Non-Inferiority Trials in Surgical Oncology

The classical randomized controlled clinical trial is designed to prove superiority of an investigational therapy over an established therapy or placebo (here referred to as "superiority trial”). Although the randomized controlled superiority trial has its well-grounded role, clinical trials of non-inferiority are equally important in the advance of medical science. Non-inferiority trials test whether a new intervention is as good as a standard treatment with respect to curing the illness (e.g., overall survival) while offering other benefits over the standard therapy, such as lower toxicity, better side-effect profile, improved ease of administration, or reduced costs. The evaluation of non-inferiority is critical in many settings. In surgical oncology, for instance, treatments often combine advantages (e.g., survival benefit) with disadvantages (e.g., high post-operative morbidity due to extensive surgery, considerable toxic effects of an aggressive chemotherapy regimen). The various aspects of different therapeutic strategies may make a treatment decision difficult, requiring a non-inferiority trial to quantify risks and benefits. However, despite their great importance in clinical cancer research, the concept, design, and objectives of non-inferiority trials remain poorly understood in the surgical community. The goal of this review is to discuss the principles, strengths, and challenges of non-inferiority trials and introduce this highly relevant topic to the surgical reader, using examples from the field of surgical oncolog

TAPP or TEP? Population-Based Analysis of Prospective Data on 4,552 Patients Undergoing Endoscopic Inguinal Hernia Repair

Background: Whether total extraperitoneal inguinal hernia repair (TEP) is associated with worse outcomes than transabdominal preperitoneal inguinal hernia repair (TAPP) continues to be a matter of debate. The objective of this large cohort study is to compare outcomes between patients undergoing TEP or TAPP. Methods: Based on prospective data of the Swiss association of laparoscopic and thoracoscopic surgery, all patients undergoing unilateral TEP or TAPP between 1995 and 2006 were included. The following outcomes were compared: conversion rates, intraoperative and postoperative complications, duration of operation. Results: Data on 4,552 patients undergoing TEP (n=3,457) and TAPP (n=1,095) were collected prospectively. Average age and American Society of Anesthesiologists score were similar in the two groups. Patients undergoing TEP had a significantly higher rate of intraoperative complications (TEP 1.9% vs. TAPP 0.9%, p=0.029) and surgical postoperative complications (TEP: 2.3% vs. TAPP: 0.8%, p=0.003). The postoperative length of stay was longer for patients undergoing TAPP (2.9 vs. 2.3days, p=0.002), whereas the duration of the operation was longer for TEP (66.6 vs. 59.0min, p<0.001) and the conversion rate was higher (TEP 1.0% vs. TAPP 0.2%, p=0.011). Conclusions: This study is one of the first population-based analyses comparing TEP and TAPP in a prospective cohort of more than 4,500 patients. Intraoperative and surgical postoperative complications were significantly higher in patients undergoing TEP. TEP is also associated with longer operating times and higher conversion rates. Therefore, on a population-based level, the TAPP technique appears to be superior to the TEP repair in patients undergoing unilateral inguinal hernia repai

Active Antigen-specific Immunotherapy of Melanoma: from Basic Science to Clinical Investigation

Advanced-stage melanoma here dismal prognosis, and novel therapeutic approaches are urgently required. The possibility of taking advantage of the immune response of patients for its treatment has been an appealing concept for almost a century. Only during the last decade, however, has the molecular identification of tumor-associated antigens (TAAs) offered the possibility of vaccinating patients (e.g., active induction of TAA-specific immune responses). Active antigen-specific immunotherapy (AASIT) is currently being investigated in a number of clinical centers as a treatment option for advanced-stage melanoma. A large number of melanoma TAAs have been molecularly characterized and are being used in vaccination trials in various molecular forms and according to various immunization protocols. Here we provide a short overview on melanoma TAAs, the technologies currently in use to induce specific cytotoxic T-lymphocyte (CTL) responses in vivo, and their monitoring. We also propose a tentative AASIT agenda for the next few years, aiming at improving the capacity to induce and monitor TAA-specific immune responses and to verify their clinical effectivenes

Impact of microsatellite status in early-onset colonic cancer

Background The molecular profile of early-onset colonic cancer is undefined. This study evaluated clinicopathological features and oncological outcomes of young patients with colonic cancer according to microsatellite status. Methods Anonymized data from an international collaboration were analysed. Criteria for inclusion were patients younger than 50 years diagnosed with stage I-III colonic cancer that was surgically resected. Clinicopathological features, microsatellite status, and disease-specific outcomes were evaluated. Results A total of 650 patients fulfilled the criteria for inclusion. Microsatellite instability (MSI) was identified in 170 (26.2 per cent), whereas 480 had microsatellite-stable (MSS) tumours (relative risk of MSI 2.5 compared with older patients). MSI was associated with a family history of colorectal cancer and lesions in the proximal colon. The proportions with pathological node-positive disease (45.9 versus 45.6 per cent; P = 1.000) and tumour budding (20.3 versus 20.5 per cent; P = 1.000) were similar in the two groups. Patients with MSI tumours were more likely to have BRAF (22.5 versus 6.9 per cent; P < 0.001) and KRAS (40.0 versus 24.2 per cent; P = 0.006) mutations, and a hereditary cancer syndrome (30.0 versus 5.0 per cent; P < 0.001; relative risk 6). Five-year disease-free survival rates in the MSI group were 95.0, 92.0, and 80.0 per cent for patients with stage I, II, and III tumours, compared with 88.0, 88.0, and 65.0 per cent in the MSS group (P = 0.753, P = 0.487, and P = 0.105 respectively). Conclusion Patients with early-onset colonic cancer have a high risk of MSI and defined genetic conditions. Those with MSI tumours have more adverse pathology (budding, KRAS/BRAF mutations, and nodal metastases) than older patients with MSI cancers. Data on 650 patients aged less than 50 years diagnosed with stage I-III colonic cancer and undergoing surgery with curative intent were collected, and the impact of microsatellite instability (MSI) on clinicopathological features and disease-specific outcomes was assessed. Patients with early-onset disease had a high risk of MSI and defined genetic conditions. Those with MSI tumours had more adverse pathology (budding, KRAS/BRAF mutations, and nodal metastases) than older patients with MSI cancers

The impact of EAES Fellowship Programme:a five-year review and evaluation

Background: The European Association of Endoscopic Surgery (EAES) fellowship programme was established in 2014, allowing nine surgeons annually to obtain experience and skills in minimally invasive surgery (MIS) from specialist centres across the Europe and United States. It aligns with the strategic focus of EAES Education and Training Committee on enabling Learning Mobility opportunities. To assess the impact of the programme, a survey was conducted aiming to evaluate the experience and impact of the programme and receive feedback for improvements.Methods: A survey using a 5-point Likert scale was used to evaluate clinical, education and research experience. The impact on acquisition of new technical skills, change in clinical practice and ongoing collaboration with the host institute was assessed. The fellows selected between 2014 and 2018 were included. Ratings were analysed in percentage; thematic analysis was applied to the free-text feedbacks using qualitative analysis.Results: All the fellows had good access to observing in operating theatres and 70.6% were able to assist. 91.2% participated in educational activities and 23.5% were able to contribute through teaching. 44.1% participated in research activities and 41.2% became an author/co-author of a publication from the host. 97.1% of fellows stated that their operative competency had increased, 94.3% gained new surgical skills and 85.7% was able to introduce new techniques in their hospitals. 74.29% agreed that the clinical experience led to a change in their practices. The most commonly suggested improvements were setting realistic target in clinical and research areas, increasing fellowship duration, and maximising theatre assisting opportunities. Nevertheless, 100% of fellows would recommend the fellowship to their peers.Conclusion: EAES fellowship programme has shown a positive impact on acquiring and adopting new MIS techniques. To further refine the programme, an individualised approach should be adopted to set achievable learning objectives in clinical skills, education and research.</p

Comprehensive Treatment Algorithms of the Swiss Peritoneal Cancer Group for Peritoneal Cancer of Gastrointestinal Origin

Peritoneal cancer (PC) is a dire finding, yet in selected patients, long-term survival is possible. Complete cytoreductive surgery (CRS) together with combination immunochemotherapy is essential to achieve cure. Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are increasingly added to the multimodal treatment. The Swiss Peritoneal Cancer Group (SPCG) is an interdisciplinary group of expert clinicians. It has developed comprehensive treatment algorithms for patients with PC from pseudomyxoma peritonei, peritoneal mesothelioma, gastric, and colorectal origin. They include multimodal neoadjuvant treatment, surgical resection, and palliative care. The indication for and results of CRS HIPEC and PIPAC are discussed in light of the current literature. Institutional volume and clinical expertise required to achieve best outcomes are underlined, while inclusion of patients considered for CRS HIPEC and PIPAC in a clinical registry is strongly advised. The present recommendations are in line with current international guidelines and provide the first comprehensive treatment proposal for patients with PC including intraperitoneal chemotherapy. The SPCG comprehensive treatment algorithms provide evidence-based guidance for the multimodal care of patients with PC of gastrointestinal origin that were endorsed by all Swiss clinicians routinely involved in the multimodal care of these challenging patients