Colorectal cancer Weitz, Jürgen; Koch, Moritz; Debus, Jürgen ...
Lancet,
01/2005, Letnik:
365, Številka:
9454
Journal Article, Book Review
Recenzirano
Every year, more than 945 000 people develop colorectal cancer worldwide, and around 492 000 patients die. This form of cancer develops sporadically, in the setting of hereditary cancer syndromes, or ...on the basis of inflammatory bowel diseases. Screening and prevention programmes are available for all these causes and should be more widely publicised. The adenoma-carcinoma sequence is the basis for development of colorectal cancer, and the underlying molecular changes have largely been identified. Prognosis depends on factors related to the patient, treatment, and tumour, and the expertise of the treatment team is one of the major determinants of outcome. New information on the molecular basis of this cancer have led to the development of targeted therapeutic options, which are being tested in clinical trials. Further clinical progress will largely depend on the broader implementation of multidisciplinary treatment strategies following the principles of evidence-based medicine.
AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse ...experimental sequence of capecitabine/erlotinib followed by gemcitabine.
281 patients with PC were randomly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib. In case of treatment failure (eg, disease progression or toxicity), patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was time to treatment failure (TTF) after 1st- and 2nd-line therapy (TTF2; non-inferiority design). KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the randomised patients.
Of the 274 eligible patients, 43 had locally advanced and 231 had metastatic disease; 140 (51%) received 2nd-line chemotherapy. Median TTF2 was estimated with 4.2 months in both arms; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine, respectively (HR 1.02, p=0.90). TTF for 1st-line therapy (TTF1) was significantly prolonged with gemcitabine/erlotinib compared to capecitabine/erlotinib (3.2 vs 2.2 months; HR 0.69, p=0.0034). Skin rash was associated with both TTF2 (rash grade 0/1/2-4:2.9/4.3/6.7 months, p<0.0001) and survival (3.4/7.0/9.6 months, p<0.0001). Each arm showed a safe and manageable toxicity profile during 1st- and 2nd-line therapy. A KRAS wild-type status (52/173 patients, 30%) was associated with an improved overall survival (HR 1.68, p=0.005).
Both treatment strategies are feasible and demonstrated comparable efficacy; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib.
The multicenter, single-arm, phase II study CEBIFOX evaluated the efficacy of a biweekly cetuximab administration in combination with FOLFOX6 as first-line therapy in KRAS (exon 2) wild-type (wt) ...metastatic colorectal cancer (mCRC).
Patients received FOLFOX6 with cetuximab (500 mg/m2) every second week. Primary endpoint was objective response rate (ORR), among others secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), and patient-reported outcome (PRO). The impact on the treatment efficacy was evaluated in explorative subgroup analyses, including extended molecular profiling and primary tumor location.
In total, 57 were included in the intention-to-treat (ITT) analyses. New RAS mutations were detected in 14.0% by post hoc next-generation sequencing analysis in 43 patients. The ORR in the all RASwt population was 70.3% with a median PFS and OS of 10.9 (95% confidence interval CI, 9.0-12.9) and 33.8 (95% CI, 21.1-45.5) months. Grade 3-5 adverse events occurred in 66.7% of the ITT, without significant impact on the PRO. Patients with right-sided primary tumors had a reduced ORR (54.5%), and median PFS and OS (10.1 and 23.8 months). BRAF mutations were detected in 11.3%. These patients had a significantly lower ORR, and median PFS and OS. Patients with RASwt/BRAFwt tumors had a notably high median PFS and OS of 14.3 and 38.9 months.
This study supports the efficacy and safety of biweekly cetuximab given in combination with FOLFOX6 in patients with RASwt/BRAFwt mCRC with left-sided primary tumor. CEBIFOX is the first trial reporting the complete dataset, including extended molecular profiling and tumor location of a biweekly administered cetuximab/FOLFOX6 in mCRC. Clinical trial number: NCT01051167.
The CEBIFOX study evaluated the efficacy of biweekly cetuximab/FOLFOX6 regimen in RAS wild-type metastatic colorectal cancer (mCRC). Fifty-seven patients were included in the intention-to-treat analyses. The objective response rate in the all RAS wild-type population was 70.3% with a median progression-free and overall survival of 10.9 and 33.8 months. This study supports the efficacy and safety of biweekly cetuximab/FOLFOX6 in RAS wild-type mCRC.
Chronic lymphocytic leukemia (CLL) is the most common subtype of adult leukemia in the western world. We here report a nationwide survey monitoring the treatment decisions concerning CLL patients in ...Germany in 2011 and compare treatment trends to sequential surveys performed previously during the last decade. The rate of patients diagnosed in early stages (Binet A/B) notably increased (2006: 66 %, 2009: 71 %, 2011: 77 %) over the years. From 2006 to 2009, the most frequent applied regime switched from chlorambucil to fludarabine containing regimes (2006 chlorambucil: 32 %, 2009: 14 %, fludarabine 2006: 23 %, 2009: 37 %). In 2011, the combination of rituximab with bendamustine (31 %) was most frequent used followed by the rituximab-fludarabine-cyclophosphamide (22 %) regime. Further, immune-chemotherapies were administered significantly more often over the observation period (2006: 15 %, 2011: 73 %). Taken together, this data reflects the change of treatment strategies over the last decade in clinical reality.
The course of viral hepatitis is thought to be affected by genetic host variability and, in particular, by genes of the major histocompatibility locus. Hepatitis A and B vaccination is a useful model ...to study the effect of host factors on the immune response to viral antigens. We aimed to assess the heritability of the HBsAg (anti-HBs) and anti-hepatitis A virus (anti-HAV) immune response and to estimate the effect of the HLA-DRB1 locus and other genetic loci unlinked to HLA.
We did an open prospective study and vaccinated 202 twin pairs with a combined recombinant HBsAg/inactivated hepatitis A vaccine. We measured antibodies to HBsAg and HAV and determined HLA-DRB1* alleles. Heritability was calculated based on variance of antibody response within pairs. Model-fitting analyses were done to analyse genetic and environmental components of vaccine responses.
Anti-HBs and anti-HAV showed heritabilities of 0·61 (95% Cl 0·41 to 0·81) and 0·36 (-0·02 to 0·73), respectively. For the anti-HBs immune response, 60% of the phenotypic variance was explained by additive genetic and 40% by non-shared environmental effects. The heritability of the HBsAg vaccine response accounted for by the DRB1* locus was estimated to be 0·25, leaving the remaining heritability of 0·36 to other gene loci.
Genetic factors have a strong effect on the immune response to HBsAg. Although genes encoded within the MHC are important for this immune response, more than half the heritability is determined outside this complex. Identification of these genes will help us to understand regulation of immune responses to viral proteins.
Hemochromatosis and Wilson disease (WD), characterized by the excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the ...frequency of p53 mutated alleles in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, we have determined the frequency of p53 mutated alleles in nontumorous liver tissue from WD and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249 (P < 0.001) and C:G to A:T transversions and C:G to T:A transitions at codon 250 (P < 0.001 and P < 0.005) were found in liver tissue from WD cases, and a higher frequency of G:C to T:A transversions at codon 249 (P < 0.05) also was found in liver tissue from hemochromatosis cases. Sixty percent of the WD and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggests nitric oxide as a source of increased oxidative stress. A high level of etheno-DNA adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochromatosis patients has been reported previously. Therefore, we exposed a wild-type p53 TK-6 lymphoblastoid cell line to 4-hydroxynonenal, an unsaturated aldehyde involved in lipid peroxidation, and observed an increase in G to T transversions at p53 codon 249 (AGG to AGT). These results are consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene.
Abstract Response to hepatitis A and B vaccines has been reported to decline with age. This open, prospective, single-site study examined the long-term response to the combined hepatitis A/B vaccine ...Twinrix ™ in 98 primary responders aged 45–67 years. Levels of antibody against hepatitis A virus (HAV) and hepatitis B surface antigen (HBs) were tested 30 months after initial vaccination. At this stage, all participants remained seropositive for anti-HAV and 70% for anti-HBs. A booster vaccination was offered to those who had responded to the first vaccination but then lost protective levels of anti-HBs. An anamnestic response was observed in all cases.
Background/Aims: In vitro studies in the subgenomic hepatitis C virus (HCV) replicon system have identified all‐trans retinoic acid (ATRA) as a potential therapeutic against hepatitis C. Thus, the ...antiviral potential of this drug should be assessed in vivo.
Methods: Twenty highly treatment experienced serotype 1 patients with non‐response to conventional or pegylated interferon‐α (Peg‐/IFN‐α) and ribavirin were randomly assigned to 12 weeks of monotherapy with ATRA (group A) or a combination of ATRA and PegIFN‐α2a (group B). HCV RNA was assessed by bDNA assay and if negative by highly sensitive polymerase chain reaction.
Results: During treatment, five of 10 patients in group A had a drop of viraemia >1log, while in group B after 8 weeks five of 10 dropped >2log, and three of 10 cleared HCV RNA from serum. Viraemia relapsed after treatment cessation. ATRA was rather well tolerated, with transient headache, dry skin and mucosa representing the most common side effects.
Conclusions: The viral load reduction under ATRA monotherapy, although limited and transient, supports the antiviral activity of ATRA. However, the rapid loss of HCV RNA in three of 10 previous non‐responders under ATRA and PegIFN‐α2a treatment demonstrates a strong additive or synergistic ATRA effect and calls for a controlled trial to assess the therapeutic potential of this drug.
Th1 and Th2 cytokines secreted by polarized effector T cells play a pivotal role in the development of autoimmune and allergic diseases. However, the genetic basis of cytokine production by T ...lymphocytes in humans is poorly understood. In this study, we investigated the genetic contribution to cytokine production and regulation of T cell-specific transcription factors in a prospective twin study. We found a substantial genetic contribution to the production of Th1 cytokines such as IFN-gamma and TNF-alpha with heritabilities of 0.85 (95% confidence intervals, 0.74-0.95) and 0.72 (0.50-0.93), respectively, whereas no genetic influence on production of the Th2 signature cytokine IL-4 was observed. Furthermore, the intrapair variability in IFN-gamma production by isolated T cells was lower in monozygotic than in dizygotic twins. In contrast to GATA-3, NFAT, and NF-kappaB, intrapair variability of T-bet, the master transcription factor of Th1 cells, was very low among monozygotic and high among dizygotic twins, indicative of a strong genetic influence on T-bet (heritability 0.93, 95% confidence interval, 0.84-1.0). Our data provide novel insights into the genetic regulation of human Th cell polarization. These data suggest that signature cytokines and cytokine signaling events of Th1 rather than Th2 cells are genetically determined and implicate that Th2-associated diseases in humans might be due to genetic variations in Th1 cytokine regulation via T-bet. This concept is highlighted by the recent finding that inactivation of the T-bet gene in mice results in development of clinical hallmark features of asthma.
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