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.

Prognostic score for recurrence after Whipple's pancreaticoduodenectomy for ampullary carcinomas; results of an AGEO retrospective multicenter cohort.

BACKGROUND: Ampullary carcinoma (AC) is a relatively rare entity often managed as a biliopancreatic carcinoma. AC has a better prognosis than peri ampullary tumors after resection, but more than a third of patients relapse. Factors predictive of recurrence are controversial, mainly because the relevant studies are very small or also included non AC tumors. There are no guidelines on the use of adjuvant or neoadjuvant chemotherapy. The aim of this study was to identify prognostic factors for recurrence after AC resection in a large multicentric cohort, and to establish a simple, practical, predictive score for recurrence in order to guide multidisciplinary decisions. METHODS: We included 152 consecutive patients who underwent Whipple's pancreaticoduodenectomy for ampullary carcinoma from January 2000 to December 2010 in 10 gastrointestinal oncology departments. RESULTS: The estimated overall 5-year disease-free survival rate (DFS) was 47.1%. In multivariate analysis, age≥ 75 years at diagnosis (p < 0.0001), poor general condition (p = 0.01), poorly (p = 0.005) or moderately differentiated tumors (p = 0.01) and TNM stage IIb or III (p = 0.05) were associated with poor DFS. Based on this multivariate analysis, we developed a prognostic score with three levels of risk: DFS at 5 years was 73.5% in the low-risk group and 20.1% in the high-risk group. CONCLUSION: This simple score based on age, general condition, tumor differentiation and TNM stage can classify patients into subgroups with different risks of recurrence and could help with therapeutic decisionmaking.

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.

Local recurrence rates after radiofrequency ablation or resection of colorectal liver metastases. Analysis of the European Organisation for Research and Treatment of Cancer #40004 and #40983.

AIM: The aim of this study is to describe local tumour control after radiofrequency ablation (RFA) and surgical resection (RES) of colorectal liver metastases (CLM) in two independent European Organisations for Research and Treatment of Cancer (EORTC) studies. BACKGROUND: Only 10-20% of patients with newly diagnosed CLM are eligible for curative RES. RFA has found a place in daily practice for unresectable CLM. There are no prospective trials comparing RFA to RES for resectable CLM. METHODS: The CLOCC trial randomised 119 patients with unresectable CLM between RFA (±RES)+adjuvant FOLFOX (±bevacizumab) versus FOLFOX (±bevacizumab) alone. The EPOC trial randomised 364 patients with resectable CLM between RES±perioperative FOLFOX. We describe the local control of resected patients with lesions ≤4 cm in the perioperative chemotherapy arm of the EPOC trial (N=81) and the RFA arm of the CLOCC trial (N=55). RESULTS: Local recurrence (LR) rate for RES was 7.4% per patient and 5.5% per lesion. LR rate for RFA was 14.5% per patient and 6.0% per lesion. When lesion size was limited to 30 mm, LR rate for RFA lesions was 2.9% per lesion. Non-local hepatic recurrences were more often observed in RFA patients than in RES patients, 30.9% and 22.3% respectively. Patients receiving RFA had a more advanced disease. CONCLUSIONS: LR rate after RFA for lesions with a limited size is low. The local control per lesion does not appear to differ greatly between RFA and surgical resection. This study supports the local control of RFA in patients with limited liver metastases. Future studies should evaluate in which patients RFA could be an equal alternative to liver resection.

[Tolerance and efficacy of preoperative radiation therapy for elderly patients treated for rectal cancer]. / Tolérance et efficacité de la radiothérapie préopératoire chez les patients âgés atteints d'un cancer du rectum.

PURPOSE: To retrospectively assess the impact of age on tolerance and oncologic outcomes treated by neoadjuvant treatment for patients of 70 years old or above with locally advanced rectal cancer. PATIENTS AND METHODS: Ninety-one consecutive patients were divided into three groups: group 1 from 70 to 75 years (n=31); group 2: 76 to 79 years (n=31) and group 3, patients aged 80 years or above (n=29). Radiation therapy was delivered according two schemes: 25Gy in five fractions (short scheme) or 45 to 50Gy with a classical fractionation (long scheme). Long scheme patients received a concomitant chemotherapy with 5-fluoro-uracile alone or associated with oxaliplatin. RESULTS: The three groups were comparable for performance status, Charlson's score and T staging. Long scheme radiation therapy and chemotherapy were performed in 77.5, 74.5 and 48.3% of patients (P=0.03) and 77.4, 71 and 41.4% (P=0.006) in the groups 1, 2 and 3, respectively. All patients treated with the short scheme irradiation received the treatment without any acute toxicity. In the long scheme group, 65% of patients received the treatment on time and grade 3 or above toxicity was observed in 12% of patients who did not receive oxaliplatin and in 48% of patients who received oxaliplatin. The overall survival rate at 3 and 5 years was 66.9% and 60.8% in the group 1, 90.5% and 75.9% in the group 2 and 80.5% and 73.8% in the group 3 (P=0.15). CONCLUSION: Neoadjuvant treatment is feasible with encouraging survival rates for patients aged 70 years and older. Short scheme radiation therapy seems to be an interesting option in this population.

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.

The role of biological agents in the resection of colorectal liver metastases.

Surgically resecting liver metastases from colorectal cancer (CLMs) offers the only potentially curative option. Chemotherapy-induced downsizing of CLMs increases the proportion of patients with resectable metastases. Several recent studies have reported that adding a biological agent such as cetuximab, panitumumab or bevacizumab to chemotherapy could further increase response and resectability rates. This overview discusses the reported resection rates for biological agents combined with chemotherapy and the difficulties of cross-trial comparisons, the pre-, peri- and postoperative roles of biological agents, particularly with regards to comparisons of surgical complications, and ongoing clinical trials in which the resectability of CLMs is a predefined end point. Currently, targeted therapies combined with chemotherapy probably increase the resection rate of CLMs, although this has been shown in only one phase III randomised study and it is difficult to draw definitive conclusions about the relative efficacy and safety of the different available biological agents in terms of converting unresectable CLMs to resectable lesions. Available data for each of them are discussed. More data from phase III trials are expected to confirm the utility of the different biological agents in converting patients with unresectable CLMs to a resectable status.

Complete calcification of colorectal liver metastases on imaging after chemotherapy does not indicate sterilization of disease.

BACKGROUND: The significance of complete calcification of liver metastases on imaging is unknown. This study was conducted to determine whether complete calcification of liver metastases after chemotherapy, as assessed by imaging, was synonymous with sterilization of disease. METHODS: Imaging by triphasic contrast-enhanced helical CT scan and abdominal ultrasound showed complete calcification of eight liver metastases in four patients after systemic chemotherapy. All eight completely calcified liver metastases were resected within four weeks of imaging. Histological and surgical findings were analyzed to see whether there was any correlation between radiological and pathological status for completely calcified liver metastases. RESULTS: The pretreatment median diameter at initial imaging of the eight liver metastases that became completely calcified after chemotherapy was 24 mm. In all eight resected calcified liver metastases, pathological examination showed the presence of residual viable tumor cells. Most of the tumor volume was occupied by calcification, necrosis and fibrosis; but small discrete islands of viable tumor cells were detected at the periphery of lesions. CONCLUSIONS: This preliminary study shows that although imaging evidence of complete calcification of liver metastases may be a good indicator of chemotherapy response, it does not imply sterilization of the malignancy.

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.

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.