Robert E. Bristow

Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm☆

OBJECTIVE To determine the impact on progression-free survival (PFS) and overall survival (OS) of a programmatic change in surgical approach to advanced epithelial ovarian cancer. METHODS Two groups of patients with stage IIIC and IV ovarian, tubal, and peritoneal carcinoma were compared. Group 1, the control group, consisted of all 168 patients who underwent primary cytoreduction from 1/96 to 12/99. Group 2, the study group, consisted of all 210 patients who underwent primary surgery from 1/01 to 12/04, during which time a more comprehensive debulking of upper abdominal disease was utilized. RESULTS There were no differences between the groups in age, primary site of disease, surgical stage, tumor grade, American Society of Anesthesiologists class, preoperative serum CA-125 and platelet levels, percentage with or amount of ascites, size or location of largest tumor mass, or type of postoperative chemotherapy. Patients in Group 2 vs Group 1 more frequently had extensive upper abdominal procedure(s) (38% vs 0%, respectively; P<0.001) and cytoreduction to residual disease <1 cm (80% vs 46%, respectively; P<0.01). Five-year PFS and OS rates were significantly improved in Group 2. For Group 2 vs Group 1 patients, 5-year PFS rates were 31% vs 14%, respectively (hazard ratio, 0.757; 95% CI, 0.601-0.953; P=0.01]; and 5-year OS rates were 47% vs 35%, respectively (HR, 0.764; 95% CI, 0.592-0.987; P=0.03]. CONCLUSION The incorporation of extensive upper abdominal procedures resulted in increased optimal cytoreduction rates and significantly improved PFS and OS. A paradigm shift toward more complete primary cytoreduction can improve survival for patients with advanced ovarian, tubal, and peritoneal carcinomas.

Cytoreductive surgery for recurrent ovarian cancer: a meta-analysis.

OBJECTIVE To determine the relative effect of multiple prognostic variables on overall post-recurrence survival time among cohorts of patients with recurrent ovarian cancer undergoing cytoreductive surgery. METHODS Forty cohorts of patients with recurrent ovarian cancer (2019 patients) meeting study inclusion criteria were identified from the MEDLINE database (1983-2007). Simple and multiple linear regression analyses, with weighted correlation calculations, were used to assess the effect on median post-recurrence survival time of the following variables: year of publication, age, disease-free interval, localized disease, tumor grade and histology, the proportion of patients undergoing complete cytoreductive surgery, requirement for bowel resection, and the sequence of cytoreductive surgery and salvage chemotherapy. RESULTS The mean weighted median disease-free interval prior to cytoreductive surgery was 20.2 months, and the mean weighted median overall post-recurrence survival time was 30.3 months. The weighted mean proportion of patients in each cohort undergoing complete cytoreductive surgery was 52.2%. Median survival improved with increasing year of publication (p=0.009); however, the only statistically significant clinical variable independently associated with post-recurrence survival time was the proportion of patients undergoing complete cytoreductive surgery (p=0.019). After controlling for all other factors, each 10% increase in the proportion of patients undergoing complete cytoreductive surgery was associated with a 3.0 month increase in median cohort survival time. CONCLUSIONS Among patients undergoing operative intervention for recurrent ovarian cancer, the proportion of patients undergoing complete cytoreductive surgery is independently associated with overall post-recurrence survival time. For this select group of patients, the surgical objective should be resection of all macroscopic disease.

A model for predicting surgical outcome in patients with advanced ovarian carcinoma using computed tomography.

A reliable model for predicting the outcome of primary cytoreductive surgery may be a useful tool in the clinical management of patients with advanced epithelial ovarian carcinoma.

Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations

Although gynecologic cancers account for only 10% of all new cancer cases in women, these cancers account for 20% of all female cancer survivors. Improvements in cancer care have resulted in almost 10 million cancer survivors, and this number is expected to grow. Therefore, determining the most cost-effective clinical surveillance for detection of recurrence is critical. Unfortunately, there has been a paucity of research in what are the most cost-effective strategies for surveillance once patients have achieved a complete response. Currently, most recommendations are based on retrospective studies and expert opinion. Taking a thorough history, performing a thorough examination, and educating cancer survivors about concerning symptoms is the most effective method for the detection of most gynecologic cancer recurrences. There is very little evidence that routine cytologic procedures or imaging improves the ability to detect gynecologic cancer recurrence at a stage that will impact cure or response rates to salvage therapy. This article will review the most recent data on surveillance for gynecologic cancer recurrence in women who have had a complete response to primary cancer therapy.

Multi-Institutional Reciprocal Validation Study of Computed Tomography Predictors of Suboptimal Primary Cytoreduction in Patients With Advanced Ovarian Cancer

PURPOSE Identify features on preoperative computed tomography (CT) scans to predict suboptimal primary cytoreduction in patients treated for advanced ovarian cancer in institution A. Reciprocally cross validate the predictors identified with those from two previously published cohorts from institutions B and C. PATIENTS AND METHODS Preoperative CT scans from patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreduction in institution A between 1999 and 2005 were retrospectively reviewed by radiologists blinded to surgical outcome. Fourteen criteria were assessed. Crossvalidation was performed by applying predictive model A to the patients from cohorts B and C, and reciprocally applying predictive models B and C to cohort A. RESULTS Sixty-five patients from institution A were included. The rate of optimal cytoreduction ( 1 cm residual disease) was 78%. Diaphragm disease and large bowel mesentery implants were the only CT predictors of suboptimal cytoreduction on univariate (P < .02) and multivariate analysis (P < .02). In combination (model A), these predictors had a sensitivity of 79%, a specificity of 75%, and an accuracy of 77% for suboptimal cytoreduction. When model A was applied to cohorts B and C, accuracy rates dropped to 34% and 64%, respectively. Reciprocally, models B and C had accuracy rates of 93% and 79% in their original cohorts, which fell to 74% and 48% in cohort A. CONCLUSION The high accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be confirmed in the cross validation. Preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant chemotherapy.

Clinically occult recurrent ovarian cancer: patient selection for secondary cytoreductive surgery using combined PET/CT.

OBJECTIVE The aim of this study was to evaluate the utility of combined positron emission tomography/computed tomography (PET/CT) for identifying ovarian cancer tumor masses > or =1 cm in patients with clinically occult recurrent disease by conventional CT imaging. METHODS Twenty-two patients with epithelial ovarian cancer, rising serum CA125 levels, and negative or equivocal conventional CT imaging > or =6 months after primary therapy underwent combined PET/CT imaging followed by surgical reassessment. Fishers exact test was used to measure the ability of PET/CT to predict macroscopic disease > or =1 cm. RESULTS The median patient age was 55 years, and 91% of patients had FIGO Stage IIIC/IV disease. The median increase in serum CA125 was 24 U/ml (range 10 to 330 U/ml). Conventional CT was reported as negative (n = 15) or equivocal (n = 7) in all cases. Eighteen patients were ultimately found to harbor recurrent ovarian cancer measuring > or =1 cm at the time of surgery, with a median maximal tumor diameter of 2.3 cm (range 1.5 to 3.2 cm). The overall patient-based accuracy of PET/CT in detecting recurrent disease > or =1 cm was 81.8%, with a sensitivity of 83.3% and positive predictive value of 93.8% (P = 0.046). Of patients with recurrent ovarian cancer > or =1 cm, complete cytoreduction to no gross residual tumor was accomplished in 72.2%. CONCLUSION PET/CT imaging demonstrates high sensitivity and positive predictive value in identifying potentially resectable, macroscopic recurrent ovarian cancer among patients with biochemical evidence of recurrence and negative or equivocal conventional CT findings. In appropriately selected patients, early identification of macroscopic recurrent disease may facilitate complete surgical cytoreduction.

Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis: A Gynecologic Oncology Group Trial

PURPOSE Sorafenib is a kinase inhibitor targeting Raf and other kinases (ie, vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Flt3, and c-KIT). This study assessed its activity and tolerability in patients with recurrent ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC). METHODS This open-label, multi-institutional, phase II study used a two-stage design. Eligible patients had persistent or recurrent OC/PPC after one to two prior cytotoxic regimens, and they experienced progression within 12 months of platinum-based therapy. Treatment consisted of sorafenib 400 mg orally twice per day. Primary end points were progression-free survival (PFS) at 6 months and toxicity by National Cancer Institute criteria. Secondary end points were tumor response and duration of PFS and overall survival. Biomarker analyses included measurement of ERK and b-Raf expression in tumors and phosphorylation of ERK (pERK) in peripheral-blood lymphocytes (PBLs) before and after 1 month of treatment. Results Seventy-three patients were enrolled, of which 71 were eligible. Fifty-nine eligible patients (83%) had measurable disease, and 12 (17%) had detectable disease. Significant grade 3 or 4 toxicities included the following: rash (n = 7), hand-foot syndrome (n = 9), metabolic (n = 10), GI (n = 3), cardiovascular (n = 2), and pulmonary (n = 2). Only patients with measurable disease were used to assess efficacy. Fourteen survived progression free for at least 6 months (24%; 90% CI, 15% to 35%). Two patients had partial responses (3.4%; 90% CI, 1% to 10%); 20 had stable disease; 30 had progressive disease; and seven could not have their tumor assessed. ERK and b-Raf were expressed in all tumors. Exploratory analyses indicated that pERK in post-treatment PBL specimens was associated with PFS. CONCLUSION Sorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.

Oncologic and Reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 Adenocarcinoma: A systematic review

OBJECTIVE The objective of this review was to analyze published contemporary oncologic and reproductive outcomes in women with endometrial hyperplasia or cancer undergoing medical management with progestin therapy. METHODS A systematic review of oncologic and pregnancy outcomes in women with complex atypical hyperplasia or grade 1 adenocarcinoma was performed using a comprehensive search of the MEDLINE literature. English language studies published from 2004 to 2011 which utilized hormonal therapy were identified using key words endometrial hyperplasia, endometrial cancer, fertility preservation, hormone and progestin therapy. Fishers exact test was used to calculate statistical differences. RESULTS Forty-five studies with 391 study subjects were identified. The median age was 31.7 years. Therapies included medroxyprogesterone (49%), megestrol acetate (25%), levonorgestrel intrauterine device (19%), hydroxyprogesterone caproate (0.8%), and unspecified/miscellaneous progestins (13.5%). Overall, 344 women (77.7%) demonstrated a response to hormonal therapy. After a median follow up period of 39 months, a durable complete response was noted in 53.2%. The complete response rate was significantly higher for those with hyperplasia than for women with carcinoma (65.8% vs. 48.2%, p=.002). The median time to complete response was 6 months (range, 1-18 months). Recurrence after an initial response was noted in 23.2% with hyperplasia and 35.4% with carcinoma during the study periods (p=.03). Persistent disease was observed in 14.4% of women with hyperplasia and 25.4% of women with carcinoma (p=.02). During the respective study periods, 41.2% of those with hyperplasia and 34.8% with a history of carcinoma became pregnant (p=.39), with 117 live births reported. CONCLUSION Based on this systematic review of the contemporary literature, endometrial hyperplasia has a significantly higher likelihood of response (66%) to hormonal therapy than grade 1 endometrial carcinoma (48%). Disease persistence is more common in women with carcinoma (25%) compared to hyperplasia (14%). Reproductive outcomes do not seem to differ between the cohorts.

Claudin-containing exosomes in the peripheral circulation of women with ovarian cancer

BackgroundThe absence of highly sensitive and specific serum biomarkers makes mass screening for ovarian cancer impossible. The claudin proteins are frequently overexpressed in ovarian cancers, but their potential as prognostic, diagnostic, or detection markers remains unclear. Here, we have explored the possible use of these proteins as screening biomarkers for ovarian cancer detection.MethodsClaudin protein shedding from cells was examined by immunoblotting of conditioned culture media. The presence of claudins in exosomes released from ovarian cancer cells was demonstrated by sucrose gradient separation and immunogold electron microscopy experiments. Claudin-4-containing exosomes in the plasma of ovarian cancer patients were evaluated in a pilot panel of 63 ovarian cancer patients and 50 healthy volunteers. The CA125 marker was also assessed in these samples and compared with claudin-4 positivity.ResultsWe show that full-length claudins can be shed from ovarian cancer cells in culture and found in the media as part of small lipid vesicles known as exosomes. Moreover, 32 of 63 plasma samples from ovarian cancer patients exhibited the presence of claudin-4-containing exosomes. In contrast, only one of 50 samples from individuals without cancer exhibited claudin-4-positive exosomes. In our small panel, at a specificity of 98%, the claudin-4 and CA125 tests had sensitivities of 51% and 71%, respectively. The two tests did not appear to be independent and were strongly correlated.ConclusionOur work shows for the first time that claudin-4 can be released from ovarian cancer cells and can be detected in the peripheral circulation of ovarian cancer patients. The development of sensitive assays for the detection of claudin-4 in blood will be crucial in determining whether this approach can be useful, alone or in combination with other screening methods, for the detection of ovarian cancer.

The National Cancer Database report on advanced-stage epithelial ovarian cancer: Impact of hospital surgical case volume on overall survival and surgical treatment paradigm

OBJECTIVE To examine the effect of hospital procedure volume and other prognostic variables on overall survival outcome and likelihood of receiving standard recommended care among patients with advanced-stage epithelial ovarian cancer. METHODS The National Cancer Data Base (NCDB) was searched for patients undergoing primary treatment for FIGO Stage IIIC/IV epithelial ovarian cancer from 1996 to 2005. The average annual surgical procedure volume was derived for each reporting hospital. Quartile ranking discriminated four groups of hospitals based on annual surgical volume: low (<9), intermediate (9-20), high (21-35), and very high (>35). Cox proportional hazards modeling was used to determine the impact on overall survival of hospital surgical volume adjusted for treatment, FIGO/AJCC stage, ethnicity, age, payer status, household income, and tumor grade. Binomial multivariate logistic regression modeling was used to assess differences in patient demographic, tumor, and treatment variables between high/very high volume hospitals and low/intermediate volume hospitals. RESULTS A total of 45,929 patients were identified. After adjusting for other factors, overall survival was significantly correlated with hospital case volume: very high (reference); high (HR 0.98, 95% CI=0.92-1.04); intermediate (HR 1.08, 95% CI=1.01-1.15); and low (HR 1.14, 95% CI=1.07-1.22). Compared to low and intermediate volume hospitals, patients treated at very high and high-volume hospitals were less likely to receive neo-adjuvant chemotherapy (OR=0.33, 95% CI=1.18-1.50) or surgery alone (OR=0.77, 95% CI=0.73-0.82) instead of initial surgery and adjuvant chemotherapy. CONCLUSIONS Hospital ovarian cancer surgical volume >or=21 cases/year is associated with a higher likelihood of patients with Stage IIIC/IV epithelial ovarian cancer receiving standard treatment (surgery followed by adjuvant chemotherapy). Even after adjusting for treatment paradigm and other factors, hospital volume >or=21 cases/year was significantly predictive of improved overall survival outcome.