Health-related quality of life after interval cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with stage III ovarian cancer.

INTRODUCTION: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery (CRS) improves recurrence-free (RFS) and overall survival (OS) in patients with FIGO stage III ovarian cancer. We evaluated the effect of HIPEC on patient's health-related quality of life (HRQoL) in the OVHIPEC trial. MATERIALS AND METHODS: OVHIPEC was a multicentre, open-label, randomized phase III trial for patients with stage III ovarian cancer. Patients were randomly assigned (1:1) to receive interval CRS with or without HIPEC with cisplatin. HRQoL was assessed using the EORTC QLQ-C30, and the ovarian (QLQ-OV28) and colorectal cancer (QLQ-CR38) modules. HRQoL questionnaires were administered at baseline, after surgery, after end of treatment, and every three months thereafter. HRQoL was a secondary endpoint, with the prespecified focus on the QLQ-C30 summary score and symptom scores on fatigue, neuropathy and gastro-intestinal symptoms. HRQoL was analysed using linear and non-linear mixed effect models. RESULTS: In total, 245 patients were randomized. One-hundred-ninety-seven patients (80%) completed at least one questionnaire. No significant difference over time in the QLQ-C30 summary scores was observed between the study arms (p-values for linear and non-linear growth: p > 0.133). The pattern over time for fatigue, neuropathy and gastro-intestinal symptoms did not significantly differ between treatment arms. CONCLUSION: The addition of HIPEC to interval CRS does not negatively impact HRQoL in patients with stage III ovarian cancer who are treated with interval CRS due to the extent of disease. These HRQoL results, together with the improvement in RFS and OS, support the viability of HIPEC as an important treatment option in this patient population. CLINICALTRIALS. GOV NUMBER: NCT00426257. EUDRACT NUMBER: 2006-003466-34.

No influence of sarcopenia on survival of ovarian cancer patients in a prospective validation study.

OBJECTIVE: Decrease in skeletal muscle index (SMI) during neoadjuvant chemotherapy (NACT) has been associated with worse outcome in patients with advanced ovarian cancer. To validate these findings, we tested if a decrease in SMI was a prognostic factor for a homogenous cohort of patients who received NACT in the randomized phase 3 OVHIPEC-trial. METHODS: CT-scans were performed at baseline and after two cycles of neoadjuvant chemotherapy in stage III ovarian cancer patients. The SMI (skeletal muscle area in cm2 divided by body surface area in m2) was calculated using SliceOMatic software. The difference in SMI between both CT-scans (ΔSMI) was calculated. Cox-regression analyses were performed to analyze the independent effect of a difference in SMI (ΔSMI) on outcome. Log-rank tests were performed to plot recurrence-free (RFS) and overall survival (OS). The mean number of adverse events per patient were compared between groups using t-tests. RESULTS: Paired CT-scans were available for 212 out of 245 patients (87%). Thirty-four of 74 patients (58%) in the group with a decrease in ΔSMI and 73 of 138 of the patients (53%) in the group with stable/increase in ΔSMI had died. Median RFS and OS did not differ significantly (p = 0.297 and p = 0.764) between groups. Patients with a decrease in SMI experienced more pre-operative adverse events, and more grade 3-4 adverse events. CONCLUSION: Decreased SMI during neoadjuvant chemotherapy was not associated with worse outcome in patients with stage III ovarian cancer included in the OVHIPEC-trial. However, a strong association between decreasing SMI and adverse events was found.

The impact of centralization of services on treatment delay in ovarian cancer: A study on process quality.

OBJECTIVE: Emphasis on improving healthcare quality has led to centralization of services for patients suspected of ovarian cancer. As centralization of services may induce treatment delays, we aimed to assess compliance with health system interval guidelines in patients suspected of ovarian cancer. DESIGN: Evaluation of health system intervals, comparison between direct and indirect referrals and between 2013 and 2014. SETTING: A managed clinical network (MCN) comprising 11 hospitals in the Netherlands. PARTICIPANTS: Patients that were treated for ovarian cancer within the University Medical Center Groningen in 2013 and 2014. INTERVENTION: Introduction of an MCN to centralize services for patients suspected of ovarian cancer. MAIN OUTCOME MEASURE: Compliance with national guidelines regarding health system intervals. RESULTS: Between 2013 and 2014 a clinically relevant improvement in compliance with guidelines was demonstrated. Within this period, median treatment intervals decreased from 34 to 29 days, and the percentage of patients in which treatment interval guidelines were met increased from 63.5 to 72.2%. New regulations and increased awareness of health system intervals inspired changes in local practice leading to improved compliance with guidelines. Compliance was highest in patients that were directly referred to our academic hospital. CONCLUSION: Evaluation of health system intervals in patients suspected of ovarian cancer was feasible and may be applicable to other MCNs. Though compliance with guidelines improved within the study period, there is potential for improvement. To facilitate real-time evaluation of compliance with national guidelines establishing uniformity of electronic patient files in the MCN is deemed essential.

Volume-controlled versus short drainage after inguinofemoral lymphadenectomy in vulvar cancer patients: A Dutch nationwide prospective study.

OBJECTIVE: Inguinofemoral lymphadenectomy for patients with vulvar squamous cell carcinoma is associated with a high incidence of postoperative wound complications, which may be influenced by inguinal drain management. The aim of this nationwide prospective study (MAMBO: Morbidity And Measurement of the BOdy) was to assess the feasibility and the incidence of complications after volume-controlled versus short drainage. METHODS: The MAMBO study consisted of two observational studies in all eight oncology centers in the Netherlands, conducted between 2012 and 2016. In the first study, the drain was removed when the production was <30ml/24h, except in the first 48h, and after a maximum of 28days (MAMBO-IA). In the second study, the drain was removed five days postoperatively regardless of production (MAMBO-IB). We assessed the complications within eight weeks after surgery using logistic regression to compare the incidence of one or more complications between the two drainage protocols, adjusting for possible confounders. RESULTS: We included 77 patients (139 groins) for volume-controlled drainage and 64 patients (112 groins) for short drainage. Volume-controlled drainage was associated with significant less lymphocele formation. Moreover, we found no difference in wound infection or primary wound breakdown. The estimated incidence of one or more complications was 46% per groin after volume-controlled drainage versus 75% after short drainage, (RD 29% (95% CI 8, 49) p=0.006). CONCLUSIONS: This prospective study shows that volume-controlled drainage is associated with significantly less complications compared to short drainage. We therefore recommend volume-controlled drainage after inguinofemoral lymphadenectomy in patients with vulvar squamous cell carcinoma.

Molecular imaging in ovarian cancer.

Ovarian cancer has a high mortality and novel-targeted treatment strategies have not resulted in breakthroughs for this disease. Insight into the molecular characteristics of ovarian tumors may improve diagnosis and selection of patients for treatment with targeted therapies. A potential way to achieve this is by means of molecular imaging. Generic tumor processes, such as glucose metabolism ((18)F-fluorodeoxyglucose) and DNA synthesis ((18)F-fluorodeoxythymidine), can be visualized non-invasively. More specific targets, such as hormone receptors, growth factor receptors, growth factors and targets of immunotherapy, can also be visualized. Molecular imaging can capture data on intra-patient tumor heterogeneity and is of potential value for individualized, target-guided treatment selection. Early changes in molecular characteristics during therapy may serve as early predictors of response. In this review, we describe the current knowledge on molecular imaging in the diagnosis and as an upfront or early predictive biomarker in patients with ovarian cancer.

Intraoperative near-infrared fluorescence imaging for sentinel lymph node detection in vulvar cancer: first clinical results.

OBJECTIVE: Disadvantages of the combined sentinel lymph node (SLN) procedure with radiocolloid and blue dye in vulvar cancer are the preoperative injections of radioactive tracer in the vulva, posing a painful burden on the patient. Intraoperative transcutaneous imaging of a peritumorally injected fluorescent tracer may lead to a one-step procedure, while maintaining high sensitivity. Aim of this pilot study was to investigate the applicability of intraoperative fluorescence imaging for SLN detection and transcutaneous lymphatic mapping in vulvar cancer. METHODS: Ten patients with early stage squamous cell carcinoma of the vulva underwent the standard SLN procedure. Additionally, a mixture of 1 mL patent blue and 1 mL indocyanin green (ICG; 0.5 mg/mL) was injected immediately prior to surgery, with the patient under anesthesia. Color and fluorescence images and videos of lymph flow were acquired using a custom-made intraoperative fluorescence camera system. The distance between skin and femoral artery was determined on preoperative CT-scan as a measure for subcutaneous adipose tissue. RESULTS: In 10 patients, SLNs were detected in 16 groins (4 unilateral; 6 midline tumors). Transcutaneous lymphatic mapping was possible in five patients (5 of 16 groins), and was limited to lean patients, with a maximal distance between femoral artery and skin of 24 mm, as determined on CT. In total, 29 SLNs were detected by radiocolloid, of which 26 were also detected by fluorescence and 21 were blue. CONCLUSIONS: These first clinical results indicate that intraoperative transcutaneous lymphatic mapping using fluorescence is technically feasible in a subgroup of lean vulvar cancer patients.

Short-term surgical outcome and safety of risk reducing salpingo-oophorectomy in BRCA1/2 mutation carriers.

OBJECTIVE: Women with a BRCA1/2 mutation or members of a hereditary breast ovarian cancer family (HBOC) have an increased risk of developing ovarian cancer. The only effective strategy to reduce this risk is a risk reducing salpingo-oophorectomy (RRSO). The aim of this study was to evaluate the short-term surgical outcome and safety of a RRSO. PATIENT AND METHODS: Included were all consecutive women with a BRCA1/2 mutation or members of a HBOC family who visited our Family Cancer Clinic between September 1995 and March 2006, and choose for RRSO. RESULTS: 159 women were included, of which 97 (61.0%) BRCA1 and 32 (20.1%) BRCA2 mutation carriers, and 30 women of a HBOC family (18.9%). The median age at RRSO was 42.9 years (30.3-61.1) in the BRCA1 group, 48.4 years (33.5-66.9) in the BRCA 2 group and 46.4 (32.8-68.7) years in the HBOC group (p=0.02). The median body mass index (BMI) was 24.9 kg/m(2), 30.1% were overweighed (BMI 25-30) and 18.7% were obese (BMI>30). The RRSO was performed by primary laparoscopy (n=154) or laparotomy (n=5). Intraoperatively, one (0.6%) major complication occurred and laparoscopy was converted to laparotomy. In one patient (0.6%) a minor complication occurred. Post-operatively five minor complications (3.1%) were observed. Median hospital stay was 1 day (0-13 days). CONCLUSION: Laparoscopic RRSO in BRCA1/2 mutation carriers seems to be a safe procedure with a low intraoperative and post-operative complication rate (1.3% and 3.1% respectively), a low conversion rate (0.6%) and a short median hospital stay (1.0 day).

Influence of different cleaning practices on endotoxin exposure at sewage treatment plants.

Exposure to endotoxin at sewage treatment plants is associated with an increased prevalence of work-related symptoms in sewage workers. Since cleaning activities are regarded as an important determinant of endotoxin exposure, workers' endotoxin exposure levels during different cleaning activities were compared in an experimental setting. Variables considered were water used (tap water, surface water or effluent), water pressure (low or high pressure, and a fire hose with the mouth open or obstructed), presence of mechanical ventilation and the distance between the worker and the object to be cleaned (concentration gradient). Experimental cleaning scenarios were defined, during which endotoxin exposure was measured with personal and stationary air sampling. Data were statistically analyzed with mixed effects models. The water used for cleaning appeared to have a large influence on endotoxin exposure, especially the use of effluent, which caused a factor 2.4 increase in exposure. Use of high pressure did not significantly add to the exposure. Use of a fire hose with fully opened mouth (spout opening) led to a 3-fold decrease in exposure when compared with a partially obstructed mouth. The presence of mechanical ventilation decreased endotoxin concentration in a room, provided that the capacity of the ventilation system was sufficient. The worker's distance to the object that was cleaned did not significantly influence exposure.

Chemotherapy induces death receptor 5 in epithelial ovarian carcinoma.

OBJECTIVES: Defects in the apoptotic pathway are a general cause for drug resistance. Chemotherapy in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has proven to be an effective strategy to induce apoptosis in vitro in ovarian tumor cells. Systemic TRAIL administration might be a therapeutic option, since no toxicity was observed in nonhuman primates. In the present study, expression of TRAIL and its apoptosis-inducing death receptors (DR4 and DR5) and inhibitory decoy receptor (DcR1) was studied in normal ovaries and in malignant ovarian tumors before and after chemotherapy to investigate the therapeutic potential of TRAIL. METHODS: DR4, DR5, DcR1, and TRAIL were studied immunohistochemically in 5 normal ovaries, 15 stages I/II, and 26 stages III/IV primary ovarian cancers, including 19 paired tumor samples (pre- and post-chemotherapy). RESULTS: Surface epithelium of normal ovaries expressed TRAIL and its receptors; ovarian stromal cells expressed only DcR1. Of the ovarian cancers, 73% expressed DR4, 51% DR5, 46% DcR1, and 34% TRAIL. Most primary ovarian cancers (88%) expressed at least one death receptor. TRAIL expression was lower in stage III/IV than in stage I/II tumors (P<0.05). In paired samples, DR5 immunostaining was more frequently (P=0.05) and stronger (P<0.01) expressed in residual tumors. CONCLUSION: Early stage tumors expressed TRAIL more frequently than advanced stage tumors. Most primary and residual ovarian tumors expressed at least one TRAIL death receptor, while in residual tumors following chemotherapy, DR5 was more frequently expressed. Therefore, human recombinant TRAIL administration might be an interesting treatment option.

Options for modulation of drug resistance in ovarian cancer.

The objective of this paper is to present an update of mechanisms responsible for drug resistance in ovarian cancer and the possible therapeutic options to modulate this resistance using literature review with emphasis on data acquired in studies comprising ovarian tumor samples. The classic concepts on resistance in ovarian cancer, namely platinum and multidrug resistance, are briefly discussed, followed by a description of more recent insights concerning the role of apoptosis in the development of chemoresistance. A wide variety of mechanisms may be responsible for drug resistance in ovarian cancer. However, a growing body of evidence indicates that defects in the intra- and extracellular apoptotic pathways are an important cause of resistance to cytotoxic agents which opens several new treatment strategies.

Drug resistance-associated markers P-glycoprotein, multidrug resistance-associated protein 1, multidrug resistance-associated protein 2, and lung resistance protein as prognostic factors in ovarian carcinoma.

Intrinsic and/or acquired resistance to chemotherapy is the major obstacle to overcome in the treatment of patients with ovarian carcinoma. The aim of the present study was to investigate the prognostic value of drug resistance-associated proteins P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), canalicular multispecific organic anion transporter (c-MOAT/MRP2), and lung resistance protein (LRP) in ovarian carcinoma. Expression of P-gp, MRP1, MRP2, and LRP was determined by immunohistochemistry of frozen tissue sections of 115 ovarian carcinoma patients and related to clinicopathological factors, response to chemotherapy, and progression-free survival. P-gp expression was observed in 20 of 115 (17%), MRP1 in 51 (44%), MRP2 in 19 (16%), and LRP in 85 (74%) tumors. Expression of MRP1 was related to MRP2 (P<0.0001) and P-gp (P<0.001) expression, whereas LRP expression was more frequently observed in patients with early stage (P<0.01), lower grade (P<0.05), and smaller residual tumor (P<0.05). Early stage (P<0.001), smaller residual tumor (P<0.001), and lower differentiation grade (P<0.05) were related to longer (progression-free) survival. P-gp, MRP1, MRP2, and LRP expression were neither related to response to first-line chemotherapy in 59 evaluable patients nor to progression-free survival in all patients. On multivariate analysis, only stage and residual tumor were independent prognostic factors for survival. In conclusion, in ovarian carcinoma, MRP1 expression is associated with MRP2 and P-gp expression, whereas LRP expression is associated with favorable clinicopathological characteristics. Assessment of P-gp, MRP1, MRP2, or LRP does not allow prediction of response to chemotherapy or survival in ovarian carcinoma.

Heat-shock-protein-27 (hsp27) expression in ovarian carcinoma: relation in response to chemotherapy and prognosis.

Heat-shock protein 27 (hsp27) is one of the small heat-shock proteins. Its expression in ovarian- and breast-cancer cell lines has been associated with resistance to cisplatin and doxorubicin. In addition, hsp27 expression appears to facilitate cellular growth, differentiation and motility. In several human carcinomas, hsp27 expression might also be related to worse prognosis. The aim of this study was to evaluate the prognostic value of hsp27 expression in patients with ovarian carcinoma in relation to their response to chemotherapy and overall survival. Hsp27 expression was assessed by immunohistochemistry in 77 patients with ovarian carcinoma stage IC-IV. All patients received cisplatin- and doxorubicin-based chemotherapy and had long-term follow-up. In 30 patients, paired tumour samples were available, obtained before and after chemotherapy. Hsp27 immunostaining was positive in 86% of patients before and in 72% of patients after chemotherapy. Hsp27 expression was not related to any clinicopathologic factor, including previously determined p53 expression. Univariate analysis showed that, in stage-III and -IV patients, younger age, no residual tumour after first laparotomy, < or = 1 litre ascites, response to first-line chemotherapy and absence of hsp27 expression were associated with longer median progression-free survival. However, in multivariate analysis, only age, ascites and response to chemotherapy retained independent prognostic value.

[Expression and prognostic value of the drug resistance markers P-gp, Mrp1, Mrp2, and Lrp in ovarian carcinoma]. / Espressione e significato prognostico dei markers di chemioresistenza P-gp, Mrp1, Mrp2 e Lrp nei carcinomi ovarici.

BACKGROUND: Intrinsic and/or acquired chemoresistance is the major obstacle to overcome in the treatment of patients with ovarian carcinoma. The aim of the present study was to investigate the prognostic value of drug resistance associated proteins P-glycoprotein (P-gp), multidrug resistance related protein (Mrp1), canalicular multispecific organic anion trans-porter (c-MOAT or Mrp2) and lung resistance protein (Lrp) in ovarian carcinoma. METHODS: Expression of P-gp, Mrp1, Mrp2 and Lrp was determined by immunohistochemistry of frozen tissue sections of 115 ovarian carcinoma patients and associated to clinico-pathological factors, response to chemotherapy and (progression free) survival. RESULTS: Expression of P-gp was observed in 20 out of 115 (17%), Mrp1 in 51 out of 115 (44%), Mrp2 in 19 out of 115 (16%) and Lrp in 85 out 115 (74%) tumors. Expression of Mrp1 was related to Mrp2 (p < 0.0001) and P-gp (p < 0.001) expression, while Lrp expression was more frequently observed in patients with stage I/II versus stage III/IV tumors (p < 0.01), grade I/II versus III tumors (p < 0.05) and residual tumor < 2 cm versus > 2 cm after laparotomy (p < 0.05). Lower stage (p < 0.001), small residual tumor after first laparotomy (p < 0.001) and lower differentiation grade (p < 0.05) were related to longer (progression free) survival. P-gp, Mrp1, Mrp2, and Lrp expression was neither related to response to first line chemotherapy (59 evaluable patients) nor to (progression free) survival (all patients). On multivariate analysis only stage and residual tumor after first laparotomy were independent prognostic factors for (progression free) survival. CONCLUSIONS: In ovarian carcinoma Mrp1 expression is associated with Mrp2 and P-gp expression, while Lrp expression is associated with favorable clinicopathological characteristics. Assessment of P-gp, Mrp1, Mrp2 or Lrp does not allow prediction of response to chemotherapy or (progression free) survival in ovarian carcinoma.

Laparoscopic placement of PAP catheters for intraperitoneal chemotherapy in ovarian carcinoma.

OBJECTIVE: To our report our experience with the laparoscopic placement of peritoneal access ports and to compare it to our experience with placement at laparotomy. METHODS: Patients with advanced ovarian carcinoma were enrolled in a study to receive intraperitoneal paclitaxel in combination with intravenous cisplatin and cyclophosphamide as first- or second-line chemotherapy. Patients had a PAP catheter placed at primary laparotomy or by a separate laparoscopic procedure under general anesthesia. RESULTS: In 13 patients a PAP catheter was placed during primary laparotomy, without complications. Thirteen patients had laparoscopic catheter placing, using routine Veress needle insufflation. After a bowel perforation at insertion of the umbilical trocar had occurred in one patient, due to extensive adhesions, we decided to use only an open laparoscopic procedure. No other procedure or catheter-related complications occurred. CONCLUSION: Laparoscopic-assisted placement of PAP catheters is feasible, but should preferably be performed by an open laparoscopic procedure in this patient population at risk for intraabdominal adhesions.