Search

Patients with resected colorectal cancer liver metastases display heterogeneous clinical behavior. The identification of new prognostic factors would help in making more accurate decisions. The aim of this study was to evaluate the survival impact of circulating tumor cells (CTCs) in this setting. We conducted a prospective study of patients with resected liver metastases of colorectal cancer. Patients were included in the study from February 2009 to January 2013. The CellSearch System™ was employed for the detection of pre- and postsurgery CTCs. A positive test was defined as two or more CTCs/7.5 mL of blood. Recurrence rate, disease-free survival, and overall survival were calculated, and univariate and multivariate analyses were performed. Forty-four patients were included in our study. After a median follow-up of 60 months (range 28–74), 32 patients experienced recurrence (72.7%). The CTCs number was determined and the test was positive in 8 patients (18.6%) before surgery and 13 patients (29.5%) after surgery. The postoperative detection of CTCs was not related to any clinical outcome; however, the preoperative detection of CTCs was significantly related to behavior. All patients in the preoperative CTC-positive group relapsed, versus 65% in the CTC-negative group (p = 0.051). Disease-free survival was 19 months in the preoperative CTC-negative group versus 7 months in the CTC-positive group (p = 0.01). Additionally, overall survival was 69 months in the preoperative CTC-negative group versus 17 months in the CTC-positive group (p = 0.004). Preoperative CTC count remained significant in multivariate analysis. In this cohort of colorectal cancer liver metastases patients, the presence of two or more preoperative CTCs was associated with disease progression and poor survival despite complete resection.

The objective of the study is to determine the correlations among the variables of dose and the sphincter function (SF) in patients with locally advanced rectal cancer treated with preoperative capecitabine/radiotherapy followed by low anterior resection (LAR) + TME. We retrospectively reviewed 92 consecutive patients with LARC treated at our center with LAR from 2006 and more than 2 years free from disease. We re-contoured the anal sphincters (AS) of patients with the help of the radiologist. SF was assessed with the Wexner scale (0–20 points, being punctuation inversely proportional to annal sphincter functionality). All questionnaires were filled out between January 2010 and December 2012. Dosimetric parameters that have been studied include V 20, V 30, V 40, V 50, mean dose (D mean), minimum dose (D min), D 90 (dose received by 90% of the sphincter) and D 98. The correlations among the variables of dose and SF were studied by the Spearman correlation coefficient. Differences in SF relating to maximum doses to the sphincter were assessed by the Mann–Whitney test. Mean Wexner score was 5.5 points higher in those patients with V 20 > 0 compared to those for which V 20 = 0 (p = 0.008). In a multivariate regression model, results suggest that the effect of V 20 on poor anal sphincter control is independent of the effect of distance, with an adjusted OR of 3.42. In order to improve the SF in rectal cancer treated with preoperative radiotherapy/capecitabine followed by conservative surgery, the maximum radiation dose to the AS should be limited, when possible, to

Purpose: This paper studies the Quality of Life (QL) of Spanish advanced non-small-cell lung cancer (NSCLC) patients receiving platinum-doublet chemotherapy, compares our results with those from studies from other cultural areas, and identifies factors associated with global QL and survival prognostic variables. Methods: EORTC QLQ-C30 and QLQ-LC13 questionnaires were completed three times by 39 patients along treatment and follow-up. Univariate and multivariate logistic regression analyses were performed to study global QL determinants (≤50 points considered low global-QL score). Analyses of prognostic variables for death were performed (Cox proportional hazards models). Results: QL mean scores in the whole sample were moderately high, with limitations (>30) in physical, role, social functioning, emotional areas, fatigue, pain, neuropathy and global QL. Differences with studies from other cultural areas were mainly found in the lower score for dyspnoea (≥15 points). There were no significant differences in QL scores between the first and second assessments. In six areas, the third assessment was lower than the first and second: fatigue, hair loss (>20 points); physical, social functioning, neuropathy (10–20 points); emotional functioning (5–10 points). The best model to explain the chances of low QL includes, as explanatory variables, high emotional functioning as protective factor and fatigue as risk factor (R2 = 0.70). Eight QL areas (four pain-related) and performance status showed a statistically significant association with survival. Conclusion: Patients adapted well to their disease and treatments. Platinum-doublet can be administered in advanced NSCLC patients. Our QL data are in line with those from other cultural areas. This study was supported by grants from the Instituto de Salud Carlos III and the Departamento de Salud del Gobierno de Navarra, Spain, to finance a research assistant to interview the patients.

A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of escalating the doses of capecitabine and fixed doses of irinotecan and oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients (mCRC). A pharmacogenomic analysis was performed to investigate the association between SNPs and treatment outcome. METHODS: Eighty-seven chemotherapy-naive mCRC patients were recruited through a two-step study design; 27 were included in the dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg m(-2)) and CPT-11 (150 mg m(-2)), both on day 1, and capecitabine doses ranging from 850 to 1500 mg m(-2) bid on days 1-7 were explored. Peripheral blood samples were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy. Univariate and multivariate Cox analysis was performed to examine associations between SNPs, ORR and PFS. RESULTS: The capecitabine RD was 1000 mg m(-2) bid. Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months, the median PFS and OS were 12 (95% CI; 10.6-13.4) and 27 months (95% CI; 17.2-36.8), respectively.The GSTP1-G genotype, the Kohne low-risk category and use of a consolidation approach strongly correlated with decreased risk of progression. Patients with all favourable variables showed a median PFS of 42 months vs 3.4 months in the group with all adverse factors. A superior clinical response was obtained in patients with one GSTP1-G allele as compared with GSTP1-AA carriers (P=0.004). CONCLUSION: First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A>G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy.

Sir, We have read with particular attention the recent article published in the BJC by Alvarez et al (2013). They, through endoscopic ultrasound elastography system and conventional immuno-histochemical assays, perform an intrinsic characterisation of tumour stroma's stiffness, fibroblast density and architecture focusing in type I collagen fibre arrangement, cancer-associated fibroblasts (CAFs) and activated CAF quantification. The analysis of post-treatment tissues from patients treated with nab-paclitaxel and gemcitabine combination showed a decrease in CAF number and changes in collagen architecture. These results reaffirm the potential ability of nab-paclitaxel to target the stroma and to change its phenotype, altering the ‘hard of the rock', as described by Garber (2010), intensifying its permeability to deliver cytotoxic agents such as gemcitabine by increasing tumour vascularisation or enzymatic inhibition (Frese et al, 2012) that would suppose a better pharmacokinetic profile (Von Hoff et al, 2011). Even though it is known the clinical benefit of nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer, the cellular or molecular mechanisms that are expressly addressing this stromal involution have not been appointed yet (Alvarez et al, 2013). In this sense, authors analysed the role of secreted protein, acidic and rich in cysteine (SPARC) although they could not find the correlation between the degree of SPARC expression and clinical or pathological responses due to its high affinity to albumin protein of nab-paclitaxel. SPARC strengthens the accumulation of nab-paclitaxel mediated by albumin in the ‘tumour's Achilles' heel' (Von Hoff, Annual meeting of the American Society of Clinical Oncology, 2009); however, the mere use of this endogenous transport system would not justify the clinical impact of this combined treatment. From our point of view the key may be in what Omary et al (2007) described as ‘a star on the rise' in pancreatic disease: the pancreatic stellate cells (PaSCs; α-SMA+ Nestin++ Vimentin++) because of their role as the main manufacturers of profibrotic extracellular matrix (ECM) components of the pancreatic tumour stroma, and which should match with the activated CAFs (SMA+ Vimentin+ fibroblasts) in Alvareźs paper. In pancreatic cancer, PaSCs show increased proliferation and migration properties, and so they could be a suitable target for nab-paclitaxel because of their ability to interfere with the mitotic activity (Gradishar, 2006). Alvarez et al (2013) demonstrate that although CAFs number decreases in patients treated with nab-paclitaxel plus gemcitabine in neoadjuvant setting, the average of activated CAFs remains unchanged. We would like to explain our hypothesis related to what is happening in the stroma: it could be a transient blockade of activated CAFs metabolism, a quiescent status forced for a pharmacologically active substance. Bachem et al (2005) show that cancer cells (CCs) induce a desmoplastic reaction in pancreatic adenocarcinoma by stimulating PaSCs in a paracrine way. So it could be an indirect elimination of principal fibrogenic mediators that stimulate proliferation (platelet-derived growth factor) and ECM synthesis (fibroblast growth factor -2 and transforming growth factor -s1) of activated PaSCs through the abrogation of CCs. In this sense, the hypothetical presence of surface cellular receptors for nab-paclitaxel in CCs could be an interesting pathway biomarker for the effectiveness of the drug as authors related. On the other hand, the ablation of physiological PaSCs functioning after nab-paclitaxel inclusion, in turn, would break the two-way communication between PaSCs and CCs (Apte et al, 2013). In this context, under normal conditions CCs recruit new PaSCs to their vicinity (Vonlaufen et al, 2008), whereas nab-paclitaxel would temporarily inhibit the main mechanism that rules the desmoplastic reaction. All these molecular mechanisms would allow to maintain and stabilise the activated CAF's number despite them being dysfunctional, and also would decline its CAF progeny. In this sense, Apte et al (2013) and Bachem et al (2005) propose that activated PaSCs can transform into a myofibroblast-like phenotype sub-population with the ability of secreting excess amounts of ECM. In conclusion, due to the dynamic nature of the stromal compartment, it is critically involved in the development and progresion of pancreatic tumours (Heinemann et al, 2013). Before using neadjuvant treatment it may be important to know the stroma's cellular activation grade with regard to PaSCs plus their number. In this sense, PaSCs or activated CAFs could give us ample information about tumoral potential of the stroma itself and so could have an important contribution for the patient's prognosis. Also, the fact that activated CAFs do not decrease after nab-paclitaxel treatment could not mean that these cells are not one of the main actors of stromal disruption but the primary target of nab-paclitaxel.

We have read with great interest the article by Iguchi et al. [1], reporting their experiences with hepatic arterial infusion (HAI) of 5-fluorouracil (5FU) through a port-catheter in patients with inoperable liver metastases of colorectal cancer. On the one hand, HAI has been evaluated in liver metastases of colorectal origin in three meta-analyses [2– 4]. In all of them, a superior response rate in the experimental arm, favoring HAI, was observed. On the other hand, fluoropyrimidine HAI did not improve survival compared with systemic chemotherapy regimens based exclusively on fluoropirymidines. To our knowledge, randomized studies comparing HAI (alone or plus systemic chemotherapy) and conventional standard chemotherapy such as FOLFIRI (5FU plus Irinotecan) or FOLFOX (5FU plus Oxaliplatin) have not been published. Please note that in the referenced article FOLFIRI and FOLFOX regimens were misspelled (FORFOX and FOLFILI, respectively). In patients with initially unresectable metastases solely in the liver, maximizing the response rate in an attempt to render patients resectable is the holy grail for every oncologist [5] hoping to impact patients’ survival [6]. In this sense, HAI using a port-catheter system could be an interesting approach for the treatment of patients with preoperative intent. In fact, it permits the use of active drugs like floxuridine (FUDR) [7, 8], oxaliplatin [9, 10], and 5FU. Moreover, an ambulatory treatment option is possible thanks to the use of implantable intra-arterial devices. Interestingly enough, Iguchi et al. [1] did not find severe complications during or after HAI, unlike the treatment-related toxicities shown with older HAI regimens, which included chemical hepatitis, biliary sclerosis, and peptic ulceration or pump-related complications such as hepatic artery thrombosis, catheter displacement, hematomas, infections, and liver perfusion [11, 12]. Perhaps this treatment administration system will allow us to develop more reliable randomized clinical trials and offer a new opportunity to show the impact of HAI-based protocols on survival, especially in patients with potentially resectable liver metastases from colorectal cancer.