A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment

<p>Abstract</p> <p>Background</p> <p>About 50% of patients with colorectal cancer are destined to develop hepatic metastases. Radical resection is the most effective treatment for patients with colorectal liver metastases offering five year survival rates between 36-60%. Unfortunately only 20% of patients are resectable at time of presentation. Radiofrequency ablation is an alternative treatment option for irresectable colorectal liver metastases with reported 5 year survival rates of 18-30%. Most patients will develop local or distant recurrences after surgery, possibly due to the outgrowth of micrometastases present at the time of liver surgery. This study aims to achieve an improved disease free survival for patients after resection or resection combined with RFA of colorectal liver metastases by adding the angiogenesis inhibitor bevacizumab to an adjuvant regimen of CAPOX.</p> <p>Methods/design</p> <p>The Hepatica study is a two-arm, multicenter, randomized, comparative efficacy and safety study. Patients are assessed no more than 8 weeks before surgery with CEA measurement and CT scanning of the chest and abdomen. Patients will be randomized after resection or resection combined with RFA to receive CAPOX and Bevacizumab or CAPOX alone. Adjuvant treatment will be initiated between 4 and 8 weeks after metastasectomy or resection in combination with RFA. In both arms patients will be assessed for recurrence/new occurrence of colorectal cancer by chest CT, abdominal CT and CEA measurement. Patients will be assessed after surgery but before randomization, thereafter every three months after surgery in the first two years and every 6 months until 5 years after surgery. In case of a confirmed recurrence/appearance of new colorectal cancer, patients can be treated with surgery or any subsequent line of chemotherapy and will be followed for survival until the end of study follow up period as well. The primary endpoint is disease free survival. Secondary endpoints are overall survival, safety and quality of life.</p> <p>Conclusion</p> <p>The HEPATICA study is designed to demonstrate a disease free survival benefit by adding bevacizumab to an adjuvant regime of CAPOX in patients with colorectal liver metastases undergoing a radical resection or resection in combination with RFA.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier NCT00394992</p

Factors influencing the local failure rate of radiofrequency ablation of colorectal liver metastases

BACKGROUND: The prognosis of patients with colorectal cancer is poor, especially when there is distant metastatic disease. Local ablation of tumor by radiofrequency ablation (RFA) has emerged as a safe and effective new treatment modality, but its long-term efficacy may be hindered by renewed local tumor growth at the site of RFA. The objectives of this study were to identify risk factors for local RFA failure and to define exclusion criteria for RFA treatment of colorectal liver metastases. METHODS: A total of 199 lesions in 87 patients were ablated with RFA. Factors influencing local failure rates were identified and compared with data from the literature. RESULTS: The local failure rate was 47.2%, and the average time to local disease progression was 6.5 months. Factors that significantly correlated with increased failure rates were metachronous occurrence of liver metastases, large mean lesion size, and central tumor location. CONCLUSIONS: Because accurate electrode placement is pivotal in achieving adequate tumor necrosis, RFA should not be performed percutaneously when electrode placement is impaired. We suggest that lesions >5 cm and lesions located near great vessels or adjacent organs should be treated with open RFA, thus allowing vascular inflow occlusion and complete mobilization of the liver. Lesions that are difficult to reach by electrodes should be approached by an open procedur

Value of intraoperative radiotherapy in locally advanced rectal cancer

PURPOSE: This study was designed to analyze the results of a multimodality treatment using preoperative radiotherapy, followed by surgery and intraoperative radiotherapy in patients with primary locally advanced rectal cancer. METHODS: Between 1987 and 2002, 123 patients with initial unresectable and locally advanced rectal cancer were identified in our prospective database, containing patient characteristics, radiotherapy plans, operation notes, histopathologic reports, and follow-up details. An evaluation of prognostic factors for local recurrence, distant metastases, and overall survival was performed. RESULTS: All patients were treated preoperatively with a median dose of 50 Gy radiotherapy. Surgery was performed six to ten weeks after radiotherapy. Twenty-seven patients were treated with intraoperative radiotherapy because margins were incomplete o

Synchronous tropical and polar temperature evolution in the Eocene

Palaeoclimate reconstructions of periods with warm climates and high atmospheric CO2 concentrations are crucial for developing better projections of future climate change. Deep-ocean1,2 and high-latitude3 palaeotemperature proxies demonstrate that the Eocene epoch (56 to 34 million years ago) encompasses the warmest interval of the past 66 million years, followed by cooling towards the eventual establishment of ice caps on Antarctica. Eocene polar warmth is well established, so the main obstacle in quantifying the evolution of key climate parameters, such as global average temperature change and its polar amplification, is the lack of continuous high-quality tropical temperature reconstructions. Here we present a continuous Eocene equatorial sea surface temperature record, based on biomarker palaeothermometry applied on Atlantic Ocean sediments. We combine this record with the sparse existing data4-6 to construct a 26-million-year multi-proxy, multi-site stack of Eocene tropical climate evolution. We find that tropical and deep-ocean temperatures changed in parallel, under the influence of both long-term climate trends and short-lived events. This is consistent with the hypothesis that greenhouse gas forcing7,8, rather than changes in ocean circulation9,10, was the main driver of Eocene climate. Moreover, we observe a strong linear relationship between tropical and deep-ocean temperatures, which implies a constant polar amplification factor throughout the generally ice-free Eocene. Quantitative comparison with fully coupled climate model simulations indicates that global average temperatures were about 29, 26, 23 and 19 degrees Celsius in the early, early middle, late middle and late Eocene, respectively, compared to the preindustrial temperature of 14.4 degrees Celsius. Finally, combining proxy- and model-based temperature estimates with available CO2 reconstructions8 yields estimates of an Eocene Earth system sensitivity of 0.9 to 2.3 kelvin per watt per square metre at 68 per cent probability, consistent with the high end of previous estimates11