higher baseline CA 125 (p=0.017). Patients readmitted within 40days of surgery had a significantly shorter interval from surgery to chemotherapy initiation (22 versus 32days, p<0.0001). Patients treated with bevacizumab had higher readmission rates in the case of patients with >1 readmission. On multivariate analysis, the odds of re-hospitalization increased with doubling of BMI (OR=1.81, 95% CI: 1.07-3.07) and PS of 2 (OR=2.05, 95% CI 1.21-3.48). CONCLUSION: Significant risk factors for readmission in ovarian cancer patients undergoing primary surgery and chemotherapy include stage, residual disease, ascites, high BMI and poor PS. Readmissions are most likely after the initial surgical procedure, a discrete period to target with a prospective intervention.

Risk of Ovarian Cancer Relapse score: a prognostic algorithm to predict relapse following treatment for advanced ovarian cancer.

OBJECTIVE: The aim of this study was to construct a prognostic index that predicts risk of relapse in women who have completed first-line treatment for ovarian cancer (OC). METHODS: A database of OC cases from 2000 to 2010 was interrogated for International Federation of Gynecology and Obstetrics stage, grade and histological subtype of cancer, preoperative and posttreatment CA-125 level, presence or absence of residual disease after cytoreductive surgery and on postchemotherapy computed tomography scan, and time to progression and death. The strongest predictors of relapse were included into an algorithm, the Risk of Ovarian Cancer Relapse (ROVAR) score. RESULTS: Three hundred fifty-four cases of OC were analyzed to generate the ROVAR score. Factors selected were preoperative serum CA-125, International Federation of Gynecology and Obstetrics stage and grade of cancer, and presence of residual disease at posttreatment computed tomography scan. In the validation data set, the ROVAR score had a sensitivity and specificity of 94% and 61%, respectively. The concordance index for the validation data set was 0.91 (95% confidence interval, 0.85-0.96). The score allows patient stratification into low (<0.33), intermediate (0.34-0.67), and high (>0.67) probability of relapse. CONCLUSIONS: The ROVAR score stratifies patients according to their risk of relapse following first-line treatment for OC. This can broadly facilitate the appropriate tailoring of posttreatment care and support.

A Phase II clinical trial of pegylated liposomal doxorubicin and carboplatin in Japanese patients with platinum-sensitive recurrent ovarian, fallopian tube or primary peritoneal cancer.

OBJECTIVE: This single-arm Phase II trial was designed to assess the safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer. METHODS: Patients with a histological diagnosis of epithelial ovarian, fallopian tube or primary peritoneal carcinoma, who were relapse-free at least 6 months after completion of first-line platinum-based chemotherapy, and who had measurable disease and gave consent to participate in this study received infusions of pegylated liposomal doxorubicin (30 mg/m(2)) at 1 mg/min, followed by carboplatin (AUC 5 mg min/ml) over 30 min every 28 days. RESULTS: Thirty-three of 35 enrolled patients were eligible for efficacy analysis. One patient (3.0%) achieved a complete response, while 16 (48.5%) achieved a partial response, with an overall objective response rate of 51.5% (95% confidence interval, 34.5-68.6%). Among the 22 patients who had evaluable CA125 levels at entry, responses were observed in 18 patients, with a response rate of 81.8% (95% confidence interval, 65.3-98.3%). The median progression-free survival and overall survival rates for all 35 patients were 10.7 months (95% confidence interval, 8.1-13.2 months) and 38.8 months (95% confidence interval, 31.0-46.7 months), respectively. The most frequent Grade 3-4 toxicities, regardless of cause, were neutropenia (82.9%), thrombocytopenia (51.4%), leukopenia (45.7%) and anemia (17.1%). CONCLUSIONS: The safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer were confirmed. Although there were concerns of severe hematological toxicity with this therapy, this potential complication was safely managed through adequate monitoring of bone marrow function.

Adnexal masses in the premenopausal patient.

Practitioners may frequently encounter adnexal masses in premenopausal women. Adnexal masses can represent a wide variety of etiologies, and therefore they can represent a diagnostic dilemma. When an adnexal mass is found the initial work up must focus on identifying acute pathology followed by determining the risk of a malignancy. Pelvic ultrasound remains the mainstay for evaluation of adnexal masses in premenopausal patients. If ultrasounds findings are indeterminate magnetic resonance imaging (MRI) is the next imaging modality of choice. The evaluation for malignancy should include serum marker screening. Aspiration of adnexal masses is generally avoided, due to the lack of therapeutic benefit and risk of seeding a tumor. When ultrasound findings are suggestive of benign disease, conservative management, including repeat imaging, should be considered. If the clinical suspicion for malignancy is high referral to a gynecologic oncologist is warranted. In other patients whom the evaluation of their adnexal mass remains unclear surgical excision with care not to disrupt the integrity of the mass should be performed for pathologic diagnosis.

Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition.

The role of endogenous androgens and sex hormone-binding globulin (SHBG) in ovarian carcinogenesis is poorly understood. Epithelial invasive ovarian cancer (EOC) is a heterogeneous disease and there are no prospective data on endogenous androgens and EOC risk by tumor characteristics (histology, grade, stage) or the dualistic model of ovarian carcinogenesis (i.e. type I vs. type II, leading to less or more aggressive tumors). We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort evaluating androgens and SHBG and invasive EOC risk by tumor characteristics. Female participants who provided a blood sample and were not using exogenous hormones at blood donation were eligible (n = 183,257). A total of 565 eligible women developed EOC; two controls (n = 1,097) were matched per case. We used multivariable conditional logistic regression models. We observed no association between androgens, SHBG and EOC overall. A doubling of androstenedione reduced risk of serous carcinomas by 21% (odds ratio (OR)log2 = 0.79, 95% confidence interval [CI] = [0.64-0.97]). Moreover, associations differed for low-grade and high-grade carcinomas, with positive associations for low-grade and inverse associations for high-grade carcinomas (e.g. androstenedione: low grade: ORlog2 = 1.99 [0.98-4.06]; high grade: ORlog2 = 0.75 [0.61-0.93], phet ≤ 0.01), similar associations were observed for type I/II tumors. This is the first prospective study to evaluate androgens, SHBG and EOC risk by tumor characteristics and type I/II status. Our findings support a possible role of androgens in ovarian carcinogenesis. Additional studies exploring this association are needed.

Primary fallopian tube cancer: domestic data and up-to-date review.

Primary fallopian tube carcinoma (PFTC) is a rare gynecological malignancy with the following characteristics: its preoperative diagnosis is easy to miss or delay because of a lack of specific symptoms and signs; it is difficult to distinguish from serous epithelial ovarian cancer or primary peritoneal serous carcinoma during or even after operation because they have the same histopathological features; and there is uncertainty regarding the optimal management because of the lack of available standard guidelines. All of these factors contribute to the major challenge of undertaking a comprehensive study of this disease. To improve our understanding of this rare disease, the domestic data were summarized first. We searched PubMed on this topic, using the term "primary fallopian tube tumor and Taiwan" (from January 1, 1990 to November 3, 2013) and identified 15 published articles, but only 11 studies focused on the outcome of patients with PFTC in Taiwan. These limited data were not enough to increase our knowledge in dealing with this disease; therefore, the addition of large series or published review articles addressing this topic was needed. According to these reports, we concluded: (1) the main type of PFTC was serous type, often poorly differentiated; (2) the diagnosis of PFTC is frequently missed or delayed; (3) PFTC is often of an earlier International Federation of Gynecology and Obstetrics (FIGO) stage than is epithelial ovarian cancer (EOC), because of the appearance of earlier but nonspecific symptoms or signs, such as abdominal pain, vaginal bleeding, and watery discharge or mass; (4) the most important clinicopathological prognostic factor was FIGO stage; (5) the therapeutic strategy is still uncertain, but is often based on the guidelines for treating EOC. An intensive surgical effort such as a complete surgical resection or optimal cytoreduction surgery with a minimal residual tumor followed by a platinum-paclitaxel combination chemotherapy with/without targeted therapy (for example, antiangiogenesis agents) may provide the best possibility of disease-free or overall survival.

A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer.

OBJECTIVE: To assess the ability of preoperative computed tomography (CT) scan of the abdomen/pelvis and serum CA-125 to predict suboptimal (>1cm residual disease) primary cytoreduction in advanced ovarian, fallopian tube, and peritoneal cancer. METHODS: This was a prospective, non-randomized, multicenter trial of patients who underwent primary cytoreduction for stage III-IV ovarian, fallopian tube, and peritoneal cancer. A CT scan of the abdomen/pelvis and serum CA-125 were obtained within 35 and 14 days before surgery, respectively. Four clinical and 20 radiologic criteria were assessed. RESULTS: From 7/2001 to 12/2012, 669 patients were enrolled; 350 met eligibility criteria. The optimal debulking rate was 75%. On multivariate analysis, three clinical and six radiologic criteria were significantly associated with suboptimal debulking: age ≥ 60 years (p=0.01); CA-125 ≥ 500 U/mL (p<0.001); ASA 3-4 (p<0.001); suprarenal retroperitoneal lymph nodes >1cm (p<0.001); diffuse small bowel adhesions/thickening (p<0.001); and lesions >1cm in the small bowel mesentery (p=0.03), root of the superior mesenteric artery (p=0.003), perisplenic area (p<0.001), and lesser sac (p<0.001). A 'predictive value score' was assigned for each criterion, and the suboptimal debulking rates of patients who had a total score of 0, 1-2, 3-4, 5-6, 7-8, and ≥ 9 were 5%, 10%, 17%, 34%, 52%, and 74%, respectively. A prognostic model combining these nine factors had a predictive accuracy of 0.758. CONCLUSIONS: We identified nine criteria associated with suboptimal cytoreduction, and developed a predictive model in which the suboptimal rate was directly proportional to a predictive value score. These results may be helpful in pretreatment patient assessment.