Monoclonal antibody-based immunotherapy of ovarian cancer: targeting ovarian cancer cells with the B7-H3-specific mAb 376.96.

OBJECTIVE: The high rate of relapse in patients with advanced ovarian cancer likely reflects the chemoresistance of cancer initiating cells (CICs). We evaluated the anti-tumor activity of monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian carcinoma cells (OCCs), in combination with the tyrosine kinase inhibitor Sunitinib and chemotherapy on chemosensitive and chemoresistant cells and CICs. METHODS: Eight ovarian cancer cell lines including platinum- and taxane-resistant cell lines were analyzed by flow cytometry to establish expression of the mAb 376.96-defined-B7-H3-epitope on differentiated ovarian cancer cells and CICs. Samples from 10 ovarian cancer patients were analyzed via immunohistochemistry for mAb 376.96-defined-B7-H3-epitope expression. In vitro studies assessed mAb 376.96 alone and in combination with Sunitinib on the growth of chemosensitive and chemoresistant cell lines and on the content of CICs. RESULTS: The mAb-376.96-defined-B7-H3 epitope is expressed on both differentiated cells and CICs in chemosensitive and chemoresistant ovarian cancer cell lines and 10 patient derived ovarian cancer tumors. In vitro treatment of chemoresistant cell lines with mAb 376.96 resulted in decreased cell viability. mAb 376.96 enhanced the cytotoxicity of Sunitinib and reduced the content of CICs. CONCLUSION: The mAb-376.96-defined-B7-H3-epitope was found to be expressed on both differentiated ovarian cancer cells and CICs in chemosensitive and chemoresistant ovarian cancer cell lines. mAb 376.96 inhibited the in vitro growth of chemosensitive and chemoresistant OCCs and reduced the content of CICs when used with Sunitinib. Further studies examining B7-H3 as a potential target of mAb-based immunotherapy for this type of malignancy are warranted.

Diabetes mellitus and ovarian cancer: more complex than just increasing risk.

OBJECTIVE: Diabetes mellitus (DM) is a risk factor for endometrial cancer and is associated with poorer outcomes in breast and colon cancers. This association is less clear in epithelial ovarian cancer (EOC). We sought to examine the effect of DM on progression-free (PFS) and overall survival (OS) in women with EOC. METHODS: A retrospective cohort study of EOC patients diagnosed between 2004 and 2009 at a single institution was performed. Demographic, pathologic and DM diagnosis data were abstracted. Pearson chi-square test and t test were used to compare variables. The Kaplan-Meier method and the log rank test were used to compare PFS and OS between non-diabetic (ND) and DM patients. RESULTS: 62 (17%) of 367 patients had a diagnosis of DM. No differences in age, histology, debulking status, or administration of intraperitoneal chemotherapy between ND and DM patients were present, although there were more stage I and IV patients in the ND group (p=0.04). BMI was significantly different between the two groups (ND vs. DM, 27.5 vs. 30.7kg/m(2), p<0.001). While there were no differences in survival based on BMI, diabetic patients had a poorer PFS (10.3 vs. 16.3months, p=0.024) and OS (26.1 vs. 42.2months, p=0.005) compared to ND patients. Metformin use among diabetic patients did not appear to affect PFS or OS. CONCLUSIONS: EOC patients with DM have poorer survival than patients without diabetes; this association is independent of obesity. Metformin use did not affect outcomes. The pathophysiology of this observation requires more inquiry.

Incidence of port site hernias and/or dehiscence in robotic-assisted procedures in gynecologic oncology patients.

OBJECTIVES: The incidence of port site hernia and/or dehiscence using bladeless trocars is 0-1.2%. Robotic surgery uses additional port sites and increases manipulation of instruments, raising the concern for more complications. We sought to characterize the incidence of port site complications following robotic surgery when fascia was not routinely closed. METHODS: Robotically-assisted (RA) procedures performed for suspected gynecologic malignancy between 1/2006 and 12/2011 were retrospectively reviewed. Bladeless 12 mm and 8mm robotic trocars were used. Fascial closure was not routinely performed except after specimen removal through the port site. The decision to close the fascia remained at the discretion of the surgeon. RESULTS: Data from 842 procedures were included. Mean patient age was 55.6 years. Mean Body Mass Index was 33.6 kg/m(2). RA-total laparoscopic hysterectomy (TLH)± unilateral or bilateral salpingo-oophorectomy (BSO)± lymphadenectomy (LND) accounted for 91.6% of procedures. Final pathology confirmed malignancy in 58.6% of cases, primarily endometrial cancer. In 35 cases, the specimen was removed through the port site; fascia was closed in 54.3% of them and no port site hernias or dehiscences occurred. Only one patient underwent a RA-TLH/BSO/LND for endometrial adenocarcinoma and had a port site dehiscence of the 8mm trocar site. No port site hernias occurred. CONCLUSION: Port site hernias and dehiscences are rare in RA gynecologic oncology procedures. When bladeless dilating trocars are used, routine closure of even up to a 12 mm port site is unnecessary, even in cases requiring removal of the specimen through the trocar sites.

The effect of the APPRISE mandate on use of erythropoiesis-stimulating agents and transfusion rates in patients with ovarian cancer receiving chemotherapy.

OBJECTIVE: Erythropoiesis-stimulating agents (ESAs) support chemotherapy-induced anemia in patients with epithelial ovarian cancer (EOC). In response to research demonstrating that ESAs increase tumor growth and shorten survival, the Food and Drug Administration mandated the new APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) guidelines for consenting patients before ESAs administration. We sought to quantify the change in ESA and red blood cell (RBC) transfusion use after the APPRISE mandate was instituted. METHODS/MATERIALS: After institutional review board approval, a retrospective chart review compared patients with EOC undergoing chemotherapy before and after the APPRISE mandate. Abstracted data included patient demographics, chemotherapy treatment status and regimen, and number of patients requiring ESAs or RBCs. A cost savings analysis was also performed. RESULTS: Eighty-four patients who underwent 367 cycles of chemotherapy after the APPRISE guidelines were compared with a matched set of 88 patients receiving 613 cycles of chemotherapy before the APPRISE guidelines. There were no statistically significant differences between the groups. Most patients had advanced stage disease and received primary taxane-/platinum-based chemotherapy. Of 88 patients, 45 (51%) in the pre-APPRISE group received a total of 196 ESA injections compared with 0 patients in the post-APPRISE group. Red blood cell transfusion in the post-APPRISE group was similar to that in the pre-APPRISE group (8.3% vs 14.8%, P = 0.28). Omission of ESAs in the post-APPRISE group resulted in a roughly $700,000 savings in billable charges. CONCLUSIONS: In our institution, the APPRISE guidelines have resulted in complete cessation of the use of ESAs in patients with primary or recurrent EOC, resulting in considerable cost savings. Importantly, RBC transfusion rates did not significantly increase after the guidelines were imposed.

Perioperative morbidity and mortality in octogenarians with ovarian cancer.

BACKGROUND: The decision to choose surgical cytoreduction in patients with newly diagnosed ovarian cancer may be influenced by their age. We compared perioperative morbidity and mortality of octogenarians compared with younger patients undergoing surgical cytoreduction. METHODS: A retrospective chart review identified patients who underwent primary surgical cytoreduction for ovarian cancer between January 2005 and December 2009. Patients were divided into 2 cohorts: younger than 80 years and 80 years or older (octogenarian). Patient demographics, surgical procedures, 30-day readmission, length of stay, 30-day mortality rates, and chemotherapy administration were examined. Student t test and χ test were used to evaluate statistical significance. RESULTS: Three hundred eighty-four patients who underwent surgical cytoreduction for ovarian cancer were identified. Three hundred fifty-two patients (91.7%) were younger than 80 years, whereas 32 patients (8.3%) were 80 years or older. Two hundred thirty-six women (67.0%) in the younger cohort had optimal cytoreduction (<1 cm) compared with 17 women (53.1%) in the older cohort (P = 0.12). Thirty-day readmission rates and postoperative complications were similar. More patients in the older cohort required preoperative admission for medical clearance (P < 0.01). Mean length of stay was significantly longer in the older cohort (10.0 vs 7.5; P = 0.02). The number of patients who received adjuvant chemotherapy was significantly lower in the older cohort (71.9% vs 93.8%; P < 0.01). The 30-day mortality rate was significantly higher in the older cohort (18.8% vs 4.0%; P < 0.01). CONCLUSIONS: Although octogenarians with ovarian cancer have similar surgical complication rates as their younger counterparts, they require more medical clearance and have a longer hospital stay. Older patients are less likely to undergo chemotherapy and have a higher 30-day mortality rate than are younger patients.

A review of B7-H3 and B7-H4 immune molecules and their role in ovarian cancer.

A number of members of the B7 superfamily of ligands have been implicated in tumor immunogenicity and cancer development. Two of these recently characterized ligands, B7-H4 and B7-H3, have been linked to ovarian tumors. B7-H4 is consistently overexpressed in ovarian tumor specimens, and its tissue and serum levels have been found to be a potential biomarker for ovarian cancer, either alone or in combination with CA125. More recently, B7-H3 has been found to be overexpressed in a large series of ovarian cancer tumor specimens and similar to other types of carcinomas, B7-H3 overexpression has been correlated with poor survival. On the basis of the results obtained by knocking down B7-H3 protein using siRNA, researchers have suggested that blocking the action of B7-H3 could reduce tumor growth, metastatic potential, and improve survival. Because siRNA knock-down is not an ideal clinical therapeutic vehicle, additional studies using antibody-mediated suppression of the B7-H3 protein are necessary to fully evaluate the clinical potential of this molecule as a therapeutic target.

The utilization of palliative care in gynecologic oncology patients near the end of life.

BACKGROUND: Palliative and supportive care services provide excellent care to patients near the end of life. It is estimated that enrollment in such services can reduce end-of-life costs; however, there is limited data available regarding the impact of palliative services in end-of-life care in gynecologic oncology patients. We examined the use of palliative services in gynecologic oncology patients during the last six months of life. METHODS: After IRB approval, a retrospective chart review of patients with a diagnosis of a gynecologic malignancy who died between June 2007 and June 2010 was performed. Abstracted data included demographics, admission and procedural history, use of anti-cancer therapy, and palliative care utilization during the last six months of life. RESULTS: 268 patients were identified. Most patients were white (76.9%) and had ovarian cancer (56.7%). During the last six months of life, 155 (57.8%) patients underwent anti-cancer therapy with chemotherapy, 19 (7.1%) patients were treated with radiation therapy, and 17 patients (6.3%) underwent treatment with both. 218 patients (81.3%) had at least one admission during this time (range 0-14). The most common reason for admission was gastrointestinal complaints (37.1%), followed by admissions for procedures (18.3%). The median time between the last admission and death was 32 days. 157 patients (58.6%) underwent at least one procedure during the last six months of life (range 0-11). The most common procedure performed was paracentesis (22.6%). 198 (73.9%) patients died at home or in a palliative care unit. 189 (70.5%) patients were referred to hospice or palliative care. 3.2% underwent a procedure or treatment with chemotherapy or radiation after hospice enrollment. The median time between hospice enrollment and death was 22 days. 55% of patients were enrolled in hospice less than 30 days before death. Of the 79 patients not referred to hospice, only 16.5% had documentation of refusing hospice services. CONCLUSIONS: During the last six months of life, the majority of gynecologic oncology patients receive anticancer therapy and many have repeated hospital admissions. While the majority of patients are referred for palliative care, it appears that most patients spend less than 30 days on hospice. Earlier referral could decrease the number of hospital admissions and procedures while providing invaluable support during this end of life transition.

Outcomes of patients with gynecologic malignancies undergoing video-assisted thoracoscopic surgery (VATS) and pleurodesis for malignant pleural effusion.

OBJECTIVES: We evaluated the indications and outcomes of patients with known gynecologic malignancies that underwent video-assisted thoracoscopic surgery (VATS) and pleurodesis for malignant pleural effusion. METHODS: After IRB approval was obtained, a retrospective study of patients with gynecologic malignancies who underwent planned VATS/pleurodesis between 1/2000 and 7/2010 was performed. Abstracted data included demographics, diagnosis, disease status, treatment history, indication for VATS, complications, and outcomes. RESULTS: Forty-two patients with a gynecologic malignancy underwent VATS/pleurodesis. Median age was 63 years. Twenty-nine patients (69%) had ovarian cancer. Fifty-seven percent had recurrent disease at the time of VATS and 57% were undergoing chemotherapy at the time of VATS. Eight patients (19%) underwent perioperative VATS to improve pulmonary status. Seven patients (17%) underwent a palliative VATS. The median length of stay was 7 days (range 1-53). Sixty-two percent had gross disease noted at the time of VATS. A mean of 1650 cc of fluid was drained at time of surgery (range 300-4500), and the majority (88%) of patients had a talc pleurodesis performed. Seven patients (17%) were readmitted within 30 days; 6 were for complications unrelated to their VATS. One patient was readmitted with hospital-acquired pneumonia and died during readmission. Median time to death after VATS was 104 days (range 4-1062). Patients who underwent a perioperative VATS had the longest survival (845 days). CONCLUSION: Patients with gynecologic malignancies may require a VATS/pleurodesis for symptomatic pleural effusions. This procedure appears to be safe and effective in this patient population.

Prognostic significance of the relative dose intensity of chemotherapy in primary treatment of epithelial ovarian cancer.

OBJECTIVE: Relative dose intensity (RDI) is the ratio of delivered dose intensity of chemotherapy to standard dose intensity. In this study, we sought to determine the prognostic significance of RDI in patients with epithelial ovarian cancer (EOC). METHODS: A retrospective analysis of chemotherapy naïve patients treated between 2001 and 2008 with intravenous taxane and platinum was performed. RDI was calculated as the delivered dose intensity (total dose delivered/total time of therapy) divided by standard dose intensity calculated for each regimen and compared to progression-free survival (PFS). Multivariate recursive partitioning survival analysis was utilized. RESULTS: 138 EOC patients completed initial taxane/platinum-based chemotherapy following surgical cytoreduction. The most common reasons for dose delays and reductions were thrombocytopenia (38%) and neutropenia (31%). 24% of treatment delays were due to social reasons such as transportation constraints or scheduling conflicts. The average RDI was 90% (range, 24-126%). The mean PFS was 31 months (range, 3-117). Patients that achieved an RDI between 70% and 110% had a mean PFS of 32 months compared to 20 months in patients with an RDI of <70% or >110% (p=0.046). 14 patients (10%) had a RDI of <70%. CONCLUSIONS: RDI is a significant predictor of survival in patients with EOC. Effort should be made to achieve an RDI of at least 70%. Dose reductions and treatment delays could be minimized by utilizing prophylactic colony stimulating factors and educating patients about the importance of adhering to their treatment schedule.

Assessment of risk factors for 30-day hospital readmission after surgical cytoreduction in epithelial ovarian carcinoma.

OBJECTIVE: To evaluate factors that place epithelial ovarian cancer (EOC) patients at increased risk for hospital readmission. METHODS: A retrospective review of patients diagnosed with EOC undergoing surgical cytoreduction at the University of Alabama at Birmingham from 2001 to 2008 was performed. Patients who required readmission were identified. Demographic data, comorbidities, surgical data including bowel resections, and hospital length of stay were evaluated. RESULTS: A total of 207 patients were identified. The mean age at diagnosis was 64 years (range, 32-89 years), 58% had optimal debulking (n=120), and the mean number of comorbidities was 1.3 (range, 0-6). Readmission within 30 days of discharge occurred in 33 (16%) of 207 patients. The readmission group had a statistically higher number of comorbidities (1.75 vs 1.01, P=0.025). The most common reasons for readmission were small bowel obstruction/ileus, wound complications, and thromboembolic events. CONCLUSIONS: The most common reason for readmission after cytoreductive surgery for EOC is small bowel obstruction/ileus. Studies assessing postoperative disease management programs including nursing telephone follow-up, administration of outpatient intravenous fluids, and continuation of antithrombotic agents may offer opportunities to reduce readmissions.

Double prophylaxis for deep venous thrombosis in patients with gynecologic oncology who are undergoing laparotomy: does preoperative anticoagulation matter?

OBJECTIVE: Double prophylaxis for deep venous thrombosis (DVT) with thromboprophylaxis plus sequential compression devices (SCDs) is recommended for high-risk surgical patients with gynecologic oncology. Despite the use of preoperative thromboprophylaxis in clinical trials, the schedule of perioperative low molecular-weight heparin varies widely. We sought to determine the effectiveness and adverse effects of a preoperative dose of anticoagulation in patients with gynecologic oncology. METHODS: A multi-institutional chart review from January 2006 to July 2008 was performed. Patients with gynecologic oncology who received double prophylaxis for laparotomy were eligible. The patients were grouped according to whether they received preoperative anticoagulation (YES PREOP vs NO PREOP). All patients received postoperative low molecular-weight heparin for thromboprophylaxis and SCDs until discharge. Demographic, surgicopathologic, and complication data were collected. RESULTS: A total of 239 patients were identified: YES PREOP (n = 101) and NO PREOP (n = 138). Groups were similar with respect to demographics, diagnosis, and length of hospital stay. There were 2 DVTs in the YES PREOP group compared with 11 in the NO PREOP group (P = 0.04; relative risk, 0.77). There were also fewer DVT-attributable deaths in the YES PREOP group (0 vs 2; P < 0.001). Postoperative hematocrit (30.2% vs 31.4%; P = 0.42) and number of transfusions (26 vs 14; P = 0.31) were similar. CONCLUSION: The use of preoperative anticoagulation seems to significantly decrease the risk of DVT in this patient population, and complication rates are not increased. Patients receiving double prophylaxis should receive a preoperative dose of anticoagulation for maximum benefit.

Invasive cervical cancer and screening: what are the rates of unscreened and underscreened women in the modern era?

OBJECTIVE: It has been reported that approximately 50% of invasive cervical malignancies are diagnosed in patients who have never been screened and that 10% of the remaining cervical cancer patients have not had a Pap smear in the 5 years before diagnosis. We sought to determine whether this holds true among a university-based gynecologic oncology patient population. METHODS: After institutional review board approval, a retrospective chart review of women in a university-based gynecologic oncology group with cervical cancer from 2002 to 2007 was conducted. Patients' demographics, referral Pap smear, method of diagnosis, histology, clinical stage, treatment, and time since last Pap smear were collected. Descriptive statistics were used during data analysis. RESULTS: A total of 419 women with cervical cancer were identified. Of these women, 67% of patients were white, 18% Hispanic, and 6% African-American. The most common referral Pap smear to our institution was high-grade squamous intraepithelial lesion (21%). Diagnosis was primarily made by cervical punch biopsy (47%). The most common histologic type was squamous cell carcinoma (70%). Of all patients, 80% were diagnosed with stage I and 9% with stage II cervical cancer, whereas stage III and IV were uncommon. The most common therapy was radical hysterectomy with lymph node dissection performed in 250 patients (60%). The length of time from last reported Pap smear to diagnosis of invasive cervical cancer ranged from 1 to 65 years, with a median of 3 years. Stage IA1 patients ranged from 1 to 12 years from last reported Pap with a median of 1 year (SD = 3.38), whereas stage III/IV patients ranged from 1 to 20 years since last screening, with a median of 4 years (SD = 6.39). Regarding length of time since last reported Pap smear, 235 patients (56%) were unable to report the length of time since their last Pap smear. Of those who reported their last Pap smear, 4 patients (1%) reported never having a Pap smear, 39 patients (9%) reported last Pap smear more than 10 years ago, and 10 patients (2%) reported a Pap smear more than 20 years ago. Of all patients, 85 (20%) reported a Pap smear within 2 years. Of these 85 patients, 71 patients (84%) were diagnosed at stage I, whereas more advanced stages were uncommon. CONCLUSIONS: Traditionally, patients diagnosed with an invasive cervical malignancy are either unscreened or underscreened with cervical cytology. Our patient population was noncompliant with the screening measures. A fraction of our patients were compliant with screening within the last 2 years, yet still developed a cervical malignancy--albeit early stage disease. As such, our data suggest that compliance continues to be an issue. However, even with adherence to screening guidelines, cervical cancer continues to develop.

Referral patterns and incidence of cervical intraepithelial neoplasia in adolescent and pregnant patients: the impact of the 2006 guidelines.

OBJECTIVE: The 2006 American Society for Colposcopy and Cervical Pathology consensus guidelines for management of abnormal cervical cytologic diagnosis made significant changes to referral recommendations for adolescent and pregnant populations. In this study, we sought to review the impact of these new guidelines on referral patterns, along with the incidence of cervical intraepithelial neoplasia 2/3 and cervical cancer in these 2 populations. MATERIALS AND METHODS: After obtaining institutional review board approval, a retrospective chart review of 12,333 patients referred to a single colposcopy clinic between January 2004 and November 2009 was performed. This colposcopy clinic serves as a statewide referral center. All adolescent patients (<21 y) and pregnant patients were included for analysis. Patients were analyzed in 2 groups with respect to implementation of the 2006 guidelines. Statistical analysis was performed using χ2 and Student t test. RESULTS: Between 2004 and 2007, before implementation of the 2006 guidelines, 9,346 patients were referred to the colposcopy clinic. Overall, 1,398 adolescents and 958 pregnant patients were identified and included in the analysis. The mean age was 23.0 years (range = 10-60 y). Of the 1,398 adolescent patients, atypical squamous cells of undetermined significance (ASCUS) Pap smears accounted for 406 referrals (29.0%). Of the 958 pregnant patients, ASCUS cytologic diagnosis accounted for 284 referrals (29.6%). One case of squamous cell carcinoma (SCC) was identified in the pregnant population (0.1%), and no cases of SCC were diagnosed in the adolescent population. After implementation of the 2006 guidelines, between 2008 and 2009, a total of 2,987 patients were referred, including 113 adolescent patients and 168 pregnant patients. Mean age was 25.5 (range = 16-54 y), which was not significantly different from 2004 to 2007, p = .79. Atypical squamous cells of undetermined significance accounted for 6 referrals (5.3%) in the adolescent population and 15 referrals (8.9%) in the pregnant population. The decrease in the proportion of ASCUS cytologic diagnosis referrals in these populations was statistically significant at p < .001. No adolescent or pregnant patients were diagnosed with SCC during their colposcopic evaluation. CONCLUSIONS: The 2006 American Society for Colposcopy and Cervical Pathology consensus guidelines decreased the number of ASCUS cytologic diagnosis referrals to colposcopy in the adolescent and pregnant populations. The overall number of patients with SCC in these populations is quite small, therefore practitioners can be reassured that the new screening guidelines are unlikely to miss this diagnosis. These guidelines provide an efficient, evidence-based approach to the cytologic evaluation of these special populations.

Outcomes of gynecologic oncology patients undergoing robotic-assisted laparoscopic procedures in a university setting.

This study evaluated intraoperative complications and postoperative outcomes of gynecologic oncology patients undergoing robotic-assisted (RA) laparoscopic procedures in a university setting. A retrospective chart review evaluated all gynecologic oncology patients at the University of Alabama at Birmingham who underwent attempted RA procedures between August 2006 and October 2011. Patient demographics, medical/surgical history, intraoperative complications, postoperative outcomes, conversion rates, readmission rates, and length of stay were examined. Total complication rates were assessed over time for each surgeon. 681 patients underwent planned RA procedures by seven gynecologic oncologists. The mean body mass index was 33.5 kg/m(2) (range 16.6-71.0 kg/m(2)). 61.4 % were diagnosed with malignancy. The most common procedure was RA hysterectomy with unilateral/bilateral salpingo-oophorectomy (37.2 %). Robotic staging was performed in 291 patients (45.1 %). Mean estimated blood loss was 75 ml (range 5-700 ml). 36 patients (5.3 %) were converted to laparotomy. The most common reason for conversion was adhesions (30.1 %), followed by uterine size (22.2 %). In 107 cases, a surgical modification was required for specimen removal including mini-laparotomy (24), extension of accessory port (36), morcellation (9), and difficult vaginal delivery (38). 3.7 % had intraoperative complications; 6 patients had a cystotomy and 5 had a vascular injury. Postoperatively, 20 patients had a febrile episode, 9 had wound complications, and 3 had a vaginal cuff dehiscence. 27 (4.2 %) patients were readmitted within 30 days. Complication rates and conversion rates were similar per surgeon. Total complication rates for evaluable surgeons were similar between the first 10 cases and subsequent 50 cases. Although patients undergoing RA procedures in a university setting are high risk, the conversion rate to laparotomy is low and intraoperative and postoperative complications are acceptable. Total complication rates for each surgeon were not impacted by the number of cases performed.