L. Perry

National toxicovigilance for pesticide exposures resulting in health care contact – An example from the UK's National Poisons Information Service

Abstract Background. Although there are extensive systems in place for pharmacovigilance, similar systems for detecting adverse health effects relating to pesticide exposure are rare. In 2004, the National Poisons Information Service (NPIS) pesticide surveillance study was implemented to identify cases requiring health care contact in the UK. This report describes the epidemiology of pesticide exposures reported to poison centres in the UK over a 9-year period. Methods. Data on exposures were gathered through monitoring access to the NPISs online clinical toxicology database TOXBASE® and through monitoring calls to the four NPIS units (Edinburgh, Cardiff, Newcastle and Birmingham). Severity was judged by both caller and NPIS staff. Results. During the 9 years, 34,092 enquiries concerning pesticides were recorded; 7,804 cases of pesticide exposure were derived from these enquiries. Exposures were predominantly unintentional and acute (6,789; 87.0%); 217 (2.8%) and 755 (9.7%) were chronic unintentional and acute deliberate self-harm exposures, respectively. The majority of cases occurred in children, especially the 0–4 year age group The minimum incidence of pesticide exposure requiring health care contact was 2.0 cases/100,000 population per year. Reported numbers were 6- to 25-fold greater than those picked up through other UK pesticide toxicovigilance schemes. There were 81 cases of severe toxicity and 38 cases of fatal exposure. Deliberate self-harm accounted for 62.3% of severe cases and 79% of deaths. Aluminium phosphide, paraquat, diquat and glyphosate were responsible for most severe and fatal cases. Conclusions. The data gathered from this pesticide surveillance study indicate that poison centre resources can usefully monitor pesticide exposures resulting in health care contact in the UK. The NPIS may usefully be one component of the UKs response to European legislation requiring surveillance of complications resulting from pesticide use.

The survival detriment of venous thromboembolism with epithelial ovarian cancer.

OBJECTIVE The aim of this study is to evaluate the effect of venous thromboembolism (VTE) chronology with respect to surgery on survival with epithelial ovarian cancer (EOC). METHODS An IRB approved, retrospective review was performed of patients treated for Stage I-IV EOC from 1996 to 2011. Cox proportional hazards model was used to assess associations between VTE and the primary outcomes of progression free survival (PFS) and overall survival (OS). SAS 9.3 was used for statistical analyses. RESULTS 586 patients met study criteria. Median age was 63 years (range, 17-94); median BMI was 27.1 kg/m(2) (range, 13.7-67.0). Most tumors were high grade serous (68.3%) and advanced stage (III/IV, 75.4%). 3.7% had a preoperative VTE; 13.2% had a postoperative VTE. Upon multivariate analysis adjusting for age, stage, histology, performance status, and residual disease, preoperative VTE was predictive of OS (HR 3.1, 95% CI: 1.6-6.1, p=0.001) but not PFS (p=0.55). Postoperative VTE was associated with shorter PFS (HR 1.45, 95% CI: 1.04-2.02, p=0.03) and OS (HR 1.8, 95% CI: 1.3-2.6, p=0.001). When VTE timing was modeled, preoperative VTE (HR 3.5, 95% CI: 1.8-6.9, p<0.001) and postoperative VTE after primary therapy (HR 2.3, 95% CI: 1.4-3.6, p=0.001) were predictive of OS. CONCLUSION Preoperative and postoperative VTE appear to have a detrimental effect on OS with EOC. When modeled as a binary variable, postoperative VTE attenuated PFS; however, when VTE timing was modeled, postoperative VTE was not associated with PFS. It is unclear whether VTE is an inherent poor prognostic marker or if improved VTE prophylaxis and treatment may enable similar survival to patients without these events.

A prognostic nomogram to predict overall survival in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy.

OBJECTIVE To develop a nomogram to predict overall survival (OS) in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy. METHODS A multicenter retrospective study was conducted. Potential prognostic variables included age; stage; grade; histology; performance status; residual disease; presence of ascites and/or pleural effusions; number of chemotherapy regimens, treatment-free interval (TFI) prior to bevacizumab administration, and platinum sensitivity. Multivariate analysis was performed using Cox proportional hazards regression. The predictive model was developed into a nomogram to predict five-year OS. RESULTS 312 women with recurrent ovarian cancer treated with bevacizumab and chemotherapy were identified; median age was 59 (range: 19-85); 86% women had advanced stage (III-IV) disease. The majority had serous histology (74%), high grade cancers (93.5%), and optimal cytoreductions (69.5%). Fifty-one percent of women received greater than two prior chemotherapeutic regimens. TFI (AHR=0.98, 95% CI 0.97-1.00, p=0.022) was the only statistically significant predictor in a multivariate progression-free survival (PFS) analysis. In a multivariate OS analysis, prior number of chemotherapy regimens, TFI, platinum sensitivity, and presence of ascites were significant. A nomogram to predict five-year OS was constructed and internally validated (bootstrap-corrected concordance index=0.737). CONCLUSION Our multivariate model identified prior number of chemotherapy regimens, TFI, platinum sensitivity, and the presence of ascites as prognostic variables for OS in women with recurrent ovarian cancer treated with bevacizumab combined with chemotherapy. Our nomogram to predict five-year OS may be used to identify women who may benefit from bevacizumab and chemotherapy, but further validation is needed.

False positive PET–CT scan and clinical examination in a patient with locally advanced vulvar cancer

► PET-CT scan was positive for metastasis of vulvar cancer to lymph nodes however they were histologically negative. ► Frozen section analysis should be performed at the time of surgery to confirm status of suspicious lymph nodes.

A Phase II trial of intravenous bevacizumab, paclitaxel and intraperitoneal cisplatin followed by intravenous bevacizumab maintenance for treatment of stage II-III ovarian cancer

Objective: Acceptance of intraperitoneal (IP) chemotherapy has not been widespread with anticipated toxicity commonly cited as a limitation of this therapy. We evaluated a modified IP regimen with IV bevacizumab to determine feasibility and assess toxicities. Methods: A phase II study was conducted in patients with advanced ovarian cancer following cytoreduction to < 1cm residual disease. The primary aim was to evaluate feasibility as defined as completion of 6 cycles. Patients received IV paclitaxel 135 mg/m2 and IV bevacizumab 15 mg/kg (cycle 2-6) on day 1 followed by cisplatin 75 mg/m2 IP day 2, repeated every 21 days x 6 cycles. Following primary therapy, patients received IV bevacizumab 15 mg/kg maintenance q21 days x 12 cycles. The FACT GOG NTX tool was used to prospectively monitor neuropathy scores over treatment. Results: 20 evaluable patients are presented including 85% with stage III disease, and 75% with no gross residual. 85% received 6 cycles of IP therapy and 77% of these received all 12 cycles of maintenance. Scores for neuropathy worsened through cycle 6, peaked at 9 and improved by 18. Toxicity was acceptable with neutropenia the most common grade 3-4 adverse event, and 8 patients experienced grade 2-3 neuropathy. With a median follow-up of 63 months, the median PFS and OS is 50 and 71 months respectively. Conclusions: Adding IV bevacizumab to a modified IP regimen is feasible. As compared to GOG 172, the lower cisplatin dose and omission of day 8 IP paclitaxel may allow a higher completion rate. Despite modifications, neuropathy remains important issue in IP based cisplatin regimens. Correspondence to: Kathleen N. Moore, MD, Stephenson Oklahoma Cancer Center, 800 NE 10th St Oklahoma City, Oklahoma 73121, USA, Tel: 405-2718707; Fax: 405-271-2976, E-mail: kathleen-moore@ouhsc.edu Received: September 30, 2015; Accepted: October 22, 2015; Published: October 26, 2015 Introduction Ovarian cancer is the leading cause of death from gynecologic cancer in the United States [1]. The high death rate stems from late presentation and tumor that has spread beyond the ovary and throughout the peritoneal cavity at the time of diagnoses [2]. Three randomized clinical trials have demonstrated the superiority of intraperitoneal (IP) over intravenous (IV) platinum based chemotherapy in patients with optimally debulked advanced stage ovarian cancer [3-5] (Table 1). The most recent is Gynecologic Oncology Group (GOG) protocol 172; a phase III randomized trial comparing IV paclitaxel plus cisplatin versus IV paclitaxel (135 mg/m2 over 24 hours on day 1) plus IP cisplatin (100 mg/m2 on day 2) and IP paclitaxel (60 mg/m2on day 8) in patients with <1 cm residual disease. Both progression-free (PFS) (median, 18.3 vs. 23.8 months) and overall survival (OS) (median, 49.7 vs. 65.6 months) was significantly improved with the IP regimen [5]. Widespread acceptance of this IP regimen was not seen because of toxicities associated with the therapy [6]. Only 42% of women on the IP arm of GOG 172 received 6 cycles of therapy, and 49% received 3 or fewer cycles [5]. Patients who were randomized to the IP therapy group in GOG-172 had higher rates of adverse events for neurologic, gastrointestinal, metabolic, infection, febrile, and hematologic toxicities [6]. Parallel with the studies of IP therapies have been investigations of targeted therapies, specifically those that target angiogenesis. Phase II studies demonstrated single agent activity of the VEGF antibody, bevacizumab, [7-9] and two phase III studies in front-line therapy were initiated based on the premise that combining chemotherapy with bevacizumab or maintenance bevacizumab following chemotherapy would improve outcomes [10,11]. The pivotal phase III GOG 218 trial demonstrated progression-free survival (PFS) benefit in patients who received concurrent and maintenance bevacizumab compared with Lanneau GL (2015) A Phase II trial of intravenous bevacizumab, paclitaxel and intraperitoneal cisplatin followed by intravenous bevacizumab maintenance for treatment of stage II-III ovarian cancer Volume 1(3): 60-65 Clin Obstet Gynecol Reprod Med, 2015 doi: 10.15761/COGRM.1000117 chemotherapy alone (14.1 months vs. 10.3 months; hazard ratio (HR) 0.717, p<0.001). However, there was no difference in overall survival (OS) reported [10]. A subset analysis was performed on the patients with stage IV disease who received bevacizumab and did find an OS benefit of 40.6 compared to 32.8 months (HR=0.72; 95% CI 0.53-0.97) [12]. In parallel ICON 7 demonstrated an improvement in PFS (19 vs. 17.3 months; HR 0.81, p=0.004, no improvement in OS except in those with stage IV and sub-optimal residual disease who had a median OS of 39.7 vs. 30.3 months [13]. This study sought to enhance IP chemotherapy delivery by reducing toxicity as well as combine IP chemotherapy with IV bevacizumab which had not been widely reported at the time of study inception. We sought to evalute the feasibiltiy of administering a modification of the GOG 172 IP regimen with the addition of IV bevacizumab. Feasibility would be judged based on the ability to complete 6 cycles of therapy and on the toxicity profile of the regimen. Methods After institutional review board approval, an open label phase II study was conducted in patients with stage II-III ovarian (epithelial and carcinosarcoma), fallopian tube, or primary peritoneal cancers with residual disease ≤ 1 cm following initial CRS. The primary aim of the study was to evaluate the feasibility of delivering IP cisplatin with IV paclitaxel and IV bevacizumab as defined by the proportion of patients able to complete 6 cycles of the IP based treatment. Eligible patients had a GOG performance status of 0-1, normal baseline hematologic, renal, and hepatic laboratory values, and had a protein/urine creatinine ratio < 1.0. All patients were to be treated within 12 weeks of surgery. Patients with borderline tumors or stage IV disease were excluded. Patients with significant cardiovascular history, uncontrolled hypertension, or nonhealing wounds were excluded. IP ports were placed either at the time of initial surgery or as a secondary procedure using the recommended surgical approaches from the GOG surgical manual. Patients received IV paclitaxel 135 mg/m2 over 3 hours and IV bevacizumab 15 mg/kg (cycle 2-6) on day 1 followed by IP cisplatin 75 mg/m2 IP on day 2. Patients received standard hypersensitivity prophylaxis and anti-emetic medications. All patients received preand postcisplatin hydration on day 2 with 2 L normal saline administered IV over 2-4 hours. Cycles were administered every 21 days for a total of 6 cycles. Following completion of primary therapy, IV bevacizumab at 15 mg/kg IV was given as maintenance therapy every 21 days for 12 cycles or until disease progression or excessive toxicity. Patients were seen each cycle and toxicities were recorded and graded by the NCI common toxicity criteria version 3.0. In addition, the FACT-GOG/ NTX4 neuropathy assessement tool was administered at baseline, following cycles 3 and 6, then after every cycle during maintneance therapy [14]. Dose delays and modifications were used to manage significant neuropathy, neutropenia, or thrombocytopenia. Blood count recovery to an absolute neutrophil count (ANC) ≥1500/ mm3 and platelets ≥100,000/mm3 were required to treat for the subsequent cycle. Patients were removed from study if a delay of >3weeks was required. Patients were required to maintain a home log of their blood pressures and these were assessed prior to each treatment and used to assess whether bevacizumab would be administered. If blood pressure was ≤150 mm/≤90 mm Hg bevacizumab was continued. Grade 3 hypertension (HTN) was managed by use of anti-hypertensive medications and treatment delays, and grade 4 HTN required discontinuation of bevacizumab. Proteinuria was monitored prior to every cycle using the protein creatinine ratio, and were continued on treatment provided the ratio was <3.5. Statistics The GOG 172 study suggested that completion rates of 6 cycles of IP based therapy was ~ 40%. It was felt that improving the rate of successful completion to 80% would be clinically relevant. With a sample size of 20 patients, 13 or more completing therapy would exceed the historical rate of completion (40%) (95% CI 13/20: 40.7-84.6%). Patients were assessed each treatment cycle, then every 3 months for two years, then every 6 months for 3 years. Imaging studies were performed based on presence of symptoms, clinical findings, or rising CA125 levels. PFS was measured from start of treatment to disease progression and OS was measured from diagnosis to death or last follow up. Results From August 2007 to September 2008, 22 patients were enrolled in the study and 20 were evaluable for feasibility of completion of 6 cycles. Of the 20 evaluable patients, median age was 59 years, 85% had stage III disease, 60% had high-grade and 20% had low-grade serous tumors (Table 2). All patients underwent primary CRS and were left with <1 cm residual disease (75% no gross). During the cytotoxic treatment phase, 3 patients were unable to complete all 6 cycles of therapy. One patient had an IP port complication at cycle 4, another had persistent grade 3 neuropathy after cycle 4, and 1 patient received 5 cycles of IP based therapy but due to grade 3 abdominal pain with IP therapy received cycle 6 intravenously. Overall, Study PFS (median) OS (median) SWOG/GOG-104 Alberts et al. [4] 49 mo (IP) vs. 41 mo (IV), p=0.02 GOG-114/SWOG Markman et al. [3] 28 mo (IP) vs. 22 (IV), p= 0.01 63 mo (IP) vs. 52 (IV), p= 0.05 GOG-172 Armstrong et al. [5] 24 mo (IP) vs.18 (IV), p= 0.05 65.6 mo (IP) vs. 49.7 (IV), p= 0.03 Table 1. Phase III IP based clinical trials. Variable N= 20 N (%) %

Outcomes of cervical cancer and positive para-aortic lymph nodes in the modern era of chemoradiation.

Objective Patients with cervical cancer with positive para-aortic lymph nodes have a poor prognosis. Our primary aim was to describe outcomes among this subgroup in the era of modern chemoradiation. Methods Patients with histologically confirmed cervical cancer metastatic to their para-aortic lymph nodes diagnosed between 1998 and 2011 and treated with curative intent were included in this analysis. Surgicopathologic, demographic, and outcome data were collected. Descriptive and survival statistics were generated to evaluate overall survival (OS) and progression-free survival (PFS) and to compare outcomes by treatment. P values were generated using both Wilcoxon and log-rank methods and listed respectively. Results The median PFS was 19 months. The median OS was 23.4 months. The median PFS for radiation only was 14 months and for chemoradiation was 20 months (P = 0.27 and 0.60, respectively). There was no difference in median OS for the radiation-only group versus chemoradiation. The median OS stratified by stage was 32 months (stage I), 21 months (stage II), 19.4 months (stage III), and 19.8 months (stage IV; P = 0.17 and 0.22). Conclusions Our study shows a median OS of 23 months, which is less than what was documented in the literature. Despite the use of modern chemoradiation therapy, most of the cohort died within 3 years. The low OS presented in our study highlights the limitations of the current treatment regimens and the need for identification of for more effective therapy.

Referrals to phase I clinical trials in a gynecologic oncology unit

OBJECTIVES Previous reviews of phase I clinical trials report limited response rates. Development of novel biologic agents and trials designs have increased these rates. A contemporary appraisal of phase I clinical trials in gynecologic malignancies could help validate these findings. METHODS Retrospectively reviewed records for 410 patients with gynecologic malignancies treated in a phase I unit, January 1999 to October 2012. Patient characteristics and treatment outcomes were abstracted and analyzed. RESULTS Patients enrolled in 43 different phase I trials, 17 phase Ia, 17 phase Ib dose escalation and 9 dose expansion. 9 trials (21%) investigated unique cytotoxic delivery methods, 15 (35%) conventional cytotoxic plus novel agents and 19 (44%) novel agents alone. For patients treated in the first-line setting, 90 (74.4%) achieved CR, 20 (16.5%) PR, 9 (7.4%) SD and 2 (1.7%) PD, yielding an overall response rate of 90.9%. In patients treated for recurrent disease, 2 (1.6%) achieved CR, 11 (8.9%) PR, 57 (46.0%) SD and 54 (43.5%) PD, yielding a response rate of 11% and an overall clinical benefit rate of 57%. Response rate for molecular targeted therapies was 11.5% with an overall clinical benefit rate of 46.2%. Patients with prior anti-angiogenic exposure had comparable median PFS to those who had not been previously exposed (3.5 vs. 4.0 months, p = 0.29). CONCLUSIONS Results support referral of gynecologic cancer patients for phase I clinical trials. Patients with advanced, heavily pretreated disease fare at least as well as they do on phase II trials and a proportion of them can attain an objective response or stabilization of their disease.

The use of biologic agents and clinical trials may prolong survival for women with primary platinum resistant ovarian carcinoma

Hispanic (8%), Asian (4%), and other races (3%). 29% were from the South, 26% from the Midwest, 25% Northeast, and 21% were from the West. 23% of hospitals were higher volume (N20 cases/year) vs. lower volume hospitals. 1647 (25%) underwent robotic surgery (RS), 820 (12%) laparoscopic (LS), vs. 4093 (62%) had open surgery (OS). The older (N 62 years, median) were more likely to have RS compared to younger (26% vs. 24%, p = 0.02). 29% of Whites had RS compared to only 20% Native Americans, 15% Hispanics, 12% Blacks, and 11% of Asians (p b 0.01). Patients from Midwest, Northeast, South and West had RS in 26%, 26%, 25%, and 23% of cases. Higher volume hospital performed 72% of all surgeries and 84% of all RS. Moreover, these higher volume hospitals were more likely to use RS compared to lower volume institutions (29% vs. 14%, p b 0.01). Those with low(b

Factors predictive of toxicity associated with bevacizumab and chemotherapy in recurrent ovarian cancer: A multi-institutional study

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A Contemporary Review of Uterine Carciosarcomas and Body Mass Index

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