Assessment of peritoneal metastases with DW-MRI, CT, and FDG PET/CT before cytoreductive surgery for advanced stage epithelial ovarian cancer.

BACKGROUND: Preoperative assessment of peritoneal metastases is an important factor for treatment planning and selection of candidates for cytoreductive surgery (CRS) in primary advanced stage (FIGO stages III-IV) epithelial ovarian cancer (EOC). The primary aim was to evaluate the efficacy of DW-MRI, CT, and FDG PET/CT used for preoperative assessment of peritoneal cancer index (PCI). MATERIAL AND METHODS: In this prospective observational cohort study, 50 advanced stage EOC patients were examined with DW-MRI and FDG PET/CT with contrast enhanced CT as part of the diagnostic program. All patients were deemed amenable for upfront CRS. Imaging PCI was determined for DW-MRI, CT, and FDG PET/CT by separate readers blinded to the surgical findings. The primary outcome was agreement between the imaging PCI and PCI determined at surgical exploration (the reference standard) evaluated with Bland-Altman statistics. RESULTS: The median surgical PCI was 18 (range: 3-32). For all three imaging modalities, the imaging PCI most often underestimated the surgical PCI. The mean differences between the surgical PCI and the imaging PCI were 4.2 (95% CI: 2.6-5.8) for CT, 4.4 (95% CI: 2.9-5.8) for DW-MRI, and 5.3 (95% CI: 3.6-7.0) for FDG PET/CT, and no overall statistically significant differences were found between the imaging modalities (DW-MRI - CT, p = 0.83; DW-MRI - FDG PET/CT, p = 0.24; CT - FDG PET/CT, p = 0.06). CONCLUSION: Neither DW-MRI nor CT nor FDG PET/CT was superior in preoperative assessment of the surgical PCI in patients scheduled for upfront CRS for advanced stage EOC.

[Protocol for the examination of surgical specimens from patients with peritoneal carcinomatosis originating in ovary, fallopian tube and peritoneum]. / Protocolo para la valoración anatomopatológica de las piezas de cirugía de carcinomatosis peritoneal de origen ovárico, tubárico y peritoneal.

Peritoneal carcinomatosis (PC) is a malignant entity with a high rate of morbimortality. It is considered an end-stage common to several abdominal and pelvic malignant tumours, such as epithelial ovarian, fallopian tubal and peritoneal cancer. Although many of these tumors have a good response to chemotherapy, prognosis is poor due to the high rate of recurrence. Surgeons, gynecologists and oncologists are increasingly concerned with improving the survival. The surgical technique described by Sugarbaker in the eighties is a plausible option. It aims for a complete resection of macroscopic carcinomatosis (cytoreductive surgery) followed by intraoperative or perioperative intraperitoneal chemotherapy. This therapeutic option necessarily involves specific multidisciplinary units; histopathology of specimens from this surgical technique is now more frequent in our department. We describe our initial experience with PC originating from epithelial ovarian, tubal and peritoneal cancer treated with the modified Sugarbaker surgery employed in our hospital. We outline our protocol designed to achieve uniformity in procedure, and summarize the initial results.

Laparoscopic Assessment to Determine the Likelihood of Achieving Optimal Cytoreduction in Patients Undergoing Primary Debulking Surgery for Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of laparoscopic assessment to determine the likelihood of achieving optimal cytoreduction (OC) in patients undergoing primary debulking surgery (PDS) for ovarian cancer. METHODS: All patients who underwent diagnostic laparoscopy and PDS at our institution from January 2008 to December 2013 were identified. We determined the likelihood of achieving optimal cytoreduction by laparoscopic assessment based on tumor site, pattern of spread, and disease burden. Sensitivity was defined as the number of patients who achieved optimal cytoreduction after laparoscopic assessment divided by the number of patients with disease deemed resectable by laparoscopy. RESULTS: We identified 55 patients during study period. Twenty-one of the 55 patients (38%) were early stage disease. Six (10.9%) patients had disease deemed unresectable and 49 (89.1%) had disease deemed resectable at the time of laparoscopy. OC was achieved in 48 of 49 (97.9%) patients. The sensitivity of laparoscopy in predicting OC was 98% (95% confidence interval, 89.3%-99.9%). The operation was completed laparoscopically in 23 of 49 patients (47%); in 26 of 49 (53%), PDS was performed by laparotomy. There were no port site metastases reported. The rate of postoperative complications was 16%. With a median follow-up of 30 months, the median overall survival was not reached and the 75th percentile for overall survival was 37 months. CONCLUSIONS: Laparoscopy was shown to have a high sensitivity in predicting OC and is a feasible tool in triaging patients with ovarian cancer. Laparoscopy is not associated with adverse surgical outcomes.

External validation of chemotherapy response score system for histopathological assessment of tumor regression after neoadjuvant chemotherapy in tubo-ovarian high-grade serous carcinoma.

OBJECTIVE: The chemotherapy response score (CRS) system based on histopathological examination has been recently proposed for tubo-ovarian high-grade serous carcinoma (HGSC) to assess response to neoadjuvant chemotherapy (NAC). This study was aimed at validating the CRS system in an external cohort of tubo-ovarian HGSC patients. METHODS: This study included 110 tubo-ovarian HGSC patients who underwent NAC followed by interval debulking surgery. The 3-tiered CRS of the omental and adnexal tissue sections was determined by 3 independent pathologists. Differences in patient outcomes according to CRS were analyzed. RESULTS: The CRS system was highly reproducible among the 3 pathologists. Fleiss' kappa value and Kendall's coefficient of concordance for the omental CRS were 0.656 and 0.669, respectively. The omental CRS significantly predicted progression-free survival (PFS). The median PFS of patients whose tumors exhibited the omental CRS 1-2 (15 months) was significantly shorter than that of patients with an omental CRS of 3 (19 months; p=0.016). In addition, after adjusting for age, stage, and debulking status, the omental CRS was an independent prognostic factor for PFS of tubo-ovarian HGSC patients who were treated with NAC (adjusted hazard ratio [HR]=1.74; 95% confidence interval [CI]=1.05-2.87). CONCLUSION: The CRS system for assessing NAC response was a reproducible prognostic tool in our cohort. The application of the CRS system after NAC can improve survival estimation in HGSC patients.

Olaparib for Maintenance Treatment of BRCA 1 or 2 Mutated, Relapsed, Platinum-Sensitive Ovarian, Fallopian Tube and Peritoneal Cancer in People Whose Relapsed Disease has Responded to Platinum-Based Chemotherapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of olaparib (AstraZeneca) to submit evidence on the clinical and cost effectiveness of olaparib for the maintenance treatment of BRCA1/2 mutated (BRCAm), platinum-sensitive relapsed (PSR) ovarian, fallopian tube and peritoneal cancer in people whose relapsed disease has responded to platinum-based chemotherapy. The Evidence Review Group (ERG) produced a critical review of the evidence contained within the company's submission (CS) to NICE. The clinical evidence related to one phase II, double-blind randomised controlled trial that recruited 265 patients with PSR serous ovarian cancer (OC) regardless of BRCAm status. Patients received olaparib 400 mg twice daily (b.i.d.) or matched placebo. In the whole population, the primary endpoint of progression-free survival (PFS) was met (hazard ratio [HR] 0.35; 95 % confidence interval [CI] 0.25-0.49, p < 0.01) for olaparib versus placebo. The BRCAm subgroup analysis (added after the study commenced but 1 month before the primary analysis was undertaken) reported an HR for PFS of 0.18 (95 % CI 0.10-0.31, p < 0.0001) for olaparib versus placebo, though interaction tests appeared inconclusive. Overall survival was not statistically significant in the whole group (HR 0.88; 95 % CI 0.64-1.21; p = 0.44) or the BRCAm subgroup (0.73; 95 % CI 0.45-1.17; p = 0.19), though treatment switching may have confounded results. The exclusion of data from sites allowing crossover resulted in an HR for overall survival (OS) of 0.52 (95 % CI 0.28-0.97, p = 0.039) in the BRCAm group. Health-related quality-of-life measures were not significantly different between groups. All post hoc exploratory outcomes (time to treatment discontinuation/death, time to first subsequent therapy/death, and time to second subsequent therapy/death) were statistically significantly better in the olaparib arm in the whole population and the BRCAm subgroup analyses. Adverse events were more frequent for olaparib but were largely minor or manageable. The company's semi-Markov model assessed the cost effectiveness of olaparib versus routine surveillance in patients with BRCAm PSR OC from a National Health Service (NHS) and Personal Social Services (PSS) perspective over a lifetime horizon. The model suggests that the incremental cost-effectiveness ratio (ICER) for olaparib versus routine surveillance is expected to be approximately £49,146 per quality-adjusted life-year (QALY) gained. The ERG did not consider the company's cost-effectiveness estimates to be credible. Additional ERG analyses suggested that the ICER is likely to be more than £92,214 per QALY gained. Additional analyses provided by the company in patients who received three or more lines of chemotherapy suggested a more favourable cost-effectiveness profile for olaparib. The NICE Appraisal Committee recommended olaparib for this subgroup provided the cost of olaparib for people who continue to receive treatment after 15 months will be met by the company.

Assessment of a new system for primary site assignment in high-grade serous carcinoma of the fallopian tube, ovary, and peritoneum.

AIMS: The available evidence indicates that most non-uterine high-grade serous carcinomas (HGSCs) arise from the fallopian tube (FT), but approaches to primary site assignment have not evolved to reflect this. The aim of this study was to assess the application of recently proposed criteria for site assignment. METHODS AND RESULTS: One hundred and fifty-one HGSCs from four centres were reviewed retrospectively. Sixty-three of 80 (79%) chemonaive (CN) and 45 of 71 (68%) post-neoadjuvant chemotherapy (NACT) cases were assigned as FT primaries with the new criteria, whereas 58 of 80 (73%) and 45 of 71 (63%) were assigned as ovarian primaries with traditional criteria (P < 0.0001). Of 111 prospectively collected HGSCs, with consistent detailed fimbrial examination, 44 of 53 (83%) CN and 44 of 58 (76%) NACT cases were assigned as FT primaries. The reproducibility of site assignment was tested in a subset of 50 cases: all four reviewing pathologists agreed on the primary site in 48 of 50 (96%) cases, and three of four agreed in 49 of 50 (98%) cases. Of the 53 prospectively studied CN cases, bilateral ovarian involvement (62%) was significantly more frequent than bilateral tubal involvement (12%, P < 0.0001), further supporting a tubal origin and ovarian metastasis in most cases. CONCLUSIONS: With currently accepted protocols, the proposed guidelines are easy to apply and result in consistent site assignment in non-uterine HGSCs. Most cases of non-uterine HGSC were considered to be primary FT neoplasms.

Assessment of published models and prognostic variables in epithelial ovarian cancer at Mayo Clinic.

OBJECTIVES: Epithelial ovarian cancer (EOC) is an aggressive disease in which first line therapy consists of a surgical staging/debulking procedure and platinum based chemotherapy. There is significant interest in clinically applicable, easy to use prognostic tools to estimate risk of recurrence and overall survival. In this study we used a large prospectively collected cohort of women with EOC to validate currently published models and assess prognostic variables. METHODS: Women with invasive ovarian, peritoneal, or fallopian tube cancer diagnosed between 2000 and 2011 and prospectively enrolled into the Mayo Clinic Ovarian Cancer registry were identified. Demographics and known prognostic markers as well as epidemiologic exposure variables were abstracted from the medical record and collected via questionnaire. Six previously published models of overall and recurrence-free survival were assessed for external validity. In addition, predictors of outcome were assessed in our dataset. RESULTS: Previously published models validated with a range of c-statistics (0.587-0.827), though application of models containing variables which are not part of routine practice were somewhat limited by missing data; utilization of all applicable models and comparison of results are suggested. Examination of prognostic variables identified only the presence of ascites and ASA score to be independent predictors of prognosis in our dataset, albeit with marginal gain in prognostic information, after accounting for stage and debulking. CONCLUSIONS: Existing prognostic models for newly diagnosed EOC showed acceptable calibration in our cohort for clinical application. However, modeling of prospective variables in our dataset reiterates that stage and debulking remains the most important predictors of prognosis in this setting.

Assessment of intraoperative tube thoracostomy after diaphragmatic resection as part of debulking surgery for primary advanced-stage Müllerian cancer.

OBJECTIVE: The present study assessed the use of an intraoperative tube thoracostomy for patients with primary advanced-stage ovarian, fallopian tube, or peritoneal cancer who underwent a diaphragmatic resection as part of debulking surgery and to define which patients are more likely to benefit from an intraoperative tube thoracostomy. METHODS: All consecutive patients with stage IIIC-IV Müllerian cancer who underwent diaphragmatic resection at our institution between April 2008 and March 2013 were retrospectively reviewed. When a full-thickness resection of the diaphragm was performed and the thoracic cavity was opened, a chest tube was routinely placed during surgery. Patient-, disease-, and surgery-related data were collected from the patients' medical records. The data were evaluated with particular attention directed at pleural effusion after diaphragmatic resection. RESULTS: A total of 37 patients were included in this study. No complications associated with the intraoperative tube thoracostomy procedures occurred. An infection of the thoracic cavity occurred in one patient, following the presence of intra-abdominal abscess. The total volume of pleural drainage ranged from 88 to 2826 mL (median, 965 mL). The estimated blood loss, intraoperative blood transfusion, and area of the diaphragmatic opening were significantly associated with the total volume of pleural drainage in univariate analyses. In a multivariate analysis, the estimated blood loss was the only factor to be significantly associated with the total volume of pleural drainage. CONCLUSIONS: A prophylactic tube thoracostomy might be considered if the volume of the estimated blood loss is higher than usual.

Initial toxicity assessment of ICON6: a randomised trial of cediranib plus chemotherapy in platinum-sensitive relapsed ovarian cancer.

BACKGROUND: Cediranib is a potent oral vascular endothelial growth factor (VEGF) signalling inhibitor with activity against all three VEGF receptors. The International Collaboration for Ovarian Neoplasia 6 (ICON6) trial was initiated based on evidence of single-agent activity in ovarian cancer with acceptable toxicity. METHODS: The ICON6 trial is a 3-arm, 3-stage, double-blind, placebo-controlled randomised trial in first relapse of platinum-sensitive ovarian cancer. Patients are randomised (2 : 3 : 3) to receive six cycles of carboplatin (AUC5/6) plus paclitaxel (175 mg m(-2)) with either placebo (reference), cediranib 20 mg per day, followed by placebo (concurrent), or cediranib 20 mg per day, followed by cediranib (concurrent plus maintenance). Cediranib or placebo was continued for 18 months or until disease progression. The primary outcome measure for stage I was safety, and the blinded results are presented here. RESULTS: Sixty patients were included in the stage I analysis. A total of 53 patients had received three cycles of chemotherapy and 42 patients had completed six cycles. In all, 19 out of 60 patients discontinued cediranib or placebo during chemotherapy because of adverse events/intercurrent illness (n=9); disease progression (n=1); death (n=3); patient decision (n=1); administrative reasons (n=1); and multiple reasons (n=4). Grade 3 and 4 toxicity was experienced by 30 (50%) and 3 (5%) patients, respectively. No gastrointestinal perforations were observed. CONCLUSION: The addition of cediranib to platinum-based chemotherapy is sufficiently well tolerated to expand the ICON6 trial and progress to stage II.

Utility and diagnostic accuracy of fallopian tube touch imprint cytology.

OBJECTIVE: To determine the diagnostic accuracy of cytology smears in distinguishing between tube and non-tube structures. METHODS: One hundred cytology smears of fallopian tube and non-tube structures (vessels, round and ovarian ligaments) were prepared from surgically removed uterus and fallopian tube specimens and stained by the Papanicolaou method. The slides were reviewed blindly by pathologists and interpreted as tube or non-tube structures. The results were compared to the histological examination of the same specimens. FINDINGS: Results indicated an overall accuracy of 97% with a specificity of 98% and sensitivity of 96% for cytology smears, taking histology as the gold standard. Positive and negative predictive values were 96.1% and 97.9%, respectively. CONCLUSION: Cytology smears are a convenient and cost effective tool for laboratory confirmation of tubal sterilization. This method can reduce the costs of laboratory examination, especially in developing countries, where tubal sterilizations are done in large cohorts. However, histological slides remain the gold standard in cases of medicolegal problems.

Primary cancer of the fallopian tube with transitional differentiation. Clinical and pathological assessment of 6 cases.

To establish prognosis, histologic appearance and p53 and c-erbB-2 expression in cancer tissue, six cases of primary transitional cancer of the fallopian tube were analyzed. Among 45 patients with the primary cancer of the fallopian tube diagnosed between 1992 and 1997, we found six cases diagnosed previously as solid (undifferentiated) cancer of the tube. p53 protein and c-erbB-2 oncoprotein expression were examined using an avidin-biothinyl-peroxydase complex method. The accumulation of p-53 protein and c-erbB-2 oncoprotein were used as prognostic marker of the transitional cancer of the tube. According to histologic picture all patients were diagnosed for primary cancer of the tube with transitional differentiation. In 4 cases strong positive and in 2 cases moderate positive reaction with antibody against p53 protein was seen for p53 protein. No positive expression of c-erbB-2 oncoprotein in membrane of cancer cells in our cases was detected. Presence p-53 protein in all our 6 cases deny the usefulness of the p53 protein as prognostic marker in primary cancer of the fallopian tube. Lack of expression of c-erbB-2 oncoprotein in membrane of cancer cells is significantly contributed to better prognosis in cases with primary cancer of the tube with transitional differentiation.

What is the role of reassessment laparoscopy in the management of gynecologic cancers in 1995?

One hundred fifty-four patients with a diagnosis of ovarian, primary peritoneal, or fallopian tube carcinoma underwent 181 reassessment procedures to detect persistent or recurrent disease between January 1, 1989 and December 31, 1994 at Cedars-Sinai Medical Center. One hundred four laparoscopic procedures were performed. Eleven of these procedures were converted to laparotomy due to severe adhesions. Therefore, a total of 88 reassessment laparotomies were performed during the study period. Fifty-seven of 93 laparoscopies and 69 of 88 laparotomies were done as second-look procedures. There was no significant difference between the two groups with respect to patient age, tumor histology, degree of primary cytoreduction, and tumor stage or grade. Significant differences were found between laparoscopy and laparotomy groups in the following outcome variables evaluated: estimated blood loss (33.9 ml vs 164.9 ml, P = 0.0001), operative time (81.3 min vs 130.4 min, P = 0.0001), days of hospitalization (0.3 days vs 6.8 days, P = 0.0001), and direct cost/case ($2765 vs $5420, P = 0.0001). Despite obtaining 50% fewer biopsies with laparoscopy than laparotomy, the ability to detect disease was similar between these two groups: 47.3% vs 55.7% for all procedures and 52.6% vs 53.6% in the patients undergoing second-look procedures. Major complications in the laparoscopy group included transverse colon perforation (1), small bowel perforation (2), enterocutaneous fistula (1), and a retroperitoneal hematoma (1). Major complications in the laparotomy group included cystotomy (1), left ureteral injury (1), enterotomy (2), and SBO (4). Laparoscopy, when technically feasible, appears equally as effective as laparotomy in detecting persistent or recurrent malignant disease with less blood loss, less days spent in the hospital, less financial burden, and no increase in patient morbidity.

An assessment of the value of frozen sections in gynecological surgery.

In 203 consecutive gynecological operations where frozen sections were performed, 35.6% were from conditions of the ovary, 22.7% from the cervix, 18.2% from the endometrium, and 11.4% from the vulva. There were 0.5% false-positive, 1.0% false-negative and 2.0% deferred diagnosis. Incorrect interpretation was the cause of the single false-positive diagnosis, while the false-negative diagnoses were due to errors in block selection. The deferred diagnoses mainly occurred in gynecological conditions where diagnosis was difficult, required extensive sampling or a formal mitotic count. As in other surgical fields, gynecological frozen sections were used principally to guide the extent of surgery. The most valuable frozen sections were in those instances where the operation was affected most. These were on lymph nodes in cases of carcinoma of the vulva and cervix, myometrial lesions in young women where myomectomy was being considered, and ovarian tumours to distinguish primary from secondary tumours. Occasionally, frozen sections were also found useful to establish margins of vulval and cervical tumours, in hysterectomy specimens of endometrial carcinomas to determine prognostic factors, and in suspected recurrences and metastases of tumours to determine the adequacy of the biopsy material. Frozen sections in obviously benign conditions, e.g., ovarian cysts without papillary or solid areas, were found to be unnecessary. Frozen sections are contraindicated when only a small amount of crucial material is available, as the paraffin diagnosis may be compromised. Pathologists should have a clear idea of the role of frozen sections in gynecological surgery and work closely with the surgeon in the management of gynecological oncology patients.