John Primrose

Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial

Summary Background Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Methods This parallel-group study reports the trials final data for progression-free survival for a protocol unspecified interim time-point, while overall survival is still being monitored. 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone (182 in perioperative chemotherapy group vs 182 in surgery group). Patients were centrally randomised by minimisation, adjusting for centre and risk score. The primary objective was to detect a hazard ratio (HR) of 0·71 or less for progression-free survival. Primary analysis was by intention to treat. Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152). This trial is registered with ClinicalTrials.gov, number NCT00006479. Findings In the perioperative chemotherapy group, 151 (83%) patients were resected after a median of six (range 1–6) preoperative cycles and 115 (63%) patients received a median six (1–8) postoperative cycles. 152 (84%) patients were resected in the surgery group. The absolute increase in rate of progression-free survival at 3 years was 7·3% (from 28·1% [95·66% CI 21·3–35·5] to 35·4% [28·1–42·7]; HR 0·79 [0·62–1·02]; p=0·058) in randomised patients; 8·1% (from 28·1% [21·2–36·6] to 36·2% [28·7–43·8]; HR 0·77 [0·60–1·00]; p=0·041) in eligible patients; and 9·2% (from 33·2% [25·3–41·2] to 42·4% [34·0–50·5]; HR 0·73 [0·55–0·97]; p=0·025) in patients undergoing resection. 139 patients died (64 in perioperative chemotherapy group vs 75 in surgery group). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 [25%] vs 27/170 [16%]; p=0·04). After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group. Interpretation Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients. Funding Swedish Cancer Society, Cancer Research UK, Ligue Nationale Contre le Cancer, US National Cancer Institute, Sanofi-Aventis.

Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies.

No consensus on the indications for surgical resection of colorectal liver metastases exists. This systematic review has been undertaken to assess the published evidence for its efficacy and safety and to identify prognostic factors. Studies were identified by computerised and hand searches of the literature, scanning references and contacting investigators. The outcome measures were overall survival, disease-free survival, postoperative morbidity and mortality, quality of life and cost effectiveness, and a qualitative summary of the trends across all studies was produced. Only 30 of 529 independent studies met all the eligibility criteria for the review, and data on 30-day mortality and morbidity only were included from a further nine studies. The best available evidence came from prospective case series, but only two studies reported outcomes for all patients undergoing surgery. The remainder reported outcomes for selected groups of patients: those undergoing hepatic resection or those undergoing curative resection. Postoperative mortality rates were generally low (median 2.8%). The majority of studies described only serious postoperative morbidity, the most common being bile leak and associated perihepatic abscess. Approximately 30% of patients remained alive 5 years after resection and around two-thirds of these are disease free. The quality of the majority of published papers was poor and ascertaining the benefits of surgical resection of colorectal hepatic metastases is difficult in the absence of randomised trials. However, it is clear that there is group of patients with liver metastases who may become long-term disease- free survivors following hepatic resection. Such survival is rare in apparently comparable patients who do not have surgical treatment. Further work is needed to more accurately define this group of patients and to determine whether the addition of adjuvant treatments results in improved survival.

Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial

BACKGROUND Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. METHODS This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m(2) (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. FINDINGS Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6-9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68-1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0-83·4) in the perioperative chemotherapy group and 54·3 months (41·9-79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6-58·3) in the perioperative chemotherapy group versus 47·8% (40·3-55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. INTERPRETATION We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. FUNDING Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.

Guidelines for resection of colorectal cancer liver metastases

There has been increasing recognition of the potential benefits of liver resection for colorectal metastases in the UK although this treatment has been established more widely in other Western countries. There are no randomised studies assessing outcome following resection compared with no treatment or other therapeutic modalities in patients with known resectable liver metastases as it is generally considered unethical not to offer surgery for resectable disease. There has been increased interest in more aggressive chemotherapy regimens that have been reported to not only control metastatic disease but also to render some advanced liver metastases resectable.1–4 Furthermore, other new modalities have become available that allow safe ablation of liver metastases without the need for surgical intervention. There is therefore a need to produce clear guidelines on the appropriate management of patients with colorectal cancer who have been shown to have hepatic metastases. These guidelines are intended to address a number of issues: 1. the principles under which patients with hepatic metastases should be managed; 2. which patients who have undergone attempted curative resection of the primary colorectal tumour should be offered surveillance; 3. what investigations are required to determine appropriate management; and 4. which treatment modality is most appropriate in a given clinical context. The process of formulating any clinical guidelines requires a guideline development group, a search strategy with review of the relevant literature, synthesis of evidence (and consensus methods for topics when evidence is lacking), followed by external review. A multidisciplinary meeting with representation from a number of interested bodies involving surgeons, gastroenterologists, oncologists, diagnostic and interventional radiologists, pathologists, general practitioners, clinical nurse specialists, nurse practitioners, and patients was held in the Pelican Centre in Basingstoke on 2–4 October 2003 (see appendix 1). The Appraisal of Guidelines Research and Evaluation (AGREE) instrument was used to provide a framework for assessing …

OncoSurge: A Strategy for Improving Resectability With Curative Intent in Metastatic Colorectal Cancer

PURPOSE Most patients with colorectal liver metastases present to general surgeons and oncologists without a specialist interest in their management. Since treatment strategy is frequently dependent on the response to earlier treatments, our aim was to create a therapeutic decision model identifying appropriate procedure sequences. METHODS We used the RAND Corporation/University of California, Los Angeles Appropriateness Method (RAM) assessing strategies of resection, local ablation and chemotherapy. After a comprehensive literature review, an expert panel rated appropriateness of each treatment option for a total of 1,872 ratings decisions in 252 cases. A decision model was constructed, consensus measured and results validated using 48 virtual cases, and 34 real cases with known outcomes. RESULTS Consensus was achieved with overall agreement rates of 93.4 to 99.1%. Absolute resection contraindications included unresectable extrahepatic disease, more than 70% liver involvement, liver failure, and being surgically unfit. Factors not influencing treatment strategy were age, primary tumor stage, timing of metastases detection, past blood transfusion, liver resection type, pre-resection carcinoembryonic antigen (CEA), and previous hepatectomy. Immediate resection was appropriate with adequate radiologically-defined resection margins and no portal adenopathy; other factors included presence of < or = 4 or > 4 metastases and unilobar or bilobar involvement. Resection was appropriate postchemotherapy, independent of tumor response in the case of < or = 4 metastases and unilobar liver involvement. Resection was appropriate only for > 4 metastases or bilobar liver involvement, after tumor shrinkage with chemotherapy. When possible, resection was preferred to local ablation. CONCLUSION The results were incorporated into a decision matrix, creating a computer program (OncoSurge). This model identifies individual patient resectability, recommending optimal treatment strategies. It may also be used for medical education.

A randomised clinical trial to assess the effect of total enteral and total parenteral nutritional support on metabolic, inflammatory and oxidative markers in patients with predicted severe acute pancreatitis (APACHEE II ≥ 6)

Background: Total enteral nutrition (TEN) within 48 h of admission has recently been shown to be safe and efficacious as part of the management of severe acute pancreatitis. Our aim was to ascertain the safety of immediate TEN in these patients and the effect of TEN on systemic inflammation, psychological state, oxidative stress, plasma glutamine levels and endotoxaemia. Methods: Patients admitted with predicted severe acute pancreatitis (APACHE II score >5) were randomised to total enteral (TEN; n = 8) or total parenteral nutrition (TPN; n = 9). Measurements of systemic inflammation (C-reactive protein), fatigue (visual analogue scale), oxidative stress (plasma thiobarbituric acid-reactive substances), plasma glutamine and anti-endotoxin IgG and IgM antibody concentrations were made on admission and repeated on days 3 and 7 thereafter. Clinical progress was monitored using APACHE II score. Organ failure and complications were recorded. Results: All patients tolerated the feeding regime well with few nutrition-related complications. Fatigue improved in both groups but more rapidly in the TEN group. Oxidative stress was high on admission and rose by similar amounts in both groups. Plasma glutamine concentrations did not change significantly in either group. In the TPN group, 3 patients developed respiratory failure and 3 developed non-respiratory single organ failure. There were no such complications in the TEN group. Hospital stay was shorter in the TEN group [7 (4–14) vs. 10 (7–26) days; p = 0.05] as was time to passing flatus and time to opening bowels [1 (0–2) vs. 2 (1–5) days; p = 0.01]. The cost of TEN was considerably less than of TPN. Conclusion: Immediate institution of nutritional support in the form of TEN is safe in predicted severe acute pancreatitis. It is as safe and as efficacious as TPN and may be beneficial in the clinical course of this disease.

Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors

Background Hepatic metastases develop in approximately 50% of colorectal cancer (CRC) cases. We performed a review and meta-analysis to evaluate survival after resection of CRC liver metastases (CLMs) and estimated the summary effect for seven prognostic factors. Methods Studies published between 1999 and 2010, indexed on Medline, that reported survival after resection of CLMs, were reviewed. Meta-relative risks for survival by prognostic factor were calculated, stratified by study size and annual clinic volume. Cumulative meta-analysis results by annual clinic volume were plotted. Results Five- and 10-year survival ranged from 16% to 74% (median 38%) and 9% to 69% (median 26%), respectively, based on 60 studies. The overall summary median survival time was 3.6 (range: 1.7–7.3) years. Meta-relative risks (95% confidence intervals) by prognostic factor were: node positive primary, 1.6 (1.5–1.7); carcinoembryonic antigen level, 1.9 (1.1–3.2); extrahepatic disease, 1.9 (1.5–2.4); poor tumor grade, 1.9 (1.3–2.7); positive margin, 2.0 (1.7–2.5); >1 liver metastases, 1.6 (1.4–1.8); and >3 cm tumor diameter, 1.5 (1.3–1.8). Cumulative meta-analyses by annual clinic volume suggested improved survival with increasing volume. Conclusion The overall median survival following CLM liver resection was 3.6 years. All seven investigated prognostic factors showed a modest but significant predictive relationship with survival, and certain prognostic factors may prove useful in determining optimal therapeutic options. Due to the increasing complexity of surgical interventions for CLM and the inclusion of patients with higher disease burdens, future studies should consider the potential for selection and referral bias on survival.

Effect of 3 to 5 Years of Scheduled CEA and CT Follow-up to Detect Recurrence of Colorectal Cancer: The FACS Randomized Clinical Trial

IMPORTANCE Intensive follow-up after surgery for colorectal cancer is common practice but is based on limited evidence. OBJECTIVE To assess the effect of scheduled blood measurement of carcinoembryonic antigen (CEA) and computed tomography (CT) as follow-up to detect recurrent colorectal cancer treatable with curative intent. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial in 39 National Health Service hospitals in the United Kingdom; 1202 eligible participants were recruited between January 2003 and August 2009 who had undergone curative surgery for primary colorectal cancer, including adjuvant treatment if indicated, with no evidence of residual disease on investigation. INTERVENTIONS Participants were randomly assigned to 1 of 4 groups: CEA only (n = 300), CT only (n = 299), CEA+CT (n = 302), or minimum follow-up (n = 301). Blood CEA was measured every 3 months for 2 years, then every 6 months for 3 years; CT scans of the chest, abdomen, and pelvis were performed every 6 months for 2 years, then annually for 3 years; and the minimum follow-up group received follow-up if symptoms occurred. MAIN OUTCOMES AND MEASURES The primary outcome was surgical treatment of recurrence with curative intent; secondary outcomes were mortality (total and colorectal cancer), time to detection of recurrence, and survival after treatment of recurrence with curative intent. RESULTS After a mean 4.4 (SD, 0.8) years of observation, cancer recurrence was detected in 199 participants (16.6%; 95% CI, 14.5%-18.7%) overall; 71 of 1202 participants (5.9%; 95% CI, 4.6%-7.2%) were treated for recurrence with curative intent, with little difference according to Dukes staging (stage A, 5.1% [13/254]; stage B, 6.1% [34/553]; stage C, 6.2% [22/354]). Surgical treatment of recurrence with curative intent was 2.3% (7/301) in the minimum follow-up group, 6.7% (20/300) in the CEA group, 8% (24/299) in the CT group, and 6.6% (20/302) in the CEA+CT group. Compared with minimum follow-up, the absolute difference in the percentage of patients treated with curative intent in the CEA group was 4.4% (95% CI, 1.0%-7.9%; adjusted odds ratio [OR], 3.00; 95% CI, 1.23-7.33), in the CT group was 5.7% (95% CI, 2.2%-9.5%; adjusted OR, 3.63; 95% CI, 1.51-8.69), and in the CEA+CT group was 4.3% (95% CI, 1.0%-7.9%; adjusted OR, 3.10; 95% CI, 1.10-8.71). The number of deaths was not significantly different in the combined intensive monitoring groups (CEA, CT, and CEA+CT; 18.2% [164/901]) vs the minimum follow-up group (15.9% [48/301]; difference, 2.3%; 95% CI, -2.6% to 7.1%). CONCLUSIONS AND RELEVANCE Among patients who had undergone curative surgery for primary colorectal cancer, intensive imaging or CEA screening each provided an increased rate of surgical treatment of recurrence with curative intent compared with minimal follow-up; there was no advantage in combining CEA and CT. If there is a survival advantage to any strategy, it is likely to be small. TRIAL REGISTRATION isrctn.org Identifier: 41458548.

Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer

Background:Human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) is associated with improved survival compared with HPV-negative disease. However, a minority of HPV-positive patients have poor prognosis. Currently, there is no generally accepted strategy for identifying these patients.Methods:We retrospectively analysed 270 consecutively treated OPSCC patients from three centres for effects of clinical, pathological, immunological, and molecular features on disease mortality. We used Cox regression to examine associations between factors and OPSCC death, and developed a prognostic model for 3-year mortality using logistic regression analysis.Results:Patients with HPV-positive tumours showed improved survival (hazard ratio (HR), 0.33 (0.21–0.53)). High levels of tumour-infiltrating lymphocytes (TILs) stratified HPV-positive patients into high-risk and low-risk groups (3-year survival; HPV-positive/TILhigh=96%, HPV-positive/TILlow=59%). Survival of HPV-positive/TILlow patients did not differ from HPV-negative patients (HR, 1.01; P=0.98). We developed a prognostic model for HPV-positive tumours using a ‘training’ cohort from one centre; the combination of TIL levels, heavy smoking, and T-stage were significant (AUROC=0·87). This model was validated on patients from the other centres (detection rate 67%; false-positive rate 5.6%; AUROC=0·82).Interpretation:Our data suggest that an immune response, reflected by TIL levels in the primary tumour, has an important role in the improved survival seen in most HPV-positive patients, and is relevant for the clinical evaluation of HPV-positive OPSCC.

Short- and long-term outcomes after laparoscopic and open hepatic resection: systematic review and meta-analysis

BACKGROUND Laparoscopic liver resection (LLR) is now considered a feasible alternative to open liver resection (OLR) in selected patients. Nevertheless studies comparing LLR and OLR are few and concerns remain about long-term oncological equivalence. The present study compares outcomes with LLR vs. OLR using meta-analytical methods. METHODS Electronic literature searches were conducted to identify studies comparing LLR and OLR. Short-term outcomes evaluated included operating time, blood loss, length of hospital stay, peri-operative morbidity and resection margin status. Longer-term outcomes included local and distant recurrence, and overall (OS) and disease-free survival (DFS). Meta-analyses were performed using the Mantel-Haenszel method and Cohens d method, with results expressed as odds ratio (OR) or standardized mean difference (SMD), respectively, with 95% confidence intervals (CI). RESULTS Twenty-six studies met the inclusion criteria with a population of 1678 patients. LLR resulted in longer operating time, but reduced blood loss, portal clamp time, overall and liver-specific complications, ileus and length of stay. No difference was found between LLR and OLR for oncological outcomes. DISCUSSION LLR has short-term advantages and seemingly equivalent long-term outcomes and can be considered a feasible alternative to open surgery in experienced hands.