Total mesorectal excision for cancer: histological and immunohistochemical evidence of nerve removal and risk-factor analysis.

AIM: Whether or not nerve-sparing rectal-cancer surgery can effectively prevent removal of the pelvic autonomic nerves has not been substantiated microscopically. We aimed to analyse the quality of nerve preservation in female patients by quantifying residual nerve fibres in total mesorectal excision specimens, to analyse pro-erectile function of the nerve fibres removed and to determine risk factors for pelvic denervation. METHOD: Serial transverse sections from female patients, 64 ± 18 years of age, were studied after the mesorectal fascia was inked and studied histologically [using anti-S100 and anti-neuronal nitric oxide synthase (nNOS) antibodies]. Nerve fibres located within 1 mm of the inked surface were counted and analysed according to type of surgery, tumour location, pT stage, circumferential resection margin and the necessity for a posterior colpectomy. RESULTS: Twelve specimens were analysed. Per specimen, the mean number of nerve-fibre sections outside the mesorectum was 5.3 ± 3.6 (range: 1-12). The mean number of fibres per specimen was 6.4 ± 4.1 in patients having a low-rectal tumour and 4.4 ± 2.9 in those with mid or higher rectal tumours (P = 0.42). The mean number of fibres was higher (9.2) for T4 tumours than for T2/T3 tumours (5.0 ± 3.5), but this difference was not statistically sigmificant (P = 0.25). Patients having abdominoperineal excision, a posterior colpectomy or a circumferential resection margin of less than 1 mm had significantly more nerve fibres in the specimen (10.6 ± 1.9 vs 4.4 ± 2.8; P = .041). Fibres localized at the anterolateral rectum corresponded to branches of the neurovascular bundle, expressing rich pro-erectile activity (positive anti-nNOS immunostaining). CONCLUSION: The neurovascular bundle is a key risk zone for pelvic denervation during total mesorectal excision. Abdominoperineal excision, posterior colpectomy and an invaded circumferential resection margin are associated with perineal denervation.

Pathological response of locally advanced rectal cancer to preoperative chemotherapy without pelvic irradiation.

AIM: Pathological response to chemotherapy without pelvic irradiation is not well defined in rectal cancer. This study aimed to evaluate the objective pathological response to preoperative chemotherapy without pelvic irradiation in middle or low locally advanced rectal cancer (LARC). METHODS: Between 2008 and 2013, 22 patients with middle or low LARC (T3/4 and/or N+ and circumferential resection margin < 2 mm) and synchronous metastatic disease or a contraindication to pelvic irradiation underwent rectal resection after preoperative chemotherapy. The pathological response of rectal tumour was analysed according to the Rödel tumour regression grading (TRG) system. Predictive factors of objective pathological response (TRG 2-4) were analysed. RESULTS: All patients underwent rectal surgery after a median of six cycles of preoperative chemotherapy. Of these, 20 (91%) had sphincter saving surgery and an R0 resection. Twelve (55%) patients had an objective pathological response (TRG 2-4), including one complete response. Poor response (TRG 0-1) to chemotherapy was noted in 10 (45%) patients. In univariate analyses, none of the factors examined was found to be predictive of an objective pathological response to chemotherapy. At a median follow-up of 37.2 months, none of the 22 patients experienced local recurrence. Of the 19 patients with Stage IV rectal cancer, 15 (79%) had liver surgery with curative intent. CONCLUSION: Preoperative chemotherapy without pelvic irradiation is associated with objective pathological response and adequate local control in selected patients with LARC. Further prospective controlled studies will address the question of whether it can be used as a valuable alternative to radiochemotherapy in LARC.

Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004).

BACKGROUND: This study investigates the possible benefits of radiofrequency ablation (RFA) in patients with non-resectable colorectal liver metastases. METHODS: This phase II study, originally started as a phase III design, randomly assigned 119 patients with non-resectable colorectal liver metastases between systemic treatment (n = 59) or systemic treatment plus RFA ( ± resection) (n = 60). Primary objective was a 30-month overall survival (OS) rate >38% for the combined treatment group. RESULTS: The primary end point was met, 30-month OS rate was 61.7% [95% confidence interval (CI) 48.2-73.9] for combined treatment. However, 30-month OS for systemic treatment was 57.6% (95% CI 44.1-70.4), higher than anticipated. Median OS was 45.3 for combined treatment and 40.5 months for systemic treatment (P = 0.22). PFS rate at 3 years for combined treatment was 27.6% compared with 10.6% for systemic treatment only (hazard ratio = 0.63, 95% CI 0.42-0.95, P = 0.025). Median progression-free survival (PFS) was 16.8 months (95% CI 11.7-22.1) and 9.9 months (95% CI 9.3-13.7), respectively. CONCLUSIONS: This is the first randomized study on the efficacy of RFA. The study met the primary end point on 30-month OS; however, the results in the control arm were in the same range. RFA plus systemic treatment resulted in significant longer PFS. At present, the ultimate effect of RFA on OS remains uncertain.

ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making.

Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.

Previous transanal full-thickness excision increases the morbidity of radical resection for rectal cancer.

AIM: The aim of the study was to determine the impact of primary full-thickness transanal excision (TAE) on the morbidity rate following radical rectal resection for cancer. METHOD: Fourteen consecutive patients underwent radical resection for lower third rectal cancer following full-thickness TAE without closure of the defect. They were compared with 25 matched patients from a prospective database of 275 rectal resections who had undergone radical resection without previous TAE for lower third rectal cancer (control group). The confounding factors were: age, sex, body mass index (BMI), classification according to the American Society of Anaesthesiologists, administration of neoadjuvant radiotherapy before rectal resection, tumour stage and type of surgical procedure. RESULTS: There were no deaths. Overall morbidity was 64.3% in the TAE group and 32% in the control group (P = 0.112). Surgical complications were significantly more frequent in the former (57.1%vs 20%; P = 0.048). The frequency of specific surgical site complications, including anastomotic complications and pelvic abscess formation requiring surgical drainage, was significantly higher in the TAE group than in the control group (42.8%vs 8%; P = 0.032). In univariate analysis, the only factors associated with specific surgical site complications were BMI > 27 and TAE before rectal resection. CONCLUSION: This case-matched study suggests that previous full-thickness TAE increases the risk of surgical complications after radical resection for lower third rectal cancer, including anastomotic dehiscence and pelvic sepsis.

Salvage colectomy for endoscopically removed malignant colon polyps: is it possible to determine the optimal number of lymph nodes that need to be harvested?

AIM: The total number of lymph nodes examined after salvage colectomy for endoscopically removed malignant polyps was evaluated and an attempt was made to determine whether there was an optimal number of lymph nodes that should be harvested. METHOD: From 2000 to 2009, 531 patients underwent segmental resection for non-metastatic colon cancer. Of these, 22 underwent a salvage colectomy for an endoscopically removed malignant polyp, the main indication for which was a resection margin of < 1 mm. The surgical procedure was identical to that used for all colon cancers. RESULTS: The mean number of lymph nodes examined was 11.6 ± 7.6 for the 22 patients with an endoscopically removed malignant polyp and 26.2 ± 13.9 for the remaining 509 patients (P = 0.0006). Fewer than 12 lymph nodes were examined in 62 (12%) of the 509 patients and in 13 (59%) of the 22 patients with an endoscopically removed malignant polyp (P < 0.0001). In the group of 22 patients who underwent a salvage colectomy, the total number of lymph nodes examined ranged from 2 to 33. At a mean follow up of 41 ± 15.6 months, no local or distant recurrence was observed in the 22 patients. CONCLUSION: The total number of lymph nodes examined after colectomy for endoscopically removed malignant polyps varies and is less than the recommended number of 12 in most cases: this does not appear to have long-term prognostic significance. There is no biological reason to explain this clinical observation.

The diagnosis and management of gastric cancer: expert discussion and recommendations from the 12th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2010.

Well-recognized experts in the field of gastric cancer discussed during the 12th European Society Medical Oncology (ESMO)/World Congress Gastrointestinal Cancer (WCGIC) in Barcelona many important and controversial topics on the diagnosis and management of patients with gastric cancer. This article summarizes the recommendations and expert opinion on gastric cancer. It discusses and reflects on the regional differences in the incidence and care of gastric cancer, the definition of gastro-esophageal junction and its implication for treatment strategies and presents the latest recommendations in the staging and treatment of primary and metastatic gastric cancer. Recognition is given to the need for larger and well-designed clinical trials to answer many open questions.

Where does pelvic nerve injury occur during rectal surgery for cancer?

AIM: Optimal treatment of rectal adenocarcinoma involves total mesorectal excision with nerve-preserving dissection. Urinary and sexual dysfunction is still frequent following these procedures. Improved knowledge of pelvic nerve anatomy may help reduce this and define the key anatomical zones at risk. METHOD: The MEDLINE database was searched for available literature on pelvic nerve anatomy and damage after rectal surgery using the key words 'autonomic nerve', 'pelvic nerve', 'colorectal surgery', and 'genitourinary dysfunction'. All relevant French and English publications up to May 2010 were reviewed. Reviewed data were illustrated using 3D reconstruction of the foetal pelvis. RESULTS: The ligation of the inferior mesenteric artery and dissection of the retrorectal space can cause damage to the superior hypogastric plexus and/or hypogastric nerve. Anterolateral dissection in the 'lateral ligament' area and division of Denonvilliers' fascia can damage the inferior hypogastric plexus and efferent pathways. Perineal dissection can indirectly damage the pudendal nerve. CONCLUSIONS: In most cases, the pelvic nerves can be preserved during rectal surgery. Complete oncological resection may require dissection close to the nerves where the tumour is located anterolaterally where it is fixed and when the pelvis is narrow.

Molecular markers and biological targeted therapies in metastatic colorectal cancer: expert opinion and recommendations derived from the 11th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2009.

The article summarizes the expert discussion and recommendations on the use of molecular markers and of biological targeted therapies in metastatic colorectal cancer (mCRC), as well as a proposed treatment decision strategy for mCRC treatment. The meeting was conducted during the 11th ESMO/World Gastrointestinal Cancer Congress (WGICC) in Barcelona in June 2009. The manuscript describes the outcome of an expert discussion leading to an expert recommendation. The increasing knowledge on clinical and molecular markers and the availability of biological targeted therapies have major implications in the optimal management in mCRC.

Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel.

The past 5 years have seen the clear recognition that the administration of chemotherapy to patients with initially unresectable colorectal liver metastases can increase the number of patients who can undergo potentially curative secondary liver resection. Coupled with this, recent data have emerged that show that perioperative chemotherapy confers a disease-free survival advantage over surgery alone in colorectal cancer (CRC) patients with initially resectable liver disease. The purpose of this paper is to build on the existing knowledge and review the issues surrounding the use of chemotherapy +/- targeted agents combined with surgery in the treatment of CRC patients with liver metastases, with a view to providing clinical recommendations. An international panel of 21 experts in colorectal oncology comprising liver surgeons and medical oncologists reviewed the available evidence. In a major change to clinical practice, the panel's recommendation was that the majority of patients with CRC liver metastases should be treated up front with chemotherapy, irrespective of the initial resectability status of their metastases.

The management of hepatocellular carcinoma. Current expert opinion and recommendations derived from the 10th World Congress on Gastrointestinal Cancer, Barcelona, 2008.

This article summarizes the expert discussion on the management of hepatocellular carcinoma (HCC), which took place during the 10th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, June 2008. A multidisciplinary approach to a patient with HCC is essential, to guarantee optimal diagnosis and staging, planning of surgical options and selection of embolisation strategies or systemic therapies. In many patients, the underlying cirrhosis represents a challenge and determines therapeutic options. There is now robust evidence in favour of systemic therapy with sorafenib in patients with advanced HCC with preserved liver function. Those involved in the care for patients with HCC should be encouraged to participate in well-designed clinical trials, to increase evidence-based knowledge and to make further progress.

Presentation and prognosis of local recurrence after total mesorectal excision.

OBJECTIVE: The aim of this study was to describe the presentation, treatment and prognosis of local recurrences following total mesorectal excision for rectal adenocarcinoma. METHOD: Between 1999 and 2002, 201 patients were treated with total mesorectal excision for mid or low rectal cancer and were followed up prospectively. RESULTS: Overall 2-year survival was 85%. The 2-year recurrence rate was 8%. Eighteen patients developed local recurrence at 3-60 months. Nine recurrences originated from the pelvic sidewall. These recurrences were symptomatic in 90% of patients. Only two patients were reoperated with a R0 resection and were alive without local recurrence after 19 and 31 months. The seven others died within 9 months. Nine recurrences originated from an anastomotic suture line. Only two had symptoms. A R0 surgical resection was performed in all patients with a 67% sphincter conservation rate. After 26-months of median follow-up (range 7-58), all patients were alive. CONCLUSION: Half of the local recurrence after total mesorectal excision was located at the anastomotic site. Rectoscopic examination should be performed regularly to detect these anatomotic recurrences that are accessible to a R0 itérative resection.

[Functional outcome after hand-sewn versus stapled colonic J pouch anastomosis for rectal carcinoma]. / Anastomoses colo-anale manuelles (ACA) et colo-sus-anale mécaniques (ACSA) avec réservoir en J, après proctectomie pour cancer: comparaison des résultats fonctionnels.

STUDY AIM: The aim of this study was to compare the surgical and functional results of hand-sewn and stapled colonic J-pouch anastomoses after proctectomies for cancer. PATIENTS AND METHODS: Over a 6-year period, 120 patients had a laparotomic conservative rectal excision with total mesorectal excision but without intersphincteric dissection, for cancer of the mid- and lower rectum: the colonic J-pouch anastomosis was hand-sewn for 49 and stapled for 71 patients. The functional results were assessed at 1 year, by a questionnaire completed by the patient. RESULTS: Morbidity was 37% in the hand-sewn group and 38% in the stapled group (ns). Mean duration of surgery in the hand-sewn group was 288 minutes and in the stapled group, 246 minutes (p<0.001). At 1 year, the rate of perfect continence was 71% for the hand-sewn group and 76% for the stapled group (ns). Significantly, more patient from the hand-sewn groups used enemas (16% versus 3%, p<0.005). On the other hand, there was no significant difference between the two groups for wearing protection, urgency, number of stools a day or gas/stool discrimination. CONCLUSIONS: There is no major difference in either the surgical or functional results between hand-sewn or stapled colonic J-pouch anastomosis by laparotomy for rectal cancer. Because it is simpler and faster to perform, a stapled pouch is preferable when the tumor site so permits.

The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007.

Knowledge of the biology and management of rectal cancer continues to improve. A multidisciplinary approach to a patient with rectal cancer by an experienced expert team is mandatory, to assure optimal diagnosis and staging, surgery, selection of the appropriate neo-adjuvant and adjuvant strategy and chemotherapeutic management. Moreover, optimal symptom management also requires a dedicated team of health care professionals. The introduction of total mesorectal excision has been associated with a decrease in the rate of local failure after surgery. High quality surgery and the achievement of pathological measures of quality are a prerequisite to adequate locoregional control. There are now randomized data in favour of chemoradiotherapy or short course radiotherapy in the preoperative setting. Preoperative chemoradiotherapy is more beneficial and has less toxicity for patients with resectable rectal cancer than postoperative chemoradiotherapy. Furthermore chemoradiotherapy leads also to downsizing of locally advanced rectal cancer. New strategies that decrease the likelihood of distant metastases after initial treatment need be developed with high priority. Those involved in the care for patients with rectal cancer should be encouraged to participate in well-designed clinical trials, to increase the evidence-based knowledge and to make further progress. Health care workers involved in the care of rectal cancer patients should be encouraged to adopt quality control processes leading to increased expertise.

Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases.

PURPOSE: To assess the rate of R(0) resection of liver metastases achieved after chemotherapy with FOLFIRINOX. PATIENTS AND METHODS: Patients with histologically proven primary colorectal cancer and bidimensionally measurable liver metastasis, not fully resectable based on technical inability to achieve R(0) resection, but potentially resectable after tumor reduction, were given FOLFIRINOX: oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), bolus fluorouracil 400 mg/m(2) and fluorouracil 46-h continuous IV infusion 2,400 mg/m(2), every 2 weeks for a maximum of 12 cycles. RESULTS: Thirty-four patients were enrolled. Response rate before surgery was 70.6% (95%CI: 52.5-84.9). Twenty-eight patients (82.4%) underwent hepatic resection and nine achieved R(0) resection [26.5% (95% CI: 12.9-44.4%)]. The rate of clinical complete remission after surgery was 79.4%. Two-year overall survival was 83%. The most frequent grade 3 or 4 toxicities were neutropenia (64.8%), diarrhea (29.4%), fatigue (23.5%), abdominal cramps (14.7%), neuropathy and nausea (11.8% each), and AST/ALT elevation (14.7/11.8%). Only one patient experienced febrile neutropenia, four patients withdrew due to toxicity and no toxic death was observed. CONCLUSION: FOLFIRINOX, with an acceptable toxicity profile, shows a high response rate in liver metastases from colorectal cancer. The rate of hepatic resection in patients initially not resectable, is attractive and warrants further assessment of this regimen in randomized studies compared to standard regimens.

Tyramine kinetics and metabolism in cirrhosis.

Hypertyraminemia is common in hepatic cirrhosis and correlates in severity with encephalopathy. The mechanism of cirrhotic hypertyraminemia has not been established. The alternative possibilities are increased production from tyrosine and impaired degradation by monoamine oxidase. This investigation determined the pharmacokinetics of tyramine after an intravenous bolus injections of [3H]-tyramine (180--200 muCi 12 Ci/mmol sp act) in 13 cirrhotics and 9 controls. In normals, [3H]tyramine levels initially declined rapidly (alpha-phase) followed by a slower decline (beta-phase) with an average t 1/2 of 20.8 min. Average normal metabolic clearance rate and production rate were 13.2 liters/min and 15.4 microgram/min, respectively. In cirrhotic patients, the plasma disappearance curve for [3H]tyramine was qualitatively similar to that of the control subjects with no apparent different in beta-t 1/2 (17.2 min). The hypertyraminemia of cirrhosis resulted primarily from overproduction of tyramine, as the production rate (32.0 microgram/min) in these patients was significantly greater (P less than 0.05) than in controls, whereas the metabolic clearance rate remained normal (average 12.2 liters/min). A difference in ratio of tyramine metabolic products was noted as well. Cirrhotics had a high ratio of plasma 4-hydroxyphenylethanol:4-hydroxyphenylacetic acid (60:40 vs. 30:70) as compared with normals. Although the tyramine clearance rates are similar in normals and cirrhotics, different mechanisms may be responsible for catabolism.