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Background At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. Methods In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3–4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. Discussion The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. Trial registration clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.

BackgroundObservational studies have supported the practice of offering minimally invasive interval debulking surgery after neoadjuvant chemotherapy for well-selected patients with advanced epithelial ovarian cancer. However, there are no prospective randomized data comparing the oncologic efficacy of minimally invasive and open interval debulking surgery in epithelial ovarian cancer.Primary objectiveThe primary objective of this study is to examine whether minimally invasive surgery is non-inferior to laparotomy in terms of disease-free survival in women with advanced stage epithelial ovarian cancer that responded to three or four cycles of neoadjuvant chemotherapy.Study hypothesisWe hypothesize that in patients who had a complete or partial response to neoadjuvant chemotherapy, minimally invasive interval debulking surgery is not inferior to laparotomy.Trial designThe Laparoscopic cytoreduction After Neoadjuvant ChEmotherapy (LANCE) trial is an international, prospective, randomized, multicenter, non-inferiority phase III trial to compare minimally invasive surgery vs laparotomy in women with advanced stage high-grade epithelial ovarian cancer that had a complete or partial response to three or four cycles of neoadjuvant chemotherapy and normalization of CA-125. The first 100 participants will be enrolled into a pilot lead-in to determine feasibility. The study will be considered feasible and will continue to Phase III under the following conditions: the accrual rate reaches at least 80% of the target rate after all pilot sites are open; the crossover rate in the minimally invasive group is less than 25%; and the difference of complete gross resection between the minimally invasive and open group is less than 20%. If the study is determined to be feasible, all remaining participants will be enrolled into the Phase III stage.Major inclusion/exclusion criteriaPatients with stage IIIC or IV high-grade epithelial ovarian, primary peritoneal or fallopian tube carcinoma who had a complete or partial response to three or four cycles of neoadjuvant chemotherapy based on imaging and normalization of CA-125 will be enrolled. Patients with evidence of tumor not amenable to minimally invasive resection on pre-operative imaging will be excluded.Primary endpointThe primary endpoint is non-inferiority of disease-free survival in minimally invasive vs laparotomic interval debulking surgery.Sample sizeTo demonstrate non-inferiority with a margin of 33% in the hazard ratio (HR=1.33), 549 patients will be randomized.

BackgroundPrimary cytoreductive surgery followed by chemotherapy has been considered standard management for patients with advanced ovarian cancer over decades. An alternative approach of interval debulking surgery following neoadjuvant chemotherapy was subsequently reported by two randomized phase III trials (EORTC‐GCG, CHORUS), which were criticized owing to important limitations, especially regarding the rate of complete resection.Primary ObjectiveTo clarify the optimal timing of surgical therapy in advanced ovarian cancer.Study HypothesisPrimary cytoreductive surgery is superior to interval cytoreductive surgery following neoadjuvant chemotherapy for overall survival in patients with advanced ovarian cancer.Trial DesignTRUST is an international open, randomized, controlled multi-center trial investigating overall survival after primary cytoreductive surgery versus neoadjuvant chemotherapy and subsequent interval cytoreductive surgery in patients with FIGO stage IIIB–IVB ovarian, tubal, and peritoneal carcinoma. To guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (eg, ≥50% complete resection rate in upfront surgery for FIGO IIIB–IVB patients, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST quality committee delegates. Patients in the primary cytoreductive surgery arm undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas patients in the interval cytoreductive surgery arm undergo 3 cycles of neoadjuvant chemotherapy after histologic confirmation of the disease, followed by interval cytoreductive surgery and subsequently, 3 cycles of platinum-based chemotherapy. The intention of surgery for both groups is complete tumor resection according to guideline recommendations.Major Inclusion/Exclusion CriteriaMajor inclusion criteria are suspected or histologically confirmed, newly diagnosed invasive epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma FIGO stage IIIB–IVB (IV only if resectable metastasis). Major exclusion criteria are non-epithelial ovarian malignancies and borderline tumors; prior chemotherapy for ovarian cancer; or abdominal/pelvic radiotherapy.Primary EndpointOverall survival.Sample Size772 patients.Estimated Dates for Completing Accrual and Presenting ResultsAccrual completion approximately mid-2019, results are expected after 5 years' follow-up in 2024.Trial Registration NCT02828618.

BackgroundThe impact of blood transfusion on ovarian cancer survival is uncertain.ObjectiveTo investigate whether peri-operative blood transfusion negatively impacted progression-free survival, overall survival, and quality of life in patients with advanced ovarian cancer.MethodsWe performed an ancillary analysis of the European Organization for Research and Treatment (EORTC) 55971 phase III trial, in which patients were randomized to primary debulking surgery versus neoadjuvant chemotherapy. Patients included in the per-protocol analysis were categorized by receipt of a transfusion.Results612 of 632 (97%) of patients had adequate data for analysis. Of those, 323 (53%) received a transfusion. The transfusion cohort was more likely to have had better Word Health Organization (WHO) performance status, serous histology, undergone primary debulking surgery, and received more aggressive surgery, with higher rates of no gross residual disease. Median overall survival was 34.0 vs 35.2 months in the no transfusion and transfusion cohorts (p=0.97). The adjusted HR for death was 1.18 (95% CI 0.94 to 1.48) in favor of the transfusion cohort. Median progression-free survival was 13.6 vs 12.6 months in the no transfusion and transfusion cohorts (p=0.96). The adjusted HR for progression was 1.14 (95% CI 0.91 to 1.43). There were no significant differences in global quality of life, fatigue, dyspnea, or physical functioning between the two cohorts at baseline or at any of the four assessment times. Grade 3 and 4 surgical site infections were more common in the transfusion cohort.ConclusionTransfusion did not negatively impact progression-free survival or overall survival; however, it was associated with increased peri-operative morbidity without improvements in quality of life.

BackgroundA Total Retroperitoneal en bloc resection Of Multivisceral-Peritoneal packet (TROMP operation) is a no-touch isolation technique in a retroperitoneal space to resect the parietal peritoneum and the affected organs in advanced ovarian cancer. The study prescribed and analysed the results of this novel technique for primary cytoreductive surgery.MethodsThe study included 208 patients operated between January 2015 and December 2017 in Charité, Berlin. The TROMP operation was performed in 58 patients, whereas the other 150 patients were operated with the conventional cytoreductive method.ResultsThe complete tumor resection rate accounts for 87.9% in TROMP group and 61.3% in the conventional surgery group. (p=0.001). This difference was even stronger in the sub-group of very advanced stages (T3c+T4) (85.1% of TROMP group and in only 53.1% in the conventional surgery group, p=0.001). The duration of the primary cytoreductive surgery was about 33 minutes shorter in TROMP group (median: 335 minutes vs 368 minutes; TROMP vs conventional, respectively) in spite of the fact that the most advanced cytoreductive procedures were performed statically significant more in TROMP operation arm in comparison with the conventional surgery arm. There was no statistically significant difference between the groups regarding the postoperative complication, blood loss or the length of stay in intensive care unit.ConclusionTotal retroperitoneal en bloc resection of multivisceral-peritoneal packet (TROMP operation) is a feasible and very effective technique of surgical therapy in advanced ovarian cancer. This technique increased the complete tumor resection rate to 87.9% without increasing the blood loss, postoperative complications or the duration of surgery. A prospective randomized study is advised to validate these results.

BackgroundOvarian cancer with extensive metastatic disease involving pelvic structures often requires rectosigmoid resection for complete gross resection; however, it is associated with increased surgical morbidity. There are limited data, and none in ovarian cancer, on near-infrared assessment of perfusion in rectosigmoid resections with anastomosis.Primary ObjectiveTo compare the rate of pelvic complications (pelvic abscesses, anastomotic leaks, and infections) within 30 days of surgery with and without near-infrared assessment of perfusion at time of rectosigmoid resection and re-anastomosis in patients undergoing cytoreductive surgery for ovarian cancer.Study HypothesisWe hypothesize the use of near-infrared technology (intravenous indocyanine green and endoscopic near-infrared fluorescence imaging), compared with standard intra-operative assessment, to evaluate anastomotic perfusion at time of rectosigmoid resection and re-anastomosis will result in lower rates of post-operative pelvic complications.Trial DesignThis is a planned multicenter randomized controlled trial. Patients who undergo rectosigmoid resection as part of their ovarian cytoreductive surgery will be randomized 1:1 to standard assessment of anastomosis with the surgeon’s usual technique (control arm) or assessment with near-infrared angiography using indocyanine green and endoscopic fluorescence imaging (experimental arm). Randomization will occur after rectosigmoid resection has been completed and the surgeon declares their plan to create a diverting ostomy. Randomization will be stratified by plan for diverting ostomy.Major Inclusion/Exclusion CriteriaMain inclusion criteria include patients with primary or recurrent ovarian, fallopian tube, or primary peritoneal cancer who are scheduled for cytoreductive surgery with suspected need for low-anterior rectosigmoid resection.Primary EndpointRate of 30-day post-operative pelvic complications.Sample Size310 (155 per arm)Estimated Dates for Completing Accrual and Presenting ResultsQ2 2027 and Q4 2027, respectively.Trial Registration NCT04878094.

Abstract Lessons learned Intravenous paricalcitol did not improve the efficacy of pembrolizumab, likely related to the short half-life. Background Immunotherapy has limited benefit in the treatment of advanced pancreatic cancer with the tumor microenvironment playing a key role in immune resistance. In preclinical studies, vitamin D receptor (VDR) agonists have been shown to sensitize pancreatic tumors to PD-1 blockade. Methods This was a randomized, double-blinded, placebo-controlled, phase II trial to evaluate pembrolizumab with or without paricalcitol as maintenance therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants were ≥18 years; histologically or cytologically confirmed metastatic PDAC showing no disease progression after frontline systemic therapy, and achieving maximal cytoreduction (eg, with no further antitumor effect), Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; adequate organ function. Study treatment included: pembrolizumab 200 mg IV every 3 weeks and either paricalcitol 25 mcg IV 3 times per week or placebo. The primary objective was to evaluate 6-month progression free survival (PFS). Secondary objectives include evaluating the toxicity of the combination and overall survival (OS). Results There was no significant difference in 6-month PFS, median PFS, median OS, nor treatment-related AEs between the 2 arms. Conclusions and relevance Paricalcitol did not improve the efficacy of pembrolizumab likely related to its short half-life of only 5-7 hours. Microbiome analysis revealed significant difference between long-term (>12 weeks) and short-term (<12 weeks) survival groups across treatment arms. Modulation of the tumor microenvironment will likely require more sustained VDR activity. Trial Registration Clinicaltrials.gov, ID: NCT03331562.

OBJECTIVESThe purpose of this study was to compare the outcomes of gynecologic oncology patients treated in the community hospital setting either under the auspices of an enhanced recovery after surgery (ERAS) protocol or in accordance with physician discretion. METHODSWe retrospectively evaluated a series of consecutive gynecologic oncology patients who were managed via open surgery in coincident with an ERAS pathway from January 2015 to December 2016. They were compared with a historical open surgery cohort who was treated from November 2013 to December 2014. The primary clinical end points encompassed hospital length of stay, hospital costs, and patient readmission rates. RESULTSThere were 86 subjects accrued in the ERAS group and 91 patients in the historical cohort. The implementation of ERAS occasioned a greater than 3-day mean reduction in hospital stay (8.04 days for the historical group vs 4.88 days for the ERAS subjects; P = 0.001) and correspondingly diminished hospital costs ($11,877.47/patient vs $9305.26/patient; P = 0.04). Moreover, there were 2 readmissions (2.3%) in the ERAS group compared with 4 (4.4%) in the historical cohort (P = 0.282). CONCLUSIONSThe results from our investigation suggest that adhering to an ERAS protocol confers beneficial hospital length of stay and hospital cost outcomes, without compromising patient readmission rates. Additional investigation scrutinizing the impact of ERAS enactment with more defined study variables in a larger, randomized setting is warranted.

BackgroundIn patients treated for advanced ovarian cancer not suitable for complete primary surgery, interval surgery after three courses of neoadjuvant chemotherapy has been considered standard management since the EORTC randomized trial published in 2010. An alternative approach with delayed surgery after six courses of neoadjuvant chemotherapy was reported in retrospective series.Primary ObjectivesTo assess the efficacy on progression free survival of interval cytoreduction surgery after three cycles of neoadjuvant chemotherapy compared with delayed surgery after six cycles of neoadjuvant chemotherapy.Study HypothesisIn women with ovarian cancer not suitable for primary surgical cytoreduction, surgery after six cycles of neoadjuvant chemotherapy will prove better disease-free survival than cytoreductive surgery after only three cycles.Trial DesignCHRONO is a multicenter, randomized phase III trial. After three courses of neoadjuvant chemotherapy, eligible patients will be randomized (1:1) to either completion surgery followed by an additional five cycles of chemotherapy (control arm) or an additional three cycles of neoadjuvant chemotherapy followed by completion surgery and then two additional cycles of chemotherapy (experimental arm). Patients in both groups will receive eight total cycles of chemotherapy.Major Inclusion/Exclusion CriteriaThe main inclusion criteria are histologically confirmed epithelial high-grade serous or endometrioid ovarian cancer, documented FIGO stage IIIB–IVA unsuitable for complete primary surgery but considered resectable after three courses of neoadjuvant chemotherapy. The main exclusion criteria are mucinous, clear cell, carcinosarcoma, or low-grade serous histologies.Primary EndpointThe primary endpoint is progression-free survival.Sample Size210 eligible patientsEstimated Dates for Completing Accrual and Presenting ResultsThe estimated date for completing accrual will be Q2 2023. The estimated date for presentation of the first results is Q3 2028.Trial Registration Number NCT03579394.

ObjectiveInformation on the benefits of enhanced recovery after surgery (ERAS) when applied to advanced ovarian cancer() is minimal. The study objectives were to prospectively evaluate whether the implementation of ERAS in AOC patients improves post-operative recovery, and reduces the length of hospital stay (LOHS), without increasing the readmission rate or surgery-related complications; and to investigate ERAS protocol compliance.MethodsThis was a prospective interventional study carried out at a single university teaching hospital. Patients undergoing laparotomy for advanced ovarian cancer (stages IIb–IV) from March 2017 to February 2018 were managed using an ERAS protocol. The conventional management (CM) period extended from January 2016 to December 2016. The primary outcome was reduction in LOHS. Secondary outcomes were ERAS protocol compliance, incidence of post-operative complications, and readmission rate.ResultsThe CM and ERAS groups each comprised 45 patients. Both the groups were comparable in terms of clinicopathological and operative characteristic. Median LOHS of the full cohort, primary debulking cohort, interval debulking cohort, staging surgery cohort (all 6 vs 4 days; p<0.001), and complex cytoreductive surgery cohort (5 vs 4 days; p=0.019) were significantly reduced in the ERAS group. The overall compliance for the ERAS protocol was 90.6%. Occurrence of moderate or severe (17.8% vs 0%; p=0.003) and ≥grade 2 extended Clavein-Dindo complications (22.2% vs 0%; p=0.001); and hospital stay due to occurrence of complications (31.1% vs 2.2%; p<0.001) were also significantly reduced in the ERAS group. There was no difference in the 30-day readmission rates.ConclusionThe results from our investigation suggest that the ERAS program can be successfully implemented in advanced ovarian cancer patients even in low-resource settings provided the program is modified to meet local needs so as not to increase healthcare costs.