Disappearing colorectal liver metastases in the era of state-of-the-art triple-modality diagnostic imaging.

INTRODUCTION: Systemic therapy can result in disappearance of colorectal liver metastases in up to 40% of patients. This might be an overestimation caused by suboptimal imaging modalities. The aim of this study was to investigate the use of imaging modalities and the incidence, management and outcome of patients with disappearing liver metastases (DLMs). METHODS: This was a retrospective study of consecutive patients treated for colorectal liver metastases at a high volume hepatobiliary centre between January 2013 and January 2015 after receiving induction or neoadjuvant systemic therapy. Main outcomes were use of imaging modalities, incidence, management and longterm outcome of patients with DLMs. RESULTS: Of 158 patients included, 32 (20%) had 110 DLMs. Most patients (88%) had initial diagnostic imaging with contrast enhanced-CT, primovist-MR and FDG-PET and 94% of patients with DLMs were restaged using primovist-MR. Patients with DLMs had significantly smaller metastases and the median initial size of DLMs was 10 mm (range 5-61). In the per lesion analysis, recurrence after "watch & wait" for DLMs occurred in 36%, while in 19 of 20 resected DLMs no viable tumour cells were found. Median overall (51 vs. 28 months, p < 0.05) and progression free survival (10 vs. 3 months, p = 0.003) were significantly longer for patients with DLMs. CONCLUSION: Even state-of-the-art imaging and restaging cannot solve problems associated with DLMs. Regrowth of these lesions occurs in approximately a third of the lesions. Patients with DLMs have better survival.

European Society of Surgical Oncology's strategy for clinical research: Paving the way for a culture of research in cancer surgery.

As part of its mission to promote the best surgical care for cancer patients, the European Society of Surgical Oncology (ESSO) has been developing multiple programmes for clinical research along with its educational portfolio. This position paper describes the different research activities of the Society over the past decade and an action plan for the upcoming five years to lead innovative and high quality surgical oncology research. ESSO proposes to consider pragmatic research methodologies as a complement to randomised clinical trials (RCT), advocates for increased funding and operational support in conducting research and aims to enable young surgeons to be active in research and establish partnerships for translational research activities.

Impact of centralization of services on outcomes in a rare tumour: Retroperitoneal sarcomas.

BACKGROUND AND AIM: The retroperitoneal tumor (RPT) service in the North West costal region of England was centralized in May 2011 by the merger of the Merseyside, Cheshire and Lancashire, Cumbria sarcoma networks. Our aim was to analyze the impact of centralization of services on patient outcomes. METHODS: An analysis from 01/12/2004 to 30/11/2017 was undertaken from prospectively maintained database and electronic patient records; follow-up was until 30/04/2018. This time period encompassed 6.5 years before and after centralization of services took place. Survival analysis was done for Retroperitoneal Sarcomas (RPS) and also compared the impact of centralization. RESULTS: 72 patients (27 men), median age 69 (21-90) years) underwent 95 operations with an intention to excise RPS. Overall there were 52 (54.7%) multi-visceral resections (MVR). 91/95 (95.8%) patients with primary tumors had surgery with a curative (R0/1) intent. 30-day and 90-day operative mortality was 3.2% (n = 3) and 4.2% (n = 4) respectively. The 5-year survival for patients undergoing resection for RPTs was 51.3%. 79 (83.1%) of the resections in this series occurred in the 6.5-years post-centralization with an increase in MVR between the two time points (p < 0.0006). Despite the more radical nature of surgery post-centralization, there was no difference in 5-year survival for RPS patients when compared to pre-centralization, p = 0.575. However the 5-yr survival post-centralization compared favorability to national outcomes. CONCLUSION: Centralization in the management of RPS has resulted in an increase in resection rates and more complex MVRs, without compromising R0/1 resection rates; peri-operative mortality or overall survival.

Precision surgery for colorectal liver metastases: Opportunities and challenges of omics-based decision making.

Precision surgery involves improving patient selection to ensure that surgical intervention that is proven to benefit on a population level is the optimal treatment for each individual patient. For patients with colorectal liver metastases (CRLM), existing prognostic scoring systems rely on well-recognised histopathological features such as size and number of lesions. Advances in preoperative imaging algorithms mean that increasingly low volume disease can be detected, improving assessment of these factors. In addition, novel imaging modalities mean that underlying tumour biology and metabolic behaviour during therapy can be assessed. Molecular analysis of tumours can provide crucial prognostic information, with the critical role of RAS/RAF mutations in prognosis well recognised. The optimal source of tissue for this level of analysis is debated, with good concordance between primary and metastatic lesions for some recognised prognostic factors but marked discrepancies for a variety of other relevant mutations. As well as mutational heterogeneity between primary and metastatic lesions, heterogeneity within tumours and dynamic changes in tumour biology over time present a significant challenge in assessing tumour for prognostic biomarkers. Circulating tumour cells offer one potential method of longitudinal tumour analysis, but are limited by current technologies. This review article summarises some of the key advances in prognostication for patients with resectable colorectal liver metastases, as well as highlighting the potential limitations of such an approach.

PARAGON II - A single arm multicentre phase II study of neoadjuvant therapy using irinotecan bead in patients with resectable liver metastases from colorectal cancer.

PURPOSE: Perioperative chemotherapy confers a 3-year progression free survival advantage following resection of colorectal liver metastases (CRLM), but is associated with significant toxicity. Chemoembolisation using drug eluting PVA microspheres loaded with irinotecan (DEBIRI) allows sustained delivery of drug directly to tumour, maximising response whilst minimising systemic exposure. This phase II single arm study examined the safety and feasibility of DEBIRI before resection of CRLM. METHODS: Patients with resectable CRLM received lobar DEBIRI 1 month prior to surgery, with a radiological endpoint of near stasis. The trial had a primary end-point of tumour resectability (R0 resection). Secondary end-points included safety, pathologic tumour response and overall survival. RESULTS: 40 patients received DEBIRI, with a median dose of 103 mg irinotecan (range 64-175 mg). Morbidity was low (2.5%, CTCAE grade 2) with no evidence of systemic chemotoxicity. All patients proceeded to surgery, with 38 undergoing resection (95%, R0 resection rate 74%). 30-day post-operative mortality was 5% (n = 2), with neither death TACE related. 66 lesions were resected, with histologic major or complete pathologic response seen in 77.3% of targeted lesions. At median follow up of 40.6 months, 12 patients (34.3%) had died of recurrent disease with a median overall survival of 50.9 months. Nominal 1, 3 and 5-year OS was 93, 78 & 49% respectively. CONCLUSIONS: Resection after neoadjuvant DEBIRI for CRLM is feasible and safe. Single treatment with DEBIRI resulted in tumour pathologic response and median overall survival comparable to that seen after systemic neoadjuvant chemotherapy. Registered at clinicaltrials.gov (NCT00844233).

Adherence to early mobilisation: Key for successful enhanced recovery after liver resection.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) has been proven effective in liver surgery. Adherence to the ERAS pathway is variable. This study seeks to evaluate adherence to key components of an ERAS protocol in liver resection, and identify the components associated with successful clinical outcomes. METHOD: All patients undergoing liver resections for two consecutive years were included in our ERAS pathway. Six key components of ERAS included preoperative assessment, nutrition and gastrointestinal function, postoperative analgesia, mobilisation and discharges. Successful accomplishment of ERAS was defined as hospital discharge by postop day (POD) 6. Adherences of these elements were compared between the successful and un-successful groups. RESULTS: During the studied period, 223 patients underwent liver resections, among which 103 had major hepatectomies. N = 147 patients (66%) were discharged within our ERAS protocol target (6 days). On multivariable analysis, sitting out of bed by POD 1 (p < 0.03), walking by POD 3 (p = 0.03), removal of urinary catheter by POD 3 (p < 0.01), and avoiding major complications (p < 0.01) were factors associated with successful completion to our ERAS protocol; whereas advanced age (p = 0.34) and discontinuation of PCA/epidural by POD 3 (p = 0.50) were not significant parameters. There was a significant difference in the length of stay (p < 0.01) following major and minor liver resection, of which the indications for surgery also varied significantly. There was no difference in hospital re-admission rate, and morbidity and mortality between major and minor liver resection. CONCLUSIONS: Facilitating early mobilisation and reducing postoperative complications are keys to successful outcomes of ERAS in liver resection.

Objective assessment of trainee operative experience in a tertiary hepatobiliary unit.

INTRODUCTION: Indicative numbers for completion of training (CCT) in the UK requires 35 upper Gastrointestinal/Hepatobiliary resections and 110 (50 non HPB trainees) cholecystectomies. We aim to identify whether the training experience in our centre meets the CCT requirements for hepatobiliary surgery and compare training opportunities to those in international fellowships. METHODS: We retrospectively reviewed our hospital's operating theatre database for all patients undergoing a liver or gallbladder resection between January 2008 and July 2015 using corresponding procedural codes and consultant name. The cohort was categorized based on case and primary operating surgeon. The training grade of the surgeon was split into junior registrar (ST3/5), senior registrar (ST6/8) and senior fellow (post-CCT). RESULTS: Over a 7.5 year period we performed 2301 hepatobiliary procedures. The senior fellows and senior registrars performed a median of 42 liver resections (range 15-94) and 77 (range 35-110) cholecystectomies as the primary operator in any given 12 month period. The academic output for the unit was 104 over this period, with a median publication rate of 1.34 papers/trainee in any given 12 months. 15/16 senior fellow/senior registrars went on to secure substantive hepatobiliary consultant posts. CONCLUSIONS: Our centre delivers in excess of the required operative volume and clinical competencies for CCT in Hepatobiliary surgery in a 12 month period and exposure of trainees to operative experience is commensurate to the best performing international fellowships.

Common variables in European pancreatic cancer registries: The introduction of the EURECCA pancreatic cancer project.

BACKGROUND: Quality assurance of cancer care is of utmost importance to detect and avoid under and over treatment. Most cancer data are collected by different procedures in different countries, and are poorly comparable at an international level. EURECCA, acronym for European Registration of Cancer Care, is a platform aiming to harmonize cancer data collection and improve cancer care by feedback. After the prior launch of the projects on colorectal, breast and upper GI cancer, EURECCA's newest project is collecting data on pancreatic cancer in several European countries. METHODS: National cancer registries, as well as specific pancreatic cancer audits/registries, were invited to participate in EURECCA Pancreas. Participating countries were requested to share an overview of their collected data items. Of the received datasets, a shared items list was made which creates insight in similarities between different national registries and will enable data comparison on a larger scale. Additionally, first data was requested from the participating countries. RESULTS: Over 24 countries have been approached and 11 confirmed participation: Austria, Belgium, Bulgaria, Denmark, Germany, The Netherlands, Slovenia, Spain, Sweden, Ukraine and United Kingdom. The number of collected data items varied between 16 and 285. This led to a shared items list of 25 variables divided into five categories: patient characteristics, preoperative diagnostics, treatment, staging and survival. Eight countries shared their first data. CONCLUSIONS: A list of 25 shared items on pancreatic cancer coming from eleven participating registries was created, providing a basis for future prospective data collection in pancreatic cancer treatment internationally.

Randomized clinical trial of prehabilitation before planned liver resection.

BACKGROUND: Patients with low fitness as assessed by cardiopulmonary exercise testing (CPET) have higher mortality and morbidity after surgery. Preoperative exercise intervention, or prehabilitation, has been suggested as a method to improve CPET values and outcomes. This trial sought to assess the capacity of a 4-week supervised exercise programme to improve fitness before liver resection for colorectal liver metastasis. METHODS: This was a randomized clinical trial assessing the effect of a 4-week (12 sessions) high-intensity cycle, interval training programme in patients undergoing elective liver resection for colorectal liver metastases. The primary endpoint was oxygen uptake at the anaerobic threshold. Secondary endpoints included other CPET values and preoperative quality of life (QoL) assessed using the SF-36®. RESULTS: Thirty-eight patients were randomized (20 to prehabilitation, 18 to standard care), and 35 (25 men and 10 women) completed both preoperative assessments and were analysed. The median age was 62 (i.q.r. 54-69) years, and there were no differences in baseline characteristics between the two groups. Prehabilitation led to improvements in preoperative oxygen uptake at anaerobic threshold (+1·5 (95 per cent c.i. 0·2 to 2·9) ml per kg per min) and peak exercise (+2·0 (0·0 to 4·0) ml per kg per min). The oxygen pulse (oxygen uptake per heart beat) at the anaerobic threshold improved (+0·9 (0·0 to 1·8) ml/beat), and a higher peak work rate (+13 (4 to 22) W) was achieved. This was associated with improved preoperative QoL, with the overall SF-36® score increasing by 11 (95 per cent c.i. 1 to 21) (P = 0·028) and the overall SF-36® mental health score by 11 (1 to 22) (P = 0·037). CONCLUSION: A 4-week prehabilitation programme can deliver improvements in CPET scores and QoL before liver resection. This may impact on perioperative outcome. REGISTRATION NUMBER: NCT01523353 (https://clinicaltrials.gov).

Rectal cancer with synchronous liver metastases: Do we have a clear direction?

Rectal cancer is a common entity and often presents with synchronous liver metastases. There are discrepancies in management guidelines throughout the world regarding the treatment of advanced rectal cancer, which are further compounded when it presents with synchronous liver metastases. The following article examines the evidence regarding treatment options for patients with synchronous rectal liver metastases and suggests potential treatment algorithms.

Variation in Cardiac Screening and Management of Carcinoid Heart Disease in the UK and Republic of Ireland.

AIMS: Screening for carcinoid heart disease is an important, yet frequently neglected aspect of the management of patients with neuroendocrine tumours (NETs). Screening is advocated in international guidelines, although recommendations on the modality and frequency are poorly defined. We mapped current practice for the screening and management of carcinoid heart disease in specialist NET centres throughout the UK and Republic of Ireland. MATERIALS AND METHODS: Thirty-five NET centres were invited to complete an online questionnaire outlining the size of NET service, patient selection criteria for carcinoid heart disease screening and the modality and frequency of screening. RESULTS: Twenty-eight centres responded (80%), representing over 5500 patients. Eleven per cent of centres screen all patients with any NET, 14% screen only patients with midgut NETs, 32% screen all patients with liver metastases and/or carcinoid syndrome and 43% screen all patients with evidence of syndrome or raised urinary/serum/plasma 5-hydroxyindoleacetic acid (5HIAA). The mode of screening included clinical examination, echocardiography and biomarker measurement: 89% of centres carry out echocardiography, ranging from at initial presentation only (24%), periodically without clearly defined intervals (28%), annually (36%) or less than annually (12%); three centres use a scoring system to report their echocardiograms. Fifty per cent of centres utilise biomarkers for screening (chromogranins, plasma/urinary 5HIAA or most commonly N-terminal pro-brain natriuretic peptide) at varying time intervals. CONCLUSION: There is considerable heterogeneity across the UK and Ireland in multiple aspects of screening and management of carcinoid heart disease.

Blood cultures in acute surgical admissions.

INTRODUCTION: Obtaining blood cultures prior to the administration of antimicrobial therapy was a key recommendation of the 2012 UK Surviving Sepsis Campaign. Few studies have examined the effect blood cultures have on clinical management and there have been none on acute surgical admissions. This retrospective study sought to evaluate the effect of blood cultures on clinical management in acute surgical admissions. METHODS: Data on acute surgical patients admitted between 1 January and 31 December 2012 were extracted from hospital records. Patients given intravenous antibiotics within 24 hours of admission were identified. Data collected included antibiotics administered, blood culture results, admission observations and white blood cell count. Case notes were reviewed for patients with positive cultures to establish whether the result led to a change in management. RESULTS: Of 5,887 acute surgical admissions, 1,346 received intravenous antibiotics within 24 hours and 978 sets of blood cultures were taken in 690 patients. The recommended two sets of cultures were obtained in 246 patients (18%). Patients who had blood cultures taken had the same in-hospital mortality as those who had none taken (3.6% vs 3.5%, p=0.97). Blood cultures were positive in 80 cases (11.6%). The presence of systemic inflammatory response syndrome did not increase positivity rates (12.9% vs 10.3%, p=0.28). Overall, cultures altered management in two patients (0.3%). CONCLUSIONS: Blood cultures rarely affect clinical management. In order to assess the additional value that blood cultures bring to sepsis management in acute surgical admissions, a prospective randomised trial focusing on outcome is needed.

A systematic review of the role of hepatectomy in the management of metastatic renal cell carcinoma.

AIM: This review sought to systematically appraise the literature to establish the role of hepatectomy in treating renal cell carcinoma hepatic metastases. METHOD: Medline and EMBASE were systematically searched for papers reporting survival of patients who underwent hepatectomy for metastatic renal cell carcinoma. RESULTS: Six studies containing 140 patients were included. There were no randomised controlled trials. Perioperative mortality was 4.3%, with reported morbidity between 13 and 30%. Patients with metachronous presentation, and a greater time interval between resection of primary tumour and development of metachronous metastases, appeared to have better survival. There was no difference in survival between patients with solitary and multiple metastases. CONCLUSION: Few patients with hepatic metastases from renal cell carcinoma are suitable for hepatectomy as metastatic disease is usually widespread. Selected patients may experience a survival benefit, but identifying these patients remains difficult.

Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality.

BACKGROUND: Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs. METHODS: Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression. RESULTS: One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l(-1) increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l(-1) increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%. CONCLUSIONS: The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death.

Controversies in the oncosurgical management of liver limited stage IV colorectal cancer.

Colorectal cancer is the fourth most common cancer diagnosis in the world (around 1.2 million diagnoses each year), and accounts for the second highest number of deaths. Over half of patients with colorectal cancer will develop liver metastases, with one quarter presenting in stage IV. There is growing evidence that patients with liver-limited disease represent a distinct biological cohort who will benefit from aggressive management. Only a minority of patients are technically resectable, but around 40% of patients with resected liver limited disease are alive 5 years after diagnosis compared with less than 1% for those with disseminated disease. Novel surgical techniques have been developed to allow more patients to undergo resection and there is also growing recognition that the chemotherapeutic manipulation of irresectable disease may bring some patients to resection with good long-term outcome. Perioperative chemotherapy can also improve long-term outcome through improved biological selection and destruction of occult micrometastases. This review outlines current oncosurgical treatment strategies for liver-limited stage IV colorectal cancer, and discusses some of the controversies surround the management of these complex patients.

Impact of specialized multi-disciplinary approach and an integrated pathway on outcomes in hilar cholangiocarcinoma.

AIMS: To assess the outcomes of patients with hilar cholangiocarcinoma following referral to a specialist multi-disciplinary team. METHODS: Over an 11-year period, patients referred with hilar cholangiocarcinoma were identified from a prospectively maintained registry. Collated data included demographics, operative findings and histo-pathological data. Survival differences and prognostic factors were determined. RESULTS: 345 patients were referred with hilar cholangiocarcinoma, of which 57 (16.5%) patients had surgery. Prior to 2008, of 143 patients referred, only 17 (11.9%) patients underwent surgery, compared to 40 (19.8%) of 202 patients referred from 2008 onwards (p = 0.051). In the surgery group, the majority of patients underwent left hemi-hepatectomy (n = 19). In addition, portal vein (n = 5), hepatic artery (n = 2) and inferior vena cava (n = 3) resections were performed. The R0 resection rate was 73.7%. The morbidity and mortality rates were 59.6% and 14.0%, respectively. The median disease-free survival was 16 (4-101) months. The presence of lymph node metastasis (p = 0.002) was the only predictor of poorer disease-free survival. The 5-year overall survival was 39.5% and was significantly better than that of the palliative group (p < 0.001). CONCLUSIONS: Surgery is the optimal treatment option for patients with hilar cholangiocarcinoma and is associated with better overall survival. Prompt referral to tertiary centres with a core team of clinicians to manage this difficult condition may allow more patients to come to potentially curative surgical resections.

The Liverpool uveal melanoma liver metastases pathway: outcome following liver resection.

AIM: To determine the outcome of patients that underwent liver resection for metastases from uveal melanoma. METHODS: Over a 9-year period, patients referred with uveal melanoma metastases were included. Following treatment of primary uveal melanoma, high-risk patients were offered to be enrolled into a 6-monthly non-contrast liver magnetic resonance imaging (MRI) surveillance. Following detection of liver metastases, patients were staged with a contrast-enhanced (Primovist(®)) liver MRI, computer tomography (CT) of the thorax and staging laparoscopy. RESULTS: 155 patients were referred with uveal melanoma liver metastases, of which 17 (11.0%) patients had liver resection and one patient was treated with percutaneous radio-frequency ablation. The majority of patients undergoing liver resection were treated with multiple metastectomies (n = 8) and three patients had major liver resections. The overall median survival for patients treated with surgery/ablation was 27 (14-90) months, and this was significantly better compared to patients treated palliatively [median = 8(1-30) months, P < 0.001]. Following surgery, 11 patients had recurrent disease [median = 13(6-36) months]. Patients who had undergone a major liver resection had a significantly poorer disease-free survival (P = 0.037). CONCLUSIONS: Patients who can undergo surgical resection for metastatic uveal melanoma have a more favorable survival compared to those who do not.

FDG-PET-CT is effective in selecting patients with poor long term survivals for colorectal liver metastases.

AIMS: Having incorporated PET-CT as part of the staging process for colorectal liver metastases (CRLM) in our unit since 2008, this study aims to evaluate the survival outcomes of all patients managed by our specialist multi-disciplinary team (MDT). METHODS: All patients with colorectal liver metastases referred to a single liver MDT between 2008 and 2011 were examined. Overall survival (OS) for palliative groups due to occult extrahepatic disease detected by PET-CT (A) and those upfront palliative patients with extensive multi-site disease as identified on baseline CT or disease progression during chemotherapy (B), and resected (C) groups were evaluated and compared. Different extents of occult extrahepatic disease as characterised by PET-CT were also compared. RESULTS: 532 patients were included in the study. Median OS for group A (n = 80), B (n = 161) and C (n = 291) were 10.9, 12.0 and 46.7 months, with a 5-year OS approaching 6.5%, 6.1% and 43.0% respectively. There were significant differences in OS of C vs. A & B (p < 0.001). Single compartment metastases had a significant better survival outcomes than non-torso metastases (p = 0.04). CONCLUSION: This is the first report of OS of patients with CRLM excluded from surgery on the basis of PET-CT. We have confirmed that PET-CT is effective in selecting patients with occult extrahepatic disease, which has poor survival outcomes. However, a subgroup with single compartment extrahepatic disease has a better than expected outcome.