[Show abstract][Hide abstract] ABSTRACT: Background:
In locally advanced rectal cancer (LARC) preoperative chemoradiation (CRT) is the standard of care, but the risk of local recurrence is low with good quality total mesorectal excision (TME), although many still develop metastatic disease. Current challenges in treating rectal cancer include the development of effective organ-preserving approaches and the prevention of subsequent metastatic disease. Neoadjuvant systemic chemotherapy (NACT) alone may reduce local and systemic recurrences, and may be more effective than postoperative treatments which often have poor compliance. Investigation of intensified NACT is warranted to improve outcomes for patients with LARC. The objective is to evaluate feasibility and efficacy of a four-drug regimen containing bevacizumab prior to surgical resection.
This is a multi-centre, randomized phase II trial. Eligible patients must have histologically confirmed LARC with distal part of the tumour 4-12 cm from anal verge, no metastases, and poor prognostic features on pelvic MRI. Sixty patients will be randomly assigned in a 1:1 ratio to receive folinic acid + flurourcil + oxaliplatin (FOLFOX) + bevacizumab (BVZ) or FOLFOX + irinotecan (FOLFOXIRI) + BVZ, given in 2 weekly cycles for up to 6 cycles prior to TME. Patients stop treatment if they fail to respond after 3 cycles (defined as ≥ 30 % decrease in Standardised Uptake Value (SUV) compared to baseline PET/CT). The primary endpoint is pathological complete response rate. Secondary endpoints include objective response rate, MRI tumour regression grade, involved circumferential resection margin rate, T and N stage downstaging, progression-free survival, disease-free survival, overall survival, local control, 1-year colostomy rate, acute toxicity, compliance to chemotherapy.
In LARC, a neoadjuvant chemotherapy regimen - if feasible, effective and tolerable would be suitable for testing as the novel arm against the current standards of short course preoperative radiotherapy (SCPRT) and/or fluorouracil (5FU)-based CRT in a future randomised phase III trial.
Clinical trial identifier BACCHUS: NCT01650428.
BMC Cancer 10/2015; 15(1):764. DOI:10.1186/s12885-015-1764-1 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Colorectal cancer (CRC) is a major cause of mortality and morbidity. The impact of inflammatory biomarkers (C-reactive protein etc.) on CRC is increasingly studied including systemic neutrophil-to-lymphocyte ratio (NLR) as they seem to predict outcome.
All patients who underwent curative resection for CRC from 2000 to 2004 at Leeds Teaching Hospitals NHS Trust had pre-operative NLR calculated. Demographic, histopathological and survival data were collected. Tissue microarrays were created and stained to determine the mismatch repair (MMR) protein status of each tumour. Local lymphocytic response to the tumour was assessed and graded.
About 358 patients were eligible. Of these 88 had an NLR ⩾5, which predicted lower overall survival and greater disease recurrence. A high NLR is associated with higher pT- and pN-stage and a greater incidence of extramural venous invasion. MMR protein status was not associated with NLR. A pronounced lymphocytic reaction at the invasive margin (IM) indicated a better prognosis and was associated with a lower NLR.
Neutrophil-to-lymphocyte ratio predicts disease-free and overall survival and is associated with a more aggressive tumour phenotype. The lymphocytic response to tumour at the IM is associated with NLR however dMMR is not. Neutrophil-to-lymphocyte ratio is a cheap, easy-to-access test that predicts outcome in CRC.British Journal of Cancer advance online publication, 30 June 2015; doi:10.1038/bjc.2015.87 www.bjcancer.com.
British Journal of Cancer 06/2015; 113(2). DOI:10.1038/bjc.2015.87 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Excellent anatomical knowledge of the rectum and surrounding structures is essential for total mesorectal excision (TME). Denonviliers' fascia (DVF) has been frequently studied, though the optimal anterior plane in TME is still disputed. The relationship of the lateral edges of DVF to the autonomic nerves and mesorectal fascia is unclear. We studied whole mout microscopic sections of en-bloc cadaveric pelvic exenteration and describe implications for TME. Methods Four donated human adult cadaveric specimens (two males, two females) were obtained from the Leeds GIFT Research Tissue Programme. Paraffin-embedded mega blocks were produced and serially sectioned at 50 and 250 μm intervals. Sections were stained with haematoxylin & eosin, Masson's trichrome and Millers' elastin. Additionally, a series of eleven human fetal specimens (embryonic age of 9-20 weeks) were studied. Results DVF consisted of multiple fascial condensations of collagen and smooth muscle fibres and was indistinguishable from the anterior mesorectal fascia and the prostatic fascia or posterior vaginal wall. The lateral edges of DVF appeared fan-shaped and the most posterior part was continuous with the mesorectal fascia. Fasciae were not identified in fetal specimens. Conclusion DVF is adherent to and continuous with the mesorectal fascia. Optimal surgical dissection during TME should be carried out anterior to DVF to ensure radical removal, particularly for anterior tumours. Autonomic nerves are at risk, but can be preserved by closely following the mesorectal fascia along the anterolateral mesorectum. The lack of evident fasciae in fetal specimens suggested that these might be formed in later developmental stages.
European Journal of Surgical Oncology 04/2015; 41(6). DOI:10.1016/j.ejso.2015.03.224 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pathologists closely interact with all members of the colorectal multidisciplinary team in order to improve patient outcomes. Consistent high-quality reporting is essential to communicate all relevant prognostic information so that the patient undergoes optimal management. Additional feedback on the interpretation of preoperative imaging, effectiveness of preoperative treatment and quality of surgery is now integral to the pathology report. For rectal cancer, the status of the circumferential resection margin and quality of the mesorectal dissection are already widely reported. However, evidence is accumulating for the benefi t of pathological feedback on the quality of the sphincter dissection in abdominoperineal excision (APE) specimens and the mesocolic dissection for colon cancer. This chapter will address current best practice for the pathological approach to TME, APE and colon cancer specimens.
[Show abstract][Hide abstract] ABSTRACT: Background
Complete mesocolic excision with central vascular ligation (CME) produces an optimal colonic cancer specimen. The ability of expert laparoscopic surgeons to produce equivalent specimens is unknown.Methods
Fresh specimen photographs and clinicopathological data from patients undergoing laparoscopically assisted CME at St Mark's Hospital, Harrow, were submitted for independent pathological review. Surgery was performed by a mixture of consultant specialists and trainees under consultant specialist supervision, between February 2010 and July 2011. The planes of surgery were graded and tissue morphometry was performed using standard methods. The results were compared with published data from open CME and non-CME surgery.ResultsIn total, 69 patients were identified, and in 96 per cent resection was performed completely or partially by surgical trainees. Laparoscopic CME produced a similar specimen to open CME. The laparoscopic mesocolic plane resection rate was similar to that for open surgery (90 versus 88 per cent). The distance between the bowel wall and site of vascular division was similar for laparoscopic and open right-sided CME (92 versus 95 mm respectively). The corresponding values for left-sided CME were also similar (103 versus 107 mm). Compared with values from two non-CME series, laparoscopic CME had a higher mesocolic plane rate (90 versus 40 and 48 per cent), and resected more tissue between the bowel wall and the vascular division (right-sided: 92 versus 72 and 76 mm; left-sided: 103 versus 85 and 70 mm). The lymph node yield remained low following laparoscopic CME compared with open CME (median 18 versus 32; P < 0·001) and identical to that of non-CME surgery (median 18).Conclusion
Laparoscopic CME can be performed to the same standard as open surgery by supervised trainees. However, this did not increase the lymph node yield.
British Journal of Surgery 08/2014; 101(11). DOI:10.1002/bjs.9602 · 5.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.
Patients and Methods:
Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.
A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.
Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.
British Journal of Cancer 04/2014; 110(9). DOI:10.1038/bjc.2014.182 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In stage III colon cancer oxaliplatin/5FU-based adjuvant chemotherapy (FOLFOX) improves disease-free survival (DFS) and overall survival (OS). In rectal adenocarcinoma following neoadjuvant chemoradiation (CRT), we examined the benefit of postoperative adjuvant capecitabine and oxaliplatin (XELOX) chemotherapy.
Eligible patients were randomly assigned following fluoropyrimidine-based CRT and curative resection to observation or 6 cycles of XELOX. The primary endpoint was DFS; secondary endpoints were acute toxicity and OS. 390 patients were required in each arm, to detect an improvement in 3-year DFS from 40% to 50.5%, with 85% power and two-sided 5% significance level.
The study closed prematurely in 2008 because of poor accrual. Only 113 patients were randomly assigned to either observation (n=59) or XELOX (n=54). Compliance was poor, 93% allocated chemotherapy started and 48% completed 6 cycles. Protocolised dose reductions in XELOX were 39%, and levels of G3/G4 toxicity 40%. After a median follow-up of 44.8 months, 16 patients (27%) in the observation arm had relapsed or died compared with 12 patients (22%) in XELOX. The 3-year DFS rate was 78% with XELOX and 71% with observation (hazard ratio [HR] for DFS=0.80; 95% CI: 0.38-1.69; p=0.56). The 3-year OS for XELOX and observation were 89% and 88% respectively (HR for OS=1.18; 95% CI: 0.43-3.26; p=0.75).
The observed improvement in DFS for adjuvant XELOX and similar OS were not statistically significant, as expected given the small number of patients and consequent low power. Our findings support the need for trials that test the role of neoadjuvant chemotherapy.
Annals of Oncology 04/2014; 25(7). DOI:10.1093/annonc/mdu147 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been evident for a while that the result after resection for colon cancer may not have been optimal. Several years ago, this was showed by some leading surgeons in the USA but a concept of improving results was not consistently pursued. Later, surgeons in Europe and Japan have increasingly adopted the more radical principle of complete mesocolic excision (CME) as the optimal approach for colon cancer. The concept of CME is a similar philosophy to that of total mesorectal excision for rectal cancer and precise terminology and optimal surgery are key factors.
There are three essential components to CME. The main component involves a dissection between the mesenteric plane and the parietal fascia and removal of the mesentery within a complete envelope of mesenteric fascia and visceral peritoneum that contains all lymph nodes draining the tumour area (Hohenberger et al., Colorectal Disease 11:354-365, 2009; West et al., J Clin Oncol 28:272-278, 2009). The second component is a central vascular tie to completely remove all lymph nodes in the central (vertical) direction. The third component is resection of an adequate length of bowel to remove involved pericolic lymph nodes in the longitudinal direction.
The oncological rationale for CME and various technical aspects of the surgical management will be explored.
The consensus conference agreed that there are sound oncological hypotheses for a more radical approach than has been common up to now. However, this may not necessarily apply in early stages of the tumour stage. Laparoscopic resection appears to be equally well suited for resection as open surgery.
International Journal of Colorectal Disease 01/2014; 29(4). DOI:10.1007/s00384-013-1818-2 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Care for patients with colon and rectal cancer has improved in the last 20 years; however, a considerable variation still exists in cancer management and outcome between European countries. Large variation is also apparent between national guidelines and patterns of cancer care in Europe. Therefore, EURECCA, which is the acronym of European Registration of Cancer Care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012, the first multidisciplinary consensus conference about cancer of the colon and rectum was held. The expert panel consisted of representatives of European scientific organizations involved in cancer care of patients with colon and rectal cancer and representatives of national colorectal registries.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 01/2014; 464(2). DOI:10.1007/s00428-013-1534-x · 2.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Although family history is well established to be a risk factor for developing colorectal cancer (CRC), much less is known about its impact on patient survival. This study aimed to link CRC patient data from the National Study of Colorectal Cancer Genetics (NSCCG) to the National Cancer Data Repository (NCDR) to examine the relationship between family history and the characteristics and outcomes of CRC.
All eligible NSCCG patients underwent a matching process to the NCDR using combinations of their personal identifiers. The characteristics and survival of CRC patients with and without a family history of CRC were compared.
Of the 10 937 NSCCG patients eligible to be matched into the NCDR, 10 782 (98.6%) could be fully linked. There were no significant differences between those with and without a family history of CRC (defined as having at least one affected first-degree relative) in terms of age, sex, tumour stage at diagnosis, presence of multiple cancers, mode of presentation to hospital and surgical management, although patients with familial CRC were more likely to have right-sided tumours (P<0.01). The survival of patients with familial CRC was significantly better than those with sporadic CRC (HR 0.89, 95%CI: 0.81–0.98, P=0.02).
We have demonstrated that it is possible to robustly match patients recruited into the NSCCG into the NCDR and, by using this record linkage, enable genetic data to be related to CRC phenotype, clinical management and outcome. This study provides evidence that a family history of CRC is associated with better survival after a diagnosis of CRC.
British Journal of Cancer 03/2013; DOI:10.1038/bjc.2013.91 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Activation of the KRAS oncogene is implicated in colorectal carcinogenesis and mutations have been reported in 30-50% of cases. BRAF mutation, though less common, is also reported and importantly associated with shorter progression-free interval. This study aims to determine the KRAS and BRAF mutation statuses of Nigerian colorectal cancers (CRC).
Mutation analysis was carried out on archival paraffin-embedded blocks of CRC tissues. KRAS codons 12, 13 and 61 and BRAF V600E were assessed by pyrosequencing after DNA extraction from 200 cases at the Leeds Institute of Molecular Medicine, St. James's University Hospital, UK. Mutation rates and the spectra were determined.
Pyrosequencing was successful in 112 of 200 cases. KRAS mutation in codons 12 and 13 was demonstrated in 23 of 112 cases (21%); none in codon 61. BRAF mutation in codon 600 was demonstrated in 4.5%.
This study shows that 21% of Nigerian CRC patients carry a KRAS mutation; half the rate in Caucasians; and that BRAF mutation also occurs in Nigerian CRC cancers.
West African journal of medicine 01/2013; 31(3):198-203.
[Show abstract][Hide abstract] ABSTRACT: Background:
The United Kingdom performs poorly in international comparisons of colorectal cancer survival with much of the deficit owing to high numbers of deaths close to the time of diagnosis. This retrospective cohort study investigates the patient, tumour and treatment characteristics of those who die in the first year after diagnosis of their disease.
Patients diagnosed with colon (n=65 733) or rectal (n=26 123) cancer in England between 2006 and 2008 were identified in the National Cancer Data Repository. Multivariable logistic regression was used to investigate the odds of death within 1 month, 1–3 months and 3–12 months after diagnosis.
In all, 11.5% of colon and 5.4% of rectal cancer patients died within a month of diagnosis: this proportion decreased significantly over the study period. For both cancer sites, older age, stage at diagnosis, deprivation and emergency presentation were associated with early death. Individuals who died shortly after diagnosis were also more likely to have missing data about important prognostic factors such as disease stage and treatment.
Using routinely collected data, at no inconvenience to patients, we have identified some important areas relating to early deaths from colorectal cancer, which merit further research.
British Journal of Cancer 01/2013; 108(3). DOI:10.1038/bjc.2012.585 · 4.84 Impact Factor