Joint Belgian recommendation on screening for DPD-deficiency in patients treated with 5-FU, capecitabine (and tegafur).

OBJECTIVES: Fluoropyrimidines such as 5-Fluorouracil (5-FU), capecitabine and tegafur are drugs that are often used in the treatment of maliginancies. The enzyme dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme of 5-FU catabolism. Genetic variations within the DPYD gene (encoding for DPD protein) can lead to reduced or absent DPD activity. Treatment of DPD deficient patients with fluoropyrimidines can result in severe and, rarely, fatal toxicity. Screening for DPD deficiency should be implemented in practice. METHODS: The available methods in routine to screen for DPD deficiency were analyzed and discussed in several group meetings involving members of the oncological, genetic and toxicological societies in Belgium: targeted genotyping based on the detection of 4 DPYD variants and phenotyping, through the measurement of uracil and dihydrouracil/uracil ratio in plasma samples. RESULTS: The main advantage of targeted genotyping is the existence of prospectively validated genotype-based dosing guidelines. The main limitations of this approach are the relatively low sensitivity to detect total and partial DPD deficiency and the fact that this approach has only been validated in Caucasians so far. Phenotyping has a better sensitivity to detect total and partial DPD deficiency when performed in the correct analytical conditions and is not dependent on the ethnic origin of the patient. CONCLUSION: In Belgium, we recommend phenotype or targeted genotype testing for DPD deficiency before starting 5-FU, capecitabine or tegafur. We strongly suggest a stepwise approach using phenotype testing upfront because of the higher sensitivity and the lower cost to society.

Ten-year survival after endoscopic stent placement as a bridge to surgery in obstructing colon cancer.

BACKGROUND AND AIMS: Self-expandable metal stents are used increasingly in the treatment of obstructing colorectal cancer (CRC). Although endoscopic colon stenting is widely accepted in palliation, disagreement exists about its role in a curative setting. This study aims to describe long-term survival data in a large patient group treated with colon stenting as a bridge to surgery for CRC. METHODS: This prospective study included 97 patients who presented in a Belgian hospital between 1998 and 2013 with obstructing, although potentially curable, CRC. All patients underwent endoscopic stenting as a bridge to surgery. Procedure-related adverse events and long-term follow-up data were retrospectively collected and compared with the CRC mortality in Belgium in the same time span. RESULTS: Overall survival in this observational cohort did not differ significantly from survival in all Belgian patients with CRC in the same period (P = .14). One-year, 5-year, and 10-year survival rates were similar in both groups (95.9% vs 79.0%; 54.7% vs 51.2%; 41.0% vs 35.6%, respectively). The technical success rate was 94.8%. Seventy-three patients did not experience any adverse event. Stent migration occurred in 9 patients, whereas micro-perforations and macro-perforations were observed in 14 patients, without influence on survival. Incidence rates of peritoneal metastases did not differ between patients with and without any type of perforation (22.2% vs 15.2%, respectively; P = .47). The type of stent influenced the overall adverse event risk, mainly driven by a significant increase in stent migration in case of Wallstent enteral (Boston Scientific Corporation, Natick, Mass). CONCLUSIONS: Colon stenting before surgery is effective and did not worsen the survival outcome in patients with obstructing CRC who were treated with curative intent, which affirms the role for stenting as a bridge to surgery.

Assessment of neovascular permeability in a pancreatic tumor model using dynamic contrast-enhanced (DCE) MRI with contrast agents of different molecular weights.

OBJECT: We evaluated the relationship of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-derived pharmacokinetic parameters and contrast agents with different molecular weights (MW) in a pancreatic tumor mouse model. MATERIALS AND METHODS: Panc02 tumors were induced in mice at the hind leg. DCE-MRI was performed using Gadolinium (Gd)-based contrast agents with different MW: Gd-DOTA (0.5 kDa), P846 (3.5 kDa), and P792 (6.47 kDa). Quantitative vascular parameters (AUC, K(trans), V(e), and V(p)) were calculated according to a modified Tofts two-compartment model. Values for all contrast groups were compared for tumor and control (muscle) tissues. RESULTS: Values for K(trans) and V(e) were significantly higher in tumor tissue than in muscle tissue. When comparing contrast agents, lowest absolute K(trans) values were observed using P792. The relative increase in K(trans) in tumor tissue compared with normal tissue was highest after the use of P792. In both tumor and normal tissues, K(trans) decreased with increasing molecular weight of the contrast agent used. CONCLUSION: It was demonstrated that values for the different DCE-MRI vascular (permeability) parameters are highly dependent on the contrast agent used. Due to their potential to better differentiate tumor from muscle tissue, higher molecular weight contrast agents show promise when evaluating tumors using DCE-MRI.

Noninvasive monitoring of therapy-induced microvascular changes in a pancreatic cancer model using dynamic contrast-enhanced magnetic resonance imaging with P846, a new low-diffusible gadolinium-based contrast agent.

A predictive technique in the management of patients with cancer could improve the therapeutic index by allowing better individualization of treatment. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive technique that can provide anatomical and physiological information on the tumor and its microenvironment. We studied the effect of chemotherapy (gemcitabine), anti-angiogenesis therapy (sunitinib) and radiotherapy on the kinetics of DCE-MRI parameters in a preclinical model of pancreatic cancer using P846, a new low-diffusible contrast agent. Mice underwent DCE-MRI before treatment (MRI1), after 1 week of treatment (MRI2), and after 1 additional week (MRI3). Combined treatment with radiotherapy and sunitinib had a synergistic effect on tumor growth. In radiotherapy/sunitinib-treated mice, a decrease in K(trans) at MRI2 predicted its superior antivascular and antitumor effect at an early time. An increased K(trans) at MRI2, as seen in gemcitabine- and gemcitabine/sunitinib-treated mice, reflects increased permeability for P846 and might predict a smaller therapeutic effect at this early time. This study shows that the kinetics of DCE-MRI parameters depends on the contrast agent used. P846 appears to be a promising low-diffusible agent to monitor therapeutic effects in this preclinical cancer model, but further studies are needed to compare its behavior with Gd-DTPA and macromolecular-weight contrast agents. Sunitinib as a radiosensitizer is promising for future clinical trials in human pancreatic cancer.

Expression of hexokinases and glucose transporters in treated and untreated oesophageal adenocarcinoma.

The aim of this study was to assess the expression pattern of the high glucose affinity glucose transporters GLUT 1, 2, 3, 4, 8 and 9 and of hexokinases I, II and III in newly diagnosed oesophageal adenocarcinoma by means of immunohistochemistry. Twenty patients eligible to undergo primary surgery and 18 patients with incomplete pathological response following induction radio chemotherapy, all suffering from oesophageal adenocarcinoma, were included in the study. The intensity and amount of positive tumour cells in the immuno-reaction (histology score (Hscore)) for GLUT 1, 3, 4, 8 and 9 as well as for hexokinase I, II and III were assessed independently by two experienced observers, blinded to the clinical results. In patients that underwent primary surgery, Hscores of GLUT8 (micro 6.7; sd3.3) and GLUT1 (micro 5.5; sd: 5.3) were significantly higher than Hscores of GLUT9 (micro 2.2; sd 1.5) and GLUT3 (micro 3.2, sd: 2.5). Hscores of hexokinase I (micro : 8.3; sd: 4.3), II (micro 5.5, sd: 4.0) and III (I 1.5, sd: 0.7) were all significantly different from each other (p<0.04). In patients that underwent radio-chemotherapy prior to surgical tumour resection, micro Hscores were 6.9 (sd: 4.4) for GLUT1, 6.8 (sd: 5.3) for GLUT3, 5.9 (sd: 4.2) for GLUT8, 3.4 for GLUT9 (sd: 2.7) and 2.3 (sd: 3.6) for GLUT 4. Hscores of GLUT1 and GLUT3 were significantly higher than Hscores of GLUT4. Finally, Hscores of patients with radio-chemotherapy for GLUT3, hexokinase II and III were significantly higher when compared to patients that underwent primary surgery.

Antiangiogenic versus cytotoxic therapeutic approaches in a mouse model of pancreatic cancer: an experimental study with a multitarget tyrosine kinase inhibitor (sunitinib), gemcitabine and radiotherapy.

This work evaluated SU11248 (sunitinib) as a potential therapeutic agent, alone or in combination with the cytotoxic agent gemcitabine or radiotherapy in a murine model of pancreatic cancer. Panc02 cells were injected subcutaneously into HsdOla/MF1 mice (n=222). Treatment was administered during 1 week: sunitinib (SUN), gemcitabine (GEM), radiotherapy (RT), RT+SUN and GEM+SUN. Mice were sacrificed 14 days after treatment. The effect on microvessel density (MVD) was measured by CD31 staining. Apoptosis (sFAS, cleaved caspase-3) and proangiogenic proteins (VEGF, PlGF, EGF) were measured with ELISA and immunohistochemistry. At day 14, tumors in all groups increased significantly despite treatment. Only after RT/SUN treatment tumor growth slowed down, although the accretion was still significant (P=0.033). Highest levels of apoptosis were seen in GEM/SUN, RT/SUN and RT treated mice (respectively P<0.001, P<0.01 and P<0.05 compared to placebo). MVD was lowest in RT/SUN treated mice [compared to placebo (P<0.05), GEM (P<0.05) and GEM/SUN (P<0.01)]. Highest VEGF levels were seen after RT and RT/SUN treatment [vs. placebo (P<0.001) and vs. other treatments (P<0.01 for all comparisons)]. GEM and SUN in monotherapy lead to an up-regulation of PlGF and EGF, respectively. In conclusion, the combination treatments RT/SUN and GEM/SUN result in a more potent anti-angiogenic and antitumor effect when compared to either treatment alone. Multitargeted angiogenesis inhibitor therapy with sunitinib combined with either radiotherapy or gemcitabine may be a novel approach for human pancreatic cancer.

Expression of SGLT1, Bcl-2 and p53 in primary pancreatic cancer related to survival.

Increased expression of glucose transporters has been reported in many cancers. It is not known whether Sodium dependent GLucose Transporter 1 (SGLT1) is up-regulated in pancreatic cancer. We studied the expression of SGLT1, Bcl-2 and p53 in primary pancreatic adenocarcinomas related to survival. In primary tumors, mean SGLT1-Hscore (n = 83) was 4.24 (median 3.0, range 0.5-15.0). Patients with positive staining for Bcl-2 had higher mean SGLT1-Hscores than those without Bcl-2 expression: 5.87 vs. 3.07 (P = 0.025). No correlation was found between expression of p53 and SGLT1 (P = 0.881). On multivariate analysis TNM stage (P = 0.015) and SGLT1 (P = 0.030) showed prognostic value for disease free survival (DFS). For overall survival (OS), TNM stage (P<0.001) and chemotherapy (P = 0.048) were prognostic and SGLT1 showed a trend (P = 0.071). In a subgroup of younger patients (age < or = median, 63.9 y) who did not receive chemotherapy, SGLT1 was a very strong predictor of DFS (P = 0.005). We conclude that high SGLT1 expression (H score > median, 3.0) in pancreatic adenocarcinomas was significantly correlated with DFS and a trend was found for OS, especially in younger patients. High SGLT1 expression in primary tumors was correlated with high Bcl-2 expression, not with p53 expression. This supports our hypothesis that SGLT1 and Bcl-2 expression could serve as prognostic markers in pancreatic cancer.

Is combined 18F-fluorodeoxyglucose-positron emission tomography/computed tomography superior to positron emission tomography or computed tomography alone for diagnosis, staging and restaging of pancreatic lesions?

BACKGROUND AND STUDY AIMS: To evaluate whether combined 18F-FDG PET/CT has an additive value over 18F-FDG-PET or CT alone for diagnosis, staging and restaging of pancreatic lesions. PATIENTS AND METHODS: Forty-six consecutive patients (23 women, 23 men; median age 62.5 years) underwent FDG-PET/CT. Analysis of PET, CT and fused PET/CT images was performed by 2 readers. Patients were divided into 2 groups: diagnosis and staging of primary tumours (n=34) and restaging: screening for recurrent or progressive pancreatic cancer (n=12). Accuracy analysis was performed lesion-by-lesion and patient-by-patient. Results were correlated with histopathology or clinical follow-up. RESULTS: Ninety-five foci were identified on PET, 140 lesions on CT and 119 on PET/CT. Thirty-four lesions were defined as 'definitely pathologic' and localised in pancreas, liver, lung or bone by all 3 techniques with equal certainty. In 11 patients malignancy was ruled out with the highest certainty by PET/CT. All 3 modalities made 2 false positive diagnoses of malignancy and missed metastases or vascular ingrowth in 7 patients. The accuracy rate of PET/CT (91.2%) for diagnosis of primary pancreatic lesions is higher compared to CT (88.2%) and PET alone (82.3%). Also for locoregional staging PET/CT has a higher accuracy rate (85.3%) compared to CT (83.8%) and PET (79.4%). When used for restaging, sensitivity (90.0%) and accuracy rate (91.6%) were highest for PET and PET/CT. CT had a lower sensitivity (80.0%). CONCLUSIONS: Topographical assignment of 'spots' with high FDG uptake is superior with PET/CT compared to PET alone. Fused PET/CT has a slightly higher sensitivity and accuracy rate for diagnosis and locoregional staging of primary pancreatic lesions compared to CT alone. PET and PET/CT perform equally well in screening for recurrent or progressive pancreatic cancer, with high accuracy. Due to its unlimited access, lower radiation exposure and cost, multidetector row CT remains the imaging technique of choice for diagnosis, staging and screening for recurrent pancreatic cancer.