Achieving high quality standards in laparoscopic colon resection for cancer: A Delphi consensus-based position paper.

AIM: To investigate the rate of laparoscopic colectomies for colon cancer using registries and population-based studies. To provide a position paper on mini-invasive (MIS) colon cancer surgery based on the opinion of experts leader in this field. METHODS: A systematic review of the literature was conducted using PRISMA guidelines for the rate of laparoscopy in colon cancer. Moreover, Delphi methodology was used to reach consensus among 35 international experts in four study rounds. Consensus was defined as an agreement ≥75.0%. Domains of interest included nosology, essential technical/oncological requirements, outcomes and MIS training. RESULTS: Forty-four studies from 42 articles were reviewed. Although it is still sub-optimal, the rate of MIS for colon cancer increased over the years and it is currently >50% in Korea, Netherlands, UK and Australia. The remaining European countries are un-investigated and presented lower rates with highest variations, ranging 7-35%. Using Delphi methodology, a laparoscopic colectomy was defined as a "colon resection performed using key-hole surgery independently from the type of anastomosis". The panel defined also the oncological requirements recognized essential for the procedure and agreed that when performed by experienced surgeons, it should be marked as best practice in guidelines, given the principles of oncologic surgery be respected (R0 procedure, vessel ligation and mesocolon integrity). CONCLUSION: The rate of MIS colectomies for cancer in Europe should be further investigated. A panel of leaders in this field defined laparoscopic colectomy as a best practice procedure when performed by an experienced surgeon respecting the standards of surgical oncology.

New insights in the neuroanatomy of the human adult superior hypogastric plexus and hypogastric nerves.

BACKGROUND: The superior hypogastric plexus (SHP) is an autonomic plexus, located ventrally to the abdominal aorta and its bifurcation, innervating pelvic viscera. It is classically described as being composed of merely sympathetic fibres. However, post-operative complications after surgery damaging the peri-aortic retroperitoneal compartment suggest the existence of parasympathetic fibres. This immunohistochemical study describes the neuroanatomical composition of the human mature SHP. MATERIAL AND METHODS: Eight pre-determined retroperitoneal localizations including the lumbar splanchnic nerves, the SHP and the HN were studied in four human cadavers. Control tissues (white rami, grey rami, vagus nerve, splanchnic nerves, sympathetic ganglia, sympathetic chain and spinal nerve) were collected to verify the results. All tissues were stained with haematoxylin and eosin and antibodies S100, tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP) and myelin basic protein (MBP) to identify pre- and postganglionic parasympathetic and sympathetic nerve fibres. RESULTS: All tissues comprising the SHP and hypogastric nerves (HN) showed isolated expression of TH, VIP and MBP, revealing the presence of three types of fibres: postganglionic adrenergic sympathetic fibres marked by TH, unmyelinated VIP-positive fibres and myelinated preganglionic fibres marked by MBP. Analysis of control tissues confirmed that TH, VIP and MBP were well usable to interpret the neurochemical composition of the SHP and HN. CONCLUSION: The human SHP and HN contain sympathetic and most likely postganglionic parasympathetic fibres. The origin of these fibres is still to be elucidated, however surgical damage in the peri-aortic retroperitoneal compartment may cause pelvic organ dysfunction related to both parasympathetic and sympathetic denervation.

Differences in circumferential resection margin involvement after abdominoperineal excision and low anterior resection no longer significant.

OBJECTIVE: The aim of this study was to evaluate whether the abdominoperineal excision (APE) is associated with an increased risk of circumferential resection margin (CRM) involvement after rectal cancer surgery in comparison with low anterior resection (LAR). BACKGROUND: The oncologic inferiority of the APE technique in comparison with LAR has been widely reported in literature. However, because of large evolvement in rectal cancer care, outcomes after APE may have improved since then. METHODS: The population-based dataset of the Dutch Surgical Colorectal Audit was used selecting 5017 patients with primary rectal cancer undergoing surgery in 2010 to 2011. Propensity scores were calculated for the likelihood of performing an APE given relevant patient and tumor characteristics, and used in the multivariate analysis of CRM involvement. RESULTS: The APE was associated with a slight, nonsignificant, increased risk of CRM involvement [odds ratio (OR) = 1.33; confidence interval (CI) = 0.93-1.90]. Absolute percentages of CRM involvement were 8% and 12% after LAR and APE, respectively.In the subgroup analysis, advanced rectal tumors (cT3-4) were associated to a higher risk of CRM involvement after APE (OR = 1.61; CI = 1.05-1.90), whereas smaller tumors (cT1-2) were not (OR = 0.62; CI = 0.27-1.40). CONCLUSIONS: The results suggest that on a national level the APE procedure itself is not a strong predictor anymore for CRM involvement after rectal cancer surgery. However, in advanced tumors, results after APE are inferior to LAR.

Comparison of magnetic resonance imaging and histopathological response to chemoradiotherapy in locally advanced rectal cancer.

BACKGROUND: Magnetic resonance imaging (MRI) methods for chemoradiotherapy (CRT) response assessment of rectal cancer include posttreatment T staging (ymrT), tumor regression grading (mrTRG), volume reduction posttreatment, and modified RECIST measurement. We compared these methods in identifying good versus poor responders with the histopathological standards of T stage (ypT) and tumor regression grading (TRG). METHODS: A total of 86 patients underwent CRT in a prospective phase II trial for MRI-defined locally advanced rectal cancer. Two readers independently assessed MRIs for ymrT, mrTRG, volume change, and RECIST. Parameters for each case were categorized as good or poor response and analyzed against ypT and TRG by univariate logistic regression. RESULTS: A total of 83 patients had evaluable imaging, and 78 had final pathology (five did not undergo surgery). Of these, 34 patients had good response (ypT0-3a) and 44 had poor response (>ypT3a). Also, 27 patients had favorable pathologic TRG (predominant fibrosis) and 51 had unfavorable TRG (predominant tumor). Good mrTRG and ymr 80 % showed an OR of 3.23 (95 % CI: 1.14-9.17), 4.25 (95 % CI: 0.92-15.45), respectively, for a good ypT score (P = 0.028), but there was no association for histopathological TRG. CONCLUSION: Favorable and unfavorable histopathology are predicted by both ymrT and mrTRG, and we recommend these parameters for post-treatment assessment of rectal cancers treated with CRT.

Multidisciplinary Rectal Cancer Management: 2nd European Rectal Cancer Consensus Conference (EURECA-CC2).

BACKGROUND AND PURPOSE: During the first decade of the 21st century a number of important European randomized studies were published. In order to help shape clinical practice based on best scientific evidence from the literature, the International Conference on 'Multidisciplinary Rectal Cancer Treatment: Looking for an European Consensus' (EURECA-CC2) was organized in Italy under the endorsement of European Society of Medical Oncology (ESMO), European Society of Surgical Oncology (ESSO), and European Society of Therapeutic Radiation Oncology (ESTRO). METHODS: Consensus was achieved using the Delphi method. The document was available to all Committee members as a web-based document customized for the consensus process. Eight chapters were identified: epidemiology, diagnostics, pathology, surgery, radiotherapy and chemotherapy, treatment toxicity and quality of life, follow-up, and research questions. Each chapter was subdivided by a topic, and a series of statements were developed. Each member commented and voted, sentence by sentence thrice. Sentences upon which an agreement was not reached after voting round # 2 were openly debated during a Consensus Conference in Perugia (Italy) from 11 December to 13 December 2008. A hand-held televoting system collected the opinions of both the Committee members and the audience after each debate. The Executive Committee scored percentage consensus based on three categories: "large consensus", "moderate consensus", and "minimum consensus". RESULTS: The total number of the voted sentences was 207. Of the 207, 86% achieved large consensus, 13% achieved moderate consensus, and only 3 (1%) resulted in minimum consensus. No statement was disagreed by more than 50% of the members. All chapters were voted on by at least 75% of the members, and the majority was voted on by >85%. CONCLUSIONS: This Consensus Conference represents an expertise opinion process that may help shape future programs, investigational protocols, and guidelines for staging and treatment of rectal cancer throughout Europe.

Expert opinion on management of gastric and gastro-oesophageal junction adenocarcinoma on behalf of the European Organisation for Research and Treatment of Cancer (EORTC)-gastrointestinal cancer group.

A multidisciplinary approach is mandatory for patients with gastric cancer. Patients should be managed by an experienced team of physicians. The outcome of patients is related to the experience of the multidisciplinary team. Surgery is the cornerstone of the management of patients with resectable gastric cancer. The standard recommendations for resectable gastric adenocarcinoma are free-margin surgery with at least D1 resection combined to removal of a minimum of 15 lymph nodes. It has been shown that the outcome of patients with resectable gastric cancer can be improved by a strategy of perioperative (pre- and postoperative) chemotherapy or by postoperative chemoradiotherapy. The evidence comes from large randomised phase 3 studies. In the treatment of unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, no chemotherapy combination was accepted as the gold standard. Cisplatin/5-FU (CF) and ECF (epirubicin plus CF) regimens have been investigated widely in clinical studies and were until recently presented as the reference regimens. Despite a relative chemosensitivity of gastric cancer, a low rate of complete response was obtained, the response duration was short and patients' outcomes remained poor. Recently, new options have been introduced in the management of advanced gastric cancer. It has been shown that capecitabine is at least as good as 5-FU and that oxaliplatin at least as good as cisplatin in these combinations. It has also been demonstrated that the addition of docetaxel to CF resulted in statistically significant improved efficacy endpoints (including patient's quality of life), but also in an increased toxicity. The DCF regimen (docetaxel, cisplatin and 5-FU) has become, therefore, a new active option in advanced gastric cancer in selected patients in good condition. Further randomised trials are therefore to be designed to further improve chemotherapy by modifying and optimising the chemotherapy regimens, and investigating novel treatment combinations. The addition of biological agents to the optimal chemotherapy regimen may achieve further improvements in efficacy.

Tumour response to preoperative anthracycline-based chemotherapy in operable breast cancer: the predictive role of p53 expression.

The aim of this retrospective study was to identify markers capable of predicting pathological complete (pCR) and overall clinical tumour response to preoperative anthracycline-based chemotherapy and clinical outcome in women with operable breast cancer. Therefore, we used the pre-treatment core biopsies from 107 patients who were enrolled in the EORTC trial 10902 to analyse tumour characteristics and the oncogenic markers Bcl-2, p53, ER, PgR, HER2, and p21. Median follow-up was 7 years (95% confidence interval [CI], 6.89-7.45). pCR was seen in seven patients (6.5%) and was associated with improved overall survival (hazards ratio, 0.39; 95% CI, 0.05-2.56; P = 0.30). In multivariate logistic regression analysis, pCR was independently predicted by p53 overexpression estimated by immunohistochemistry (odds ratio [OR], 16.83; 95% CI, 1.78-159.33; P = 0.01). Fifty-eight patients showed clinical tumour response (>50% decrease in tumour size), however responders experienced no benefit in clinical outcome. Clinical tumour response was independently predicted by p53 overexpression (OR, 5.57; 95% CI, 1.58-19.65; P = 0.008) and small clinical tumour size (OR, 10.26; 95% CI, 2.01-52.48; P = 0.005). In multivariate Cox regression analysis, negative pathological lymph node status, low tumour grade and use of tamoxifen showed improved overall survival. In conclusion, our data suggest p53 expression is of predictive significance in anthracycline-containing chemotherapeutic regimens.

Low rectal cancer: a call for a change of approach in abdominoperineal resection.

PURPOSE: Despite the major improvements that have been made due to total mesorectal excision (TME), low rectal cancer still remains a challenge. METHODS: By investigating a prospective randomized rectal cancer trial in which surgeons had undergone training in TME the factors responsible for the poor outcome were determined and a new method for assessing the quality of surgery was tested. RESULTS: Survival differed greatly between abdominoperineal resection (APR) and anterior resection (AR; 38.5% v 57.6%, P = .008). Low rectal carcinomas have a higher frequency of circumferential margin involvement (26.5% v 12.6%, P < .001). More positive margins were present in the patients operated with APR (30.4%) compared to AR (10.7%, P = .002). Furthermore, more perforations were present in these specimens (13.7% v 2.5%, P < .001). The plane of resection lies within the sphincteric muscle, the submucosa or lumen in more than 1/3 of the APR cases, and in the remainder lay on the sphincteric muscles. CONCLUSION: We systematically described and investigated the pathologic properties of low rectal cancer in general, and APR in particular, in a prospective randomized trial including surgeons who had been trained in TME. The poor prognosis of the patients with an APR is ascribed to the resection plane of the operation leading to a high frequency of margin involvement by tumor and perforation with this current surgical technique. The clinical results of this operation could be greatly improved by adopting different surgical techniques and possibly greater use of radiochemotherapy.

The multidisciplinary rectal cancer treatment: main convergences, controversial aspects and investigational areas which support the need for an European Consensus.

BACKGROUND AND PURPOSE: During the past decades staging and treatment of rectal cancer are used different in Europe and in North America. To promote a process to integrate the daily practice with the best evidence of the literature an International Conference was organized in Italy. Agreement between Experts, Centres, and specialists who participated in the Conference are reported. METHODS: Five aspects were analyzed and a questionnaire was tailored for this purpose. The questionnaire had 159 questions. During the Conference, at the beginning of each Session, the moderators showed the answers from the Experts and the Centres, and, at the end of the session, the audience voted in all controversial issues. Agreements were scored at three levels: minimum, if it was between 51 and 74% of votes for each group; moderate, between 75 and 94%; large, more than 94%. RESULTS: The main results are: staging: endoanal ultrasound was considered as mandatory in T staging, in the evaluation of sphincter infiltration, and in the restaging of T after chemoradiotherapy (chRT). Magnetic Resonance Imaging is mandatory in the evaluation of mesorectal fascia infiltration. Endoscopy had a moderate agreement for the definition of tumour location, and the barium enema as optional. Digital rectal examination is complementary for staging and PET-CT investigational for T, N and yT staging. Preoperative radiotherapy: for T4 stage chRT was always the preferred treatment, often with moderate agreement, for any tumour location and N status. For T3, chRT received the same agreement except for high location and N0-N1. For T2 stage, N2 and positive nodes outside the mesorectum, chRT received minimum agreement for low and middle tumours; for high tumours only positive nodes outside the mesorectum was agreed upon. Preoperative radiotherapy, negative specimen and sphincter preservation: chRT was agreed by many for all T stages and N presentations of lower third tumours, except for T1-2 N0-N1. Postoperative treatments: the selection for these treatments often received moderate agreement according to the infiltration of surrounding organs, positive nodal status and circumferential radial margins. Therapy of metastatic disease: an agreement was found for FOLFOX as first-line therapy and for FOLFIRI as second-line, although comparative studies show similar activity of FOLFOX and FOLFIRI regimens. CONCLUSIONS: This process represents an expertise opinion process that may contribute to increased scientific debate and to promote the development of 'guidelines', 'clinical recommendations' and ultimately a Consensus on the evolving approach to rectal cancer treatment.

A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.

BACKGROUND: Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse. METHODS: We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival. RESULTS: Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported--183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04). CONCLUSIONS: Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment.

Bcl-2 overexpression does not prevent but retards adriamycin toxicity in CC531 colon carcinoma cells.

BACKGROUND: The Bcl-2 protein is a critical regulator of susceptibility towards cell death induced by antineoplastic drugs. Reduced growth activity and increased glutathione (GSH) levels protect against adriamycin toxicity. We recently demonstrated statistically significantly reduced growth activity and elevated cellular GSH levels in exponentially growing rat CC531 colon carcinoma cells overexpressing the full-length human Bcl-2 protein (CCbcl2#A3). METHODS: To assess the importance of reduced growth activity or increased GSH levels, we determined the mitochondrial function, 24 h after adriamycin treatment, in CCbcl2#A3 cells, parental CC531 cells and cells overexpressing the Bcl-2 protein lacking the N-terminal BH4 domain (CC Delta BH4): these latter cells contained elevated cellular GSH levels but were not reduced in growth activity. RESULTS: CCbcl2#A3, but not CC Delta BH4, cells were 3-fold less susceptible than parental cells suggestive of a protective role for reduced growth but not for increased GSH levels in BCL-2 transfectants. This was confirmed in several growth-inhibited CC531 transfectants and in slowly proliferating (ca. 100% confluent) cell populations compared to exponentially growing (ca. 50% confluent) cell populations. Reduced growth activity might delay the onset of cell death. Therefore, we tested the effect of adriamycin five days after treatment. In this long-term assay we found no differences between the various cells. CONCLUSION: Reduction of growth activity, for instance by an overexpression of the Bcl-2 protein, only transiently reduced the susceptibility towards adriamycin treatment.

Serum total gangliosides and TA90-IC levels: novel immunologic markers in colorectal cancer.

BACKGROUND: Because of the challenge in defining prognostic markers predictive of recurrence or progression, carcinoembryonic antigen (CEA) remains the most frequently used marker in colorectal cancer, despite its low sensitivity. We hypothesized that TA90-IC status and serum ganglioside levels might be useful markers and might be of prognostic significance in colorectal cancer. METHODS: Serum samples from 68 patients undergoing surgical treatment for histologically proven colorectal cancer were analyzed for the presence of CEA, serum gangliosides, and TA90-IC. Forty-one patients had node-negative disease, whereas 27 patients had limited metastatic disease. The intent was curative resection, even for patients with metastatic disease. Cryopreserved serum specimens were analyzed in a blinded fashion for total serum ganglioside levels (by an assay that detects lipid-associated sialic acids), for CEA, and for TA90-IC (by a murine monoclonal antibody-based enzyme-linked immunosorbent assay). A positive value for TA90-IC levels was defined as an optical density (OD) of more than 0.410 at 405 nm. RESULTS: Serum ganglioside levels were elevated more frequently than CEA concentrations (84% vs 44%). The combination of serum ganglioside and CEA values was more sensitive (88%) than CEA value alone (44%) in identifying patients with early-stage colorectal cancer. TA90-IC levels were elevated more frequently than CEA concentrations (56% vs 32%). The combination of TA90-IC and CEA values was more sensitive (72%) than CEA value alone (32%) in identifying patients with advanced-stage colorectal cancer. At an enzyme-linked immunosorbent assay cutoff level of 0.410, 15 (56%) patients had positive TA90-IC values. Fourteen patients alive with residual disease had a median OD TA90-IC level of 0.879, and only three patients had levels below the OD cutoff value of 0.410. Thirteen patients with no evidence of disease had a median level of 0.277, and only four patients had OD levels > or = 0.410. TA90-IC was significantly higher in the alive with residual disease patients than those rendered no evidence of disease (P = 0.02). CONCLUSIONS: We speculate that a multiple-marker analysis that combines CEA values with serum ganglioside and TA90-IC values may be more sensitive than CEA value alone for detecting colorectal cancer. The potential prognostic significance of TA90-IC status in advanced disease warrants further investigation.

Will we need lymph node dissection at all in the future?

Traditionally in the treatment of primary breast cancer, axillary lymph node dissection (ALND) plays an important role. However, a substantial and increasing percentage of patients appear to have no nodal involvement and have been subjected to ALND unnecessarily. The first reason to perform an ALND is axillary nodal staging. After reviewing the literature, it can be concluded that in clinically node-negative patients an adequately conducted lymphatic mapping by sentinel node procedure is equal to ALND for this purpose. The second reason to perform an ALND is to establish the extent of nodal involvement, which might have an impact on adjuvant treatment recommendations. However, there is no evidence available that patients with extensive nodal involvement (= 4 positive nodes) benefit more from adjuvant systemic treatment (either standard or high dose) in terms of reduction of odds of recurrence and mortality compared to patients with limited nodal involvement and optimally administered so-called standard adjuvant treatment. The third reason to perform an ALND is to ensure axillary tumor control. Reviewing the different treatment options, it can be concluded that in clinically node-negative patients axillary control after axillary radiotherapy appears to be similar to axillary control after ALND. In clinically overt axillary involvement, ALND (with or without adjuvant radiotherapy) may result in an improved regional control. In the near future, ALND will not be the standard of care but will be reserved for those patients with proven axillary lymph node involvement. In microscopic disease, radiotherapy may be an alternative with equal control and less morbidity.