Search

Histopathological growth patterns (HGPs) are a reliable, reproducible, and strong prognostic biomarker that can be assessed on haematoxylin and eosin-stained sections of resected colorectal liver metastases (CRLM). Assessment estimates the relative fraction of the tumour–liver interface for each of the three growth patterns; the desmoplastic HGP reflects good prognosis. Whether preoperative chemotherapy affects the HGP is currently unclear. The present international multicentre study evaluates this in an original cohort of 877 consecutive patients treated in the Netherlands, an external validation cohort of 1,203 consecutive patients treated in the USA, and a post hoc analysis from the phase III randomised controlled European Organization for Research and Treatment of Cancer (EORTC) 40983 trial (n = 70). All patients underwent resection of CRLM with or without preoperative systemic chemotherapy. Trial patients were randomised between perioperative chemotherapy and resection or resection alone. HGPs were determined according to consensus guidelines and compared for preoperative treatment status. Data from three separate tumour regression grading systems were available for the trial cohort. These were correlated with HGP stratified for treatment arm. In the original cohort, the average presence of desmoplastic HGP was 43% for chemo-naïve versus 67% for preoperatively treated patients (p < 0.001). A significant association between chemotherapy and desmoplastic HGP was found on multivariable analysis (β [95% confidence interval, CI]: 24.57 [18.28–30.87], p < 0.001). In the validation cohort, the average presence of desmoplastic HGP was 40% for chemo-naïve versus 63% for preoperatively treated patients (p < 0.001). This association remained on multivariable analysis (β [95% CI]: 24.18 [18.70–29.66], p < 0.001). In the EORTC 40983 trial, the average desmoplastic HGP presence was 33% in the resection arm versus 61% in the chemotherapy arm (p = 0.005). Chemotherapy was independently associated with an increase in desmoplastic HGP (β [95% CI]: 23.29 [1.78–44.79], p = 0.022). All three tumour regression gradings were significantly associated with the desmoplastic HGP in the chemotherapy arm (all p < 0.04). None were associated in the resection arm (all p > 0.11). Preoperative chemotherapy induces histopathological changes that alter the HGP of CRLM.

PURPOSE The PETACC 6 trial investigates whether the addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative capecitabine improves disease-free survival (DFS) in locally advanced rectal cancer. METHODS Between November 2008 and September 2011, patients with rectal adenocarcinoma within 12 cm from the anal verge, T3/4 and/or node positive, were randomly assigned to 5 weeks preoperative capecitabine-based chemoradiation (45-50.4 Gy) followed by six cycles of adjuvant capecitabine, both without (control arm, 1) or with (experimental arm, 2) oxaliplatin. The primary end point was improvement of 3-year DFS by oxaliplatin from 65% to 72% (hazard ratio [HR], 0.763). RESULTS A total of 1,094 patients were randomly assigned (intention to treat), and 1,068 eligible patients started their allocated treatment (arm 1, 543; arm 2, 525), with completion of protocol treatment in 68% (arm 1) v 54% (arm 2). A higher rate of grade 3/4 adverse events was reported in the experimental arm (14.4% v 37.3% and 23.4% v 46.6% for neoadjuvant and adjuvant treatment, respectively). At a median follow-up of 68 months (interquartile range, 58-74 months), 157 and 156 DFS events were observed in arms 1 and 2, respectively (adjusted HR, 1.02; 95% CI, 0.82 to 1.28; P = .835). Three-year DFS rate was not different, with 76.5% (95% CI, 72.7% to 79.9%) in arm 1, which is higher than anticipated, and 75.8% (95% CI, 71.9% to 79.3%) in arm 2. The 7-year DFS and overall survival (OS) rates were not different as well, with DFS of 66.1% v 65.5% (HR, 1.02) and OS of 73.5% v 73.7% (HR, 1.19) in arms 1 and 2, respectively. Subgroup analyses revealed heterogeneity in treatment effect according to German versus non-German site location, without detectable confounding factors in multivariable analysis. CONCLUSION The addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative adjuvant chemotherapy impairs tolerability and feasibility and does not improve efficacy.

Background Radiofrequency ablation (RFA) is a valid treatment for liver metastases from colorectal cancer (CRLM) smaller than 25 mm and unsuitable for surgical resection. Tumor size is predictive for local tumor progression (LTP). The aim of this study was to evaluate whether RFA is indicated for lesions >25 mm at presentation but Method Patients who underwent RFA for CRLM after chemotherapy (January 2004–December 2012) were reviewed. Metastases were classified according to their size. Group 1: ≤25 mm before and after chemotherapy. Group 2A: >25 mm before but ≤25 mm after chemotherapy. Group 2B: >25 mm before and after chemotherapy. Results 133 CRLM were ablated in 83 patients (median follow-up 56 months). At 1-year, the LTP rate was higher in group 2A than in group 1 (32% vs. 16%, p ≤ 0.001). The highest rate of 1-year LTP was 64% in group 2B. Time to LTP (TLTP) was shorter in group 2A than in group 1 (HR: 2.89; 95% CI [1.04–8.01]; p = 0.004). Following multivariate analysis, the group type was the only predictive factor for TLTP (p Conclusions RFA is not the optimal treatment for CRLM > 25 mm at presentation.

Rectal preservation has been proposed as an alternative to radical resection in patients with presumed complete or major response to chemoradiotherapy (CRT). The aim of this prospective study was to evaluate the accuracy of digital rectal examination (DRE) and magnetic resonance imaging (MRI) to predict major or complete rectal cancer response to CRT. Over 2 years, 61 patients underwent radical resection after CRT for rectal cancer. DRE and MRI were carried out before and 6 to 8 weeks after the end of CRT. Data from DRE and MRI post-CRT were compared with pathological examinations. At pathological examination, major/complete responses were recorded for tumors classified ypT1N0 and ypT0N0, respectively. DRE post-CRT showed major/complete response in 26 cases, of which 14 (54%) were confirmed by pathology. The positive (PPV) and negative (NPV) predictive values of DRE to predict major/complete response were 54 and 88 per cent, respectively. MRI post-CRT showed major/complete response in 12 cases, of which nine (75%) were confirmed by pathology. The PPV and NPV of MRI to predict major/complete response were 75 and 82 per cent, respectively. Data from DRE and RMI post-CRT were concordant in 45 patients. The PPV and NPV of concordant DRE and MRI to predict major/complete response were 82 and 91 per cent, respectively. DRE and MRI do not appear to be sufficiently accurate for safe selection of patients appropriate for a rectum-sparing strategy because the risk of leaving an invasive tumor untreated is 18 per cent.

Background Few data are available on management of very elderly colon cancer patients, especially concerning the parameters of therapeutic decisions and the role of geriatricians. Methods We retrospectively reviewed the charts of patients over 80 years of age who underwent surgery for a localised colon cancer in a French academic hospital. Results A total of 176 patients underwent surgery (postoperative morbidity and mortality rates: 25% and 6.7%). Adjuvant chemotherapy was discussed at a multidisciplinary team meeting for 91% of stage III patients, but only 13.5% of them were treated. Twenty-five patients relapsed: 19 were discussed at the multidisciplinary meeting and 16 were treated (5 had a metastasectomy). Despite their increase with time, geriatric assessments were infrequent, 17% (33% after 2006), and had no impact on postoperative morbi-mortality. Median overall survival and recurrence-free survival were 65.3 months and 65.1 months, respectively. Age, emergency surgery, and Charlson comorbidity index were independent prognostic factors. Conclusion Selected elderly colon cancer patients have significant access to surgery. However, postoperative morbi-mortality rates remain high and adjuvant chemotherapy rarely prescribed. Perioperative geriatric assessment, especially before surgery, should be routinely proposed to these patients to evaluate its impact on postoperative morbi-mortality and prescription of adjuvant treatment.

E. Van Cutsem1, A. Cervantes2, B. Nordlinger3 & D. Arnold4, on behalf of the ESMO Guidelines Working Group* Digestive Oncology, University Hospitals Leuven, Leuven, Belgium; Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain; Department of General Surgery and Surgical Oncology, Hopital Ambroise Pare, Assistance Publique – Hopitaux de Paris, Paris, France; Klinik fur Tumorbiologie, Freiburg, Germany

Surgical resection is associated with prolonged survival for patients with limited lung or liver metastatic colorectal cancer. The benefit of resection of colorectal liver metastases is widely accepted. However, after complete resection of colorectal liver metastases, up to 70 % of patients develop recurrence. Oncosurgical strategies, including complete resection and chemotherapy, have been developed to improve oncological outcome and to reduce recurrence after resection of colorectal liver metastases. Chemotherapy in combination with liver resection can be administered before, after, or before and after the surgical procedure. Perioperative chemotherapy has been revealed to reduce the risk of recurrence and has been accepted as a standard of care for patients with resectable liver metastases. Research, including intensification of chemotherapy administered in combination with surgery, is ongoing to further improve outcomes for patients with resectable liver metastases. There are currently few data regarding the benefit of chemotherapy administered in association with resection of lung metastases from colorectal cancer. A large prospective trial is currently evaluating the benefit of resection of lung metastases from colorectal cancer.

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

SCOPUS: ed.j, info:eu-repo/semantics/published

No standard treatment for advanced rectal cancer with synchronous resectable liver metastases (LM) has been defined. Radiochemotherapy prior to simultaneous or staged curative resection of both primary tumor and LM is one of the treatment options available. The response of LM to radiochemotherapy has never been evaluated and, in particular, the risk for progression of LM is unknown.Between 2000 and 2011, 20 patients underwent preoperative radiochemotherapy for advanced rectal cancer with synchronous limited but resectable LM. Imaging responses of LM to radiochemotherapy were analyzed on per-patient and per-lesion bases using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.Of the patients, 20 had 41 LM; 15 of the 20 patients (75%) had rectal cancer with expected circumferential margins1 mm on magnetic resonance imaging (MRI), and 50% had a solitary LM before treatment. Of the patients, 13 received oxaliplatin-based chemotherapy, and 7 received fluorouracil (FU)-based chemotherapy in combination with radiation. Of the 41 LM, 7 showed complete response (17%); 7 showed partial response (17%); 20 remained stable (49%); and 7 progressed (17%). Of the 25 LM treated with oxaliplatin-based chemotherapy, only 1 LM (4%) progressed. All 20 patients were suitable for resection of LM with curative intent after the radiochemotherapy.In patients with advanced rectal cancer and synchronous limited, but resectable LM, the risk for progression of LM during radiochemotherapy is low, especially if the chemotherapy regimen contains oxaliplatin. This low risk does not compromise a curative surgical approach to LM.

BACKGROUND To validate pathologic markers of response to preoperative chemotherapy as predictors of disease-free survival (DFS) after resection of colorectal liver metastases (CLM). METHODS One hundred seventy-one patients who underwent resection of CLM after preoperative chemotherapy at 4 centers were studied. Pathologic response—defined as the proportion of tumor cells remaining (complete, 0%; major

Systemic therapy for colorectal cancer liver metastases (CRLM) has undergone significant development in the past 15 years. Therapy regimens consisting of combinations of cytotoxic chemotherapeutic agents have demonstrated greater efficacy and contributed to a significant survival improvement. As the majority of patients who undergo resection for liver‐only CRLM are at risk of disease recurrence and cancer‐related death, combining resection with systemic therapy appears sensible. However, trial‐based evidence is sparse to support this concept. Peri‐operative FOLFOX has demonstrated a progression‐free survival benefit in a single Phase III trial; the safety of chemotherapy and subsequent operations was acceptable and only a few patients showed initial progression. Chemotherapy‐associated liver injury (CALI), including sinusoidal obstruction syndrome and steatohepatitis, has been observed after cytotoxic therapy, and should have implications for chemotherapy plans prior to hepatectomy. In general, pre‐operative chemotherapy should not extend beyond 3 months. For patients with unresectable liver‐only CRLM, a response to chemotherapy could establish resectability and should be considered an initial treatment goal. In patients with unresectable CRLM, oxaliplatin‐ or irinotecan‐containing combinations represent the standard options, although single‐agent choices may be appropriate for individual patients. The addition of bevacizumab carries the potential for a greater response and possibly for reduced CALI risks. In tumours without K‐ras mutations, anti‐epidermal growth factor receptor (EGFR) agents are also reasonable choices for a greater response and improved survival outcomes. It is crucial that all systemic CRLM treatment decisions include proper definitions of treatment goals and endpoints, and are derived based on appropriate multidisciplinary considerations for other potentially applicable local or regional modalities.

Surgical resection is the only method for treating colorectal liver metastases, because it can ensure long-term survival and cure in some patients. Only approximately 20 % of colorectal cancer patients with liver metastases can undergo liver resection at the time of diagnosis. Modern chemotherapy regimens are received by other patients, which could achieve high response rates but are insufficient for cure. Recurrences are observed in the majority of patients who undergo liver resection despite developed surgical technique and improved surgical skills. Many patients with resectable metastases undergo neoadjuvant chemotherapy before liver resection. Its benefit in terms of long-term disease control has been recently demonstrated, but neoadjuvant chemotherapy has also potential disadvantages, in particular chemotherapy-associated liver injury.

Colorectal cancer is one of the leading causes of cancer death worldwide and in Asia. The most frequent cause of death in patients with colorectal cancer is due to liver metastases. Liver metastases can be detected at the time of diagnosis of the primary tumor (synchronous liver metastases) or during the follow-up of a patient treated for a colorectal cancer (metachronous liver metastases). Early detection by imaging of colorectal liver metastases is needed since liver resection allows prolonged survival in a subset of patients with resectable liver metastases (10–15 % of patients with colorectal liver metastases). After resection, 5-year survival rate can approach 50 % of the patients. Recurrences after liver resection for colorectal occur in nearly half of the patient. Objectives in the future for the treatment of colorectal liver metastases should be to increase the resectability rate and to decrease the recurrence rate after curative liver resection. Multimodality treatment including combined strategy could lead to improve oncologic results of surgery for colorectal liver metastases.

Background: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach. Methods: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat. Results: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm. Conclusions: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases.

This article summarizes the expert discussion on the management of pancreatic cancer, which took place during the 8th World Congress on Gastrointestinal Cancer in June 2006 in Barcelona. A multidisciplinary approach to a patient with pancreatic cancer is essential, in order to guarantee an optimal staging, surgery, selection of the appropriate (neo-)adjuvant strategy and chemotherapeutic choice management. Moreover, optimal symptomatic management requires a dedicated team of health care professionals. Quality control of surgery and pathology is especially important in this disease with a high locoregional failure rate. There is now solid evidence in favour of chemotherapy in both the adjuvant and palliative setting, and gemcitabine combined with erlotinib, capecitabine or platinum compounds seems to be slightly more active than gemcitabine alone in advanced pancreatic cancer. There is a place for chemoradiotherapy in selected patients with locally advanced disease, while the role in the adjuvant setting remains controversial. Those involved in the care for patients with pancreatic cancer should be encouraged to participate in well-designed clinical trials, in order to increase the evidence-based knowledge and to make further progress. © 2007 European Society for Medical Oncology.

This article summarizes the expert discussion on the management of pancreatic cancer, which took place during the 8th World Congress on Gastrointestinal Cancer in June 2006 in Barcelona. A multidisciplinary approach to a patient with pancreatic cancer is essential, in order to guarantee an optimal staging, surgery, selection of the appropriate (neo-)adjuvant strategy and chemotherapeutic choice management. Moreover, optimal symptomatic management requires a dedicated team of health care professionals. Quality control of surgery and pathology is especially important in this disease with a high locoregional failure rate. There is now solid evidence in favour of chemotherapy in both the adjuvant and palliative setting, and gemcitabine combined with erlotinib, capecitabine or platinum compounds seems to be slightly more active than gemcitabine alone in advanced pancreatic cancer. There is a place for chemoradiotherapy in selected patients with locally advanced disease, while the role in the adjuvant setting remains controversial. Those involved in the care for patients with pancreatic cancer should be encouraged to participate in well-designed clinical trials, in order to increase the evidence-based knowledge and to make further progress.

Conducting high-quality prospective clinical trials in surgical oncology remains a challenge, and many seemingly well-designed trials lack this high quality because of inadequate recruitment accrual, lack of clinician interest, or evolution of treatment strategy during the many years over which such trials are conducted. In this Perspectives we examine some of the failures in published surgical oncology trials and discuss why they failed, and we make a critical assessment of the established prospective trial methodology in oncological practice (that is, phase 0, I, II, III and IV trials, and large prospective comparative audits) and how these methods might be used more effectively in future evaluation of cancer-surgery practice.

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.

Surgery is the reference treatment of resectable colorectal liver metastases (CLM) as it is associated with 5-year survival rate as high as 50 % in selected patients. Unfortunately, most patients have too advanced metastatic disease to undergo liver resection with curative intent and are therefore treated by systemic chemotherapy. In patients undergoing resection of CLM, disease recurrence can occur in up to 70 % and consequently, adjuvant treatment to surgery have been tested to improve oncologic outcome. In patients with unresectable CLM, chemotherapy is initially the sole treatment option. The considerable improvement of the efficacy of anticancer agents has contributed to increase the response rate in patients with advanced colorectal cancer. In case of major response to chemotherapy, surgery with curative intent can be offered to patients with initially unresectable liver metastases.

During the last decades, the evolution of treatment - including radiotherapy, chemotherapy and targeted agents - has improved the cure and survival of patients with gastrointestinal (GI) cancer. Within the past 50 years of the EORTC's existence, significant progress has been made in the fight against cancer. During this time several cancer clinical trials were completed, and through these we are able to identify the most notable advances in GI cancer research done by the EORTC Gastrointestinal Tract Cancer Group (GI Group). Several EORTC clinical trials results have changed practice (e.g. standard of care of liver metastases of colorectal cancer has been changed by the EPOC trial) or have helped to support new treatment strategies in either early- or advanced-stage GI cancers. In addition to its clinical activities the group has started an extensive program of translational research. This changed strategy towards a translational, multidisciplinary program regarded as the basis for future developments. This review of the major achievements of the GI Group shows that it has played an important role in the scientific development of the understanding and treatment of GI cancer over the last 50 years. © 2012 European Organisation for Research and Treatment of Cancer., SCOPUS: ar.j, info:eu-repo/semantics/published

Synchronous colorectal liver metastases include a wide variety of clinical presentation depending on the location and the extent of the primary tumor, the extent of metastatic disease in the liver, and the presence of extrahepatic disease. Only a minority of patients with synchronous colorectal liver metastases and an intact primary tumor can be candidates for a curative treatment approach. In the past two decades, considerable progress with both antitumor agents and surgical strategies has contributed to increase the number of patients that can achieve complete resection of primary tumor and liver metastases. Optimal treatment of colorectal resectable liver metastases includes preoperative chemotherapy that can be administered after resection of the primary tumor and before resection of liver metastases in a ‘classical’ fashion, before combined resection of the primary tumor and liver metastases, and before liver resection of liver metastases followed by resection of the primary tumor in the reverse strategy. With regard to the large variety of clinical presentations in patients with synchronous colorectal liver metastases, none of these treatment strategies can be recommended in all patients. The complexity and the multiplicity of available treatment options underline the need for a multidisciplinary approach to this disease.

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

Prediction of chemosensitivity is a major goal of modern oncology. The aim of this study was to establish a simple and effective model of primary culture of colorectal cancer fragments and to test whether it allows prediction of chemosensitivity.Colorectal cancer fragments (primary tumors or liver metastases) of 94 consecutive and previously untreated patients were obtained, prepared, and cultured in polyHEMA. For each fragment cultured, a proliferative index (PI) was calculated after immunostaining at d 0 and after 7 d in culture with media alone or supplemented for 24h with the topoisomerase I inhibitor metabolite SN-38. The correlation between in vitro response (decrease in PI after exposure to the drug) and in vivo response (RECIST criteria) was studied in a subset of patients who had measurable metastases and were treated with a topoisomerase I inhibitor.PolyHEMA allowed three-dimensional culture of tumor fragments up to 7 d without fibroblastic invasion and with a slight but significant decrease of PI (59% at d 0 versus 51% after 7 d in culture, P0.001). In vitro drug efficacy was tested in 67 fragments, the mean PI after culture with SN-38 dropped to 22% (P0.001). In a subset of 12 patients, there was no statistically significant correlation between in vitro and in vivo response (P = 0.13).Primary culture in polyHEMA was easy to perform successfully in 71% of cases. On this model, the antiproliferative effect of SN-38 could be measured and results correlated to clinical data.

Neoadjuvant chemotherapy is increasingly used to improve outcome in patients with colorectal liver metastases (CLM). In patients with unresectable CLM, recent clinical trials evaluate the ability of chemotherapy to increase the resectability rate. In patients with resectable CLM, the objective is to decrease the risk of recurrence after hepatectomy that still remains elevated despite the improvement of the surgical technique. A multidisciplinary approach of patients with CLM is desirable whatever the initial status of resectability. J. Surg. Oncol. 2010;102:932–936. © 2010 Wiley-Liss, Inc.

Combining surgery and chemotherapy in the treatment of patients with colorectal hepatic metastases is increasingly becoming the standard of care. However, controversy remains regarding the juxtapositioning of chemotherapy and surgery, the duration of chemotherapy, and particularly, the use of preoperative chemotherapy in the treatment of patients with initially resectable metastases. The arguments for and against the different approaches presented are based on the data published in the medical literature and on the data presented at the most recent major oncology meetings, coupled with the personal experience of the authors. For patients with liver metastases that are resectable at presentation, perioperative chemotherapy has become the standard treatment in many institutions, with the recommendation that surgery is performed after a maximum of 6 cycles of systemic therapy. In the case of patients with initially unresectable liver metastases receiving preoperative systemic therapy, patients should be carefully monitored and surgery performed as soon as the metastases become resectable. All patients should, where possible, be treated by a multidisciplinary team. Going forward, it needs to be established whether more intensive treatment (ie, perioperative versus postoperative systemic therapy) is merited for the treatment of patients with initially resectable disease, and what the precise contribution of new therapeutic agents in these settings is, based on new prospective randomized trial data.

3500Background: The PETACC-6 trial investigated the role of oxaliplatin in combination with preoperative capecitabine-based chemoradiation (CRT) and postoperative capecitabine (CT) to improve disea...

Liver metastases develop in 40-50% of patients with colorectal cancer and represent the major cause of death in this disease. Surgical resection remains the only treatment procedure that can ensure long-term survival and provide cure when liver metastases can be totally resected with clear margins, when the primary cancer is controlled, and when there is no nonresectable extrahepatic disease. Five-year survival rate after surgical resection of colorectal metastases varies from 25% to 55%, but cancer relapse is observed in most patients.To review the potential benefits and disadvantages of neoadjuvant chemotherapy administered before surgery to patients with initially resectable metastases.European Organization for Research and Treatment of Cancer (EORTC) study 40983 has shown that neoadjuvant chemotherapy could reduce the risk of relapse by one-quarter, and allows to test the chemosensitivity of the cancer, to help to determine the appropriateness of further treatments, and to observe progressive disease, which contraindicates immediate surgery. Neoadjuvant chemotherapy can induce damage to the remnant liver. Oxaliplatin-based combination regimen is associated with increased risk of vascular lesions, whereas irinotecan-containing regimens have been associated with increased risks of steatosis and steatohepatitis. Analysis of EORTC study 40983 showed that administration of six cycles of neoadjuvant systemic chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was associated with moderate increase of the risk of reversible complications after surgery, but mortality rate was below 1% and not increased. If patients are not overtreated, chemotherapy before surgery is well tolerated. The integration of novel targeted agents in combination with cytotoxic drugs is a promising way to improve outcome in patients with advanced colorectal cancer. Preliminary trials have shown that targeted agents combined with cytotoxic regimens can increase tumor response rates. Another impact of preoperative chemotherapy is that metastases that respond to treatment may no longer be visible on computed tomography (CT) scan or at surgery. Patients should be carefully monitored and receive surgery before metastases disappear.Treatment of most patients with liver metastases-those with resectable metastases as well as those with initially unresectable metastases-should start with chemotherapy. If drugs are well chosen and the duration of treatment is monitored with care during multidisciplinary meetings, benefits largely outweigh potential disadvantages.

Chemotherapy for colorectal liver metastases (CLM) may be associated with pathologic changes to the liver parenchyma, possibly increasing the risk of surgery. The aim of this study was to determine the risk factors for chemotherapy-associated liver injuries (CALI).From 1998 to 2006, 146 patients underwent a liver resection for CLM within 3 months of preoperative chemotherapy. CALI were defined as follows: steatosisor =30%, or steatohepatitis, or moderate or severe sinusoidal lesions. Univariate and multivariate analysis were used to examine the relationship between CALI and 36 other preoperative factors.Pathologic examination showed CALI in 74/146 patients (51%), including sinusoidal lesions (n = 50), steatosisor = 30% (n = 32), and steatohepatitis (n = 15). Twenty-three patients had overlapping CALI. In multivariate analysis, BMI27 (P = .002), hyperglycemia7 mmol/l (P = .006), and an interval between chemotherapy and surgery4 weeks (P = .011) were independent risk factors for CALI, whereas aspirin intake was associated with reduced risk of CALI (P = .002). In multivariate analysis, synchronous metastases (P = .015), unresectable liver metastases at diagnosis (P = .034), GGT plasma level1.5N (P = .028), and oxaliplatin-based chemotherapy (P.01) were risk factors for sinusoidal lesions. Aspirin intake was associated with reduced risk for sinusoidal lesions (P = .03). In multivariate analysis, BMI27 (P = .026) was the only risk factor for steatosis or steatohepatitis.In patients with CLM, there are few preoperative risk factors for CALI. In patients treated by oxaliplatin-based chemotherapy, aspirin intake appears to be associated with a reduced risk of sinusoidal lesions and should be tested in a randomized phase II study.

The aim of this study was to determine the effect of chemotherapy on the accuracy of CT scan for the preoperative evaluation of colorectal liver metastases (LM). Between 1999 and 2005, 92 patients with less than six LM at diagnosis underwent surgery within four weeks of CT scan. Of these 92 patients, 60 had received chemotherapy before surgery (chemotherapy group), whereas 32 were operated without preoperative treatment (control group). Histological and surgical findings were compared with helical CT results. On a per lesion basis, the sensitivity of CT scan for the detection of LM was 71% in the chemotherapy group and 76% in the control group. On a per patient basis, the sensitivity of CT scan was 54% in the chemotherapy group and 69% in the control group. Discrepancies between CT scan and surgical or histological findings, including both false-negative and false-positive lesions, were found in 32 patients from the chemotherapy group and 10 patients from the control group (p=0.0471). In multivariate analysis, chemotherapy (p=0.032), number of LM > 3 (p=0.034), and steatosis > 30% (p=0.012) were risk factors for inadequate staging of LM by CT scan. Chemotherapy reduces the accuracy of CT scan for preoperative evaluation of colorectal LM.

Objective: The aim of the study was to evaluate the prognostic value of the ratio of metastatic to examined lymph nodes (LNR) in patients with rectal cancer. Summary Background Data: Lymph nodes ratio (LNR) has been shown to have prognostic value in patients with colon cancer. The impact of LNR on disease-free and overall survival in patients with rectal cancer is unknown. Patients and Methods: From 1998 to 2004, 307 patients underwent rectal resection for adenocarcinoma. The relationships between overall and disease-free survival at 3 years and 15 variables, including the presence or absence of metastatic lymph nodes, the total number of lymph nodes examined, and LNR, were analyzed by multivariate analysis. Patients were then assigned to 4 groups based on LNR: LNR = 0 (N0 patients), LNR = 0.01 to 0.07, LNR >0.07 to 0.2, LNR >0.2. Results: The mean number of lymph nodes examined was 22 ± 12. In the multivariate analysis, LNR was a significant prognostic factor for both disease-free (P = 0.006) and overall survival (P = 0.0003), whereas the presence or absence of metastatic lymph nodes was not. LNR remained a significant prognostic factor in the 59 patients in whom fewer than 12 lymph nodes were examined (P = 0.0058). According to LNR values, disease-free and overall survival decreased significantly with increasing LNR (P Conclusions: LNR is the most significant prognostic factor for both overall and disease-free survival in patients with rectal cancer, even in patients with fewer than 12 lymph nodes examined.

The identification of individuals who should undergo hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing remains a critical issue. The Bethesda guidelines were developed to preselect patients for microsatellite instability (MSI) testing before germline mutation screening. These criteria have been revised, and a new set of recommendations, the revised Bethesda guidelines, has been proposed.To evaluate the performance of these revised guidelines for identifying patients with HNPCC in a series of unselected consecutive patients and compare this revised guidelines-based approach with a molecular strategy (MSI testing for all tumors, followed by exclusion of MSI-positive sporadic cases from mutational testing).The study included 214 patients with newly diagnosed colorectal cancer. The MSI analysis was performed for all tumors. Germline testing, guided by immunohistochemical staining for mismatch repair proteins, was performed for patients with MSI-positive tumors. Sporadic MSI-positive tumors were identified by screening for BRAF mutation and MLH1 promoter methylation.Ninety patients (42.1%) met the revised guidelines. Twenty-one patients (9.8%) had MSI-positive tumors. Germline testing identified eight mutations (3.7%) (MSH2 N = 5, MLH1 N = 2, MSH6 N =1). The revised guidelines failed to identify 2 of the 8 probands (aged 67 and 81 yr, both with no family history). In contrast, the molecular strategy identified all patients requiring testing for germline mutation. The percentages of patients selected for germline testing by the revised guidelines and the molecular strategy were 4.2% and 5.1%, respectively.The revised Bethesda guidelines did not identify all HNPCC cases in our series. The molecular approach identified all HNPCC patients with MSI-positive tumors, increasing the workload for germline testing only slightly.

A multidisciplinary approach is necessary to determine the optimal treatment for individual patients with liver metastases. The benefits of surgical resection and systemic chemotherapy are well established Surgical resection is the only treatment that can ensure long-term survival and cure in some cases. However, only a minority of patients with liver metastases are amenable to surgery and recurrences are still observed after resection in two-thirds of patients. Efforts are being made to increase the number of candidates for surgery and to reduce the risk of post-operative recurrence, notably by means of perioperative chemotherapy and new surgical techniques.

All of the methods proposed for measuring portal blood flow are either invasive, estimate total rather than nutrient flow, and none has proved reliable in cirrhotic patients. A method has been derived from pharmacokinetic principles used for the calculation of bioavailability of drugs according to the route of administration (i.v. or p.o.) and tested experimentally in 20 pigs. A tracer dose of [14C]ursodeoxycholic acid, a biliary acid with a high-liver first-pass effect, is administered in the duodenum, and serial peripheral blood samples are taken. Later, the same dose of the same drug is administered i.v. The shunt fraction of portal blood F is obtained by the ratio of the areas under the plasma level vs. time curves ("AUC") after p.o. and i.v. administrations: (see formula in text). The pigs were divided into three experimental groups. (i) Group I: undisturbed portal flow; (ii) Group II: total diversion of portal blood with an end-to-side portacaval shunt, and (iii) Group III: partial diversion of portal blood through a side-to-side portacaval shunt. Portal flow was measured during surgery with an electromagnetic flowmeter above and below the shunt and the degree of shunting calculated. Results show that the shunt fraction measured with ursodeoxycholic acid is well-correlated with hemodynamic data. No overlap between Groups I and III is observed. It is concluded that the shunt fraction of nutrient portal blood can be measured with this noninvasive method. Minute amounts of ursodeoxycholic acid were used in order to be completely metabolized by the liver, even in spite of hepatocellular dysfunction. Therefore, this method should be valid in cirrhotic patients and be useful to decide the type of portasystemic shunt to propose for the decompression of gastroesophageal varices.

To assess the rate of R(0) resection of liver metastases achieved after chemotherapy with FOLFIRINOX.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.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.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.