A multi-centred randomised trial of radical surgery versus adjuvant chemoradiotherapy after local excision for early rectal cancer

Background: Rectal cancer surgery is accompanied with high morbidity and poor long term functional outcome. Screening programs have shown a shift towards more early staged cancers. Patients with early rectal cancer can potentially benefit significantly from rectal preserving therapy. For the earliest stage cancers, local excision is sufficient when the risk of lymph node disease and subsequent recurrence is below 5 %. However, the majority of early cancers are associated with an intermediate risk of lymph node involvement (5-20 %) suggesting that local excision alone is not sufficient, while completion radical surgery, which is currently standard of care, could be a substantial overtreatment for this group of patients. Methods/Study design: In this multicentre randomised trial, patients with an intermediate risk T1-2 rectal cancer, that has been locally excised using an endoluminal technique, will be randomized between adjuvant chemo-radiotherapylimited to the mesorectum and standard completion total mesorectal excision (TME). To strictly monitor the risk of locoregional recurrence in the experimental arm and enable early salvage surgery, there will be additional follow up with frequent MRI and endoscopy. The primary outcome of the study is three-year local recurrence rate. Secondary outcomes are morbidity, disease free and overall survival, stoma rate, functional outcomes, health related quality of life and costs. The design is a non inferiority study with a total sample size of 302 patients. Discussion: The results of the TESAR trial will potentially demonstrate that adjuvant chemoradiotherapy is an oncological safe treatment option in patients who are confronted with the difficult clinical dilemma of a radically removed intermediate risk early rectal cancer by polypectomy or transanal surgery that is conventionally treated with subsequent radical surgery. Preserving the rectum using adjuvant radiotherapy is expected to significantly improve morbidity, function and quality of life if compared to completion TME surgery. Trial registration:NCT02371304, registration date: February 2015

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting

Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. Trial registration:NCT03088150 , January 11th 2017

Exploring industry specific social welfare maximizing rates of water pollution abatement in linked terrestrial and marine ecosystems

Marine ecosystems are severely affected by water pollution originating from coastal catchments, while these ecosystems are of vital importance from an environmental as well as an economic perspective. To warrant sustainable economic development of coastal regions, we need to balance the marginal costs from coastal catchment water pollution abatement and the associated marginal benefits from marine resource appreciation. Water pollution abatement costs are, however, not equal across industries and, consequently, the question arises to what extent marine water quality improvement can efficiently be pursued across industries. In this paper we develop an optimal control approach to explore, analytically as well as quantitatively, social welfare maximizing rates of water pollution abatement across industries. For a case study of Dissolved Inorganic Nitrogen (DIN) water pollution in the Great Barrier Reef region of Australia, water pollution abatement cost functions for two agricultural industries are estimated to, in turn, explore social welfare maximizing rates of water pollution abatement per industry. Results for the Tully-Murray catchment show that DIN water pollution can be reduced by about 25% through the adoption of win-win management practices in the sugarcane industry. However, when taking into account the benefits from reduced DIN water pollution in the downstream marine environment, this study shows that maximum social welfare gains can be obtained by reducing DIN water pollution through a reduction in the agricultural production area in combination with the adoption of lose-win management practices in the sugarcane as well as the grazing industry

Paddock to Reef Monitoring & Evaluation - Economic analysis of ‘ABCD’ cane management for Tully

The economic analysis is based on the A, B, C and D management practice framework for water quality improvement developed in 2007/2008 by the respective natural resource management region. This document focuses on the economic implications of these management practices in the Tully region. A review of the management practices is currently being undertaken to clarify some issues and incorporate new knowledge since the earlier version of the framework. However, this updated version is not yet complete and so the Paddock to Reef project has used the most current available version of the framework for the modelling and economics

Paddock to Reef Monitoring & Evaluation - Economic analysis of ‘ABCD’ cane management for the Burdekin River Irrigation Area.

The economic analysis is based on the A, B, C and D management practice framework for water quality improvement developed in 2007/2008 by the respective natural resource management region. This document focuses on the economic implications of these management practices in the Burdekin River Irrigation Area (BRIA). A review of the management practices is currently being undertaken to clarify some issues and incorporate new knowledge since the earlier version of the framework. However, this updated version is not yet complete and so the Paddock to Reef project has used the most current available version of the framework for the modelling and economics

Paddock to Reef Monitoring and Evaluation - Economic analysis of ‘ABCD’ cane management for the Burdekin Delta region.

The economic analysis is based on the A, B, C and D management practice framework for water quality improvement developed in 2007/2008 by the respective natural resource management region. This document focuses on the economic implications of these management practices in the Burdekin Delta region. A review of the management practices is currently being undertaken to clarify some issues and incorporate new knowledge since the earlier version of the framework. However, this updated version is not yet complete and so the Paddock to Reef project has used the most current available version of the framework for the modelling and economics

Exploring industry specific social welfare maximizing rates of water pollution abatement in linked terrestrial and marine ecosystems

Marine ecosystems are severely affected by water pollution originating from coastal catchments, while these ecosystems are of vital importance from an environmental as well as an economic perspective. To warrant sustainable economic development of coastal regions, we need to balance the marginal costs from coastal catchment water pollution abatement and the associated marginal benefits from marine resource appreciation. Water pollution abatement costs are, however, not equal across industries and, consequently, the question arises to what extent marine water quality improvement can efficiently be pursued across industries. In this paper we develop an optimal control approach to explore, analytically as well as quantitatively, social welfare maximizing rates of water pollution abatement across industries. For a case study of Dissolved Inorganic Nitrogen (DIN) water pollution in the Great Barrier Reef region of Australia, water pollution abatement cost functions for two agricultural industries are estimated to, in turn, explore social welfare maximizing rates of water pollution abatement per industry. Results for the Tully-Murray catchment show that DIN water pollution can be reduced by about 25% through the adoption of win-win management practices in the sugarcane industry. However, when taking into account the benefits from reduced DIN water pollution in the downstream marine environment, this study shows that maximum social welfare gains can be obtained by reducing DIN water pollution through a reduction in the agricultural production area in combination with the adoption of lose-win management practices in the sugarcane as well as the grazing industry