There is currently no standard of care for the second-line treatment of advanced pancreatic cancer. The aim of this analysis was to compare the different therapeutic approaches in this setting.
We ...carried out a systematic analysis of second-line studies in advanced pancreatic cancer that have progressed on or following gemcitabine and published or presented from 2000 to 2012.
Forty-four clinical trials (t) were identified; of which 34 met the inclusion criteria treating an aggregate total of 1503 patients (n). Patients who received treatments (t: 33; n: 1269) had a median overall survival (OS) of 6 months compared with 2.8 months for patients who received best supportive care only (t: 2; n: 234) (P = 0.013). The gemcitabine and platinum-based combination (t: 5; n: 154) provided a median progression-free survival and OS of 4 and 6 months compared with 1.6 and 5.3 for the rest of the regimens (t: 29; n: 1349) (P = 0.059 and 0.10, respectively) and 2.9 and 5.7 for the combination of 5-fluorouracil and platinum agents (t: 12; n: 450) (P = 0.60 and 0.22, respectively).
Although not conclusive, these data showed that the advantage of second-line chemotherapy in pancreatic cancer is very limited and there is a need for more studies.
The effects on immune cells and the inflammatory microenvironment of commonly applied cancer treatments (chemotherapeutic or biologic agents, interventional radiologic procedures) have become better ...appreciated. Likewise, the contribution of the immune system toward the effectiveness of these treatments is clearer. The relevance of immune evasion by developing tumors is endorsed by its inclusion as one of the (updated) hallmarks of cancer. A greater understanding of this dimension can potentially lead to novel applications of existing standard of care therapies, in addition to potentiating their effect. This review summarizes the immune aspects of currently employed therapies—cytotoxic chemotherapeutics, biologic agents and interventional radiologic procedures—in solid tumor malignancies with a particular focus on those agents used in gastrointestinal cancers.
In colorectal cancer patients, a high density of cytotoxic CD8+ T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/β-catenin-dependent ...autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8+ T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8+ T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer.
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•Increased mitophagy in IECs triggers lysosomal membrane permeabilization•Lysosomal membrane permeabilization enhances antigen presentation in IECs•Enhanced antigen presentation in IECs augments MHC class I presentation•Mitophagy and lysosomal integrity in IECs regulate anti-tumor immunity
Enhanced mitophagy in intestinal epithelial cells promotes anti-tumor immunity through increasing lysosomal membrane permeabilization that augments MHC I presentation and CD8+ T cell activation.
The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a ...second‐generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose‐limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m2 biweekly. Efficacy was evaluated in 15 patients with irinotecan‐refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre‐ and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre‐ and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.
What's new?
Antisense technologies offer a number of potential advantages over more traditional therapeutic approaches, including improved specificity. Here the authors treated individuals afflicted with chemo‐refractory colorectal cancer with an antisense oligonucleotide (ASO) against eIF4E, a critical translational factor often dysregulated in malignant tumors. Treatment was performed in combination with the chemotherapeutic irinotecan and halted disease progression in less than half of the treated individuals. The authors speculate based on detection of the ASO in tumor biopsies that stromal binding may reduce intracellular penetrance and lower effectiveness of the treatment.
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. However, treatment options are limited and often inefficient. The aim of this study was to determine current survival rates ...for patients diagnosed with HCC and to identify prognostic factors, which will help in choosing optimal therapies for individual patients. A retrospective analysis of medical records was performed on 389 patients who were identified through the central tumour registry at our institution from 1998 to 2003. Clinical parameters, treatments received and survival curves from time of diagnosis were analysed. Overall median survival was 11 months. Liver cirrhosis was diagnosed in 80.5% of all patients. A total of 170 patients received transarterial chemoembolisation (TACE) and/or percutaneous ethanol injections (PEI) with a median survival rate of 16 months for patients receiving TACE, 11 months for patients receiving PEI and 24 months for patients receiving TACE followed by PEI. Independent negative prognostic parameters for survival were the presence of portal vein thrombosis, advanced liver cirrhosis (Child-Pugh score B or C) and a score of >2. This study will help to estimate survival rates for patients with HCC according to their clinical status at diagnosis and the treatments received.
A link between inflammation and cancer has long been suspected, but its molecular nature remained ill defined. A key player in inflammation is transcription factor NF-κB whose activity is triggered ...in response to infectious agents and proinflammatory cytokines via the IκB kinase (IKK) complex. Using a colitis-associated cancer model, we show that although deletion of IKKβ in intestinal epithelial cells does not decrease inflammation, it leads to a dramatic decrease in tumor incidence without affecting tumor size. This is linked to increased epithelial apoptosis during tumor promotion. Deleting IKKβ in myeloid cells, however, results in a significant decrease in tumor size. This deletion diminishes expression of proinflammatory cytokines that may serve as tumor growth factors, without affecting apoptosis. Thus, specific inactivation of the IKK/NF-κB pathway in two different cell types can attenuate formation of inflammation-associated tumors. In addition to suppressing apoptosis in advanced tumors, IKKβ may link inflammation to cancer.
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Conventional cytotoxic chemotherapy has failed to show a substantial benefit for patients with HCC. Recently, a number of new ...drugs targeting molecular mechanisms involved in liver cell transformation have entered into clinical trials and led to encouraging results. In this review we summarise this data and point to a number of new compounds, which are currently being tested and can potentially broaden our therapeutic arsenal even further.
We aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in pancreatic cancer (PC) patients treated with the anti-EGFR agent erlotinib within the phase 3 randomised ...AIO-PK0104 study.
AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC; primary study end point was the time-to-treatment failure after first- and second-line therapy (TTF2). Translational analyses were performed for KRAS exon 2 mutations, EGFR expression, PTEN expression, the EGFR intron 1 and exon 13 R497K polymorphism (PM). Biomarker data were correlated with TTF, overall survival (OS) and skin rash.
Archival tumour tissue was available from 208 (74%) of the randomised patients. The KRAS mutations were found in 70% (121 out of 173) of patients and exclusively occurred in codon 12. The EGFR overexpression was detected in 89 out of 181 patients (49%) by immunohistochemistry (IHC), and 77 out of 166 patients (46%) had an EGFR gene amplification by fluorescence in-situ hybridisation (FISH); 30 out of 171 patients (18%) had a loss of PTEN expression, which was associated with an inferior TTF1 (first-line therapy; HR 0.61, P=0.02) and TTF2 (HR 0.66, P=0.04). The KRAS wild-type status was associated with improved OS (HR 1.68, P=0.005); no significant OS correlation was found for EGFR-IHC (HR 0.96), EGFR-FISH (HR 1.22), PTEN-IHC (HR 0.77), intron 1 (HR 0.91) or exon 13 R497K PM (HR 0.83). None of the six biomarkers correlated with the occurrence of skin rash.
The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study; it remains to be defined whether this association is prognostic or predictive.
To assess the efficacy of a second-line regimen of oxaliplatin and folinic acid-modulated fluorouracil in patients with advanced pancreatic cancer who have experienced progression while receiving ...gemcitabine monotherapy.
A randomized, open-label, phase III study was conducted in 16 institutions throughout Germany. Recruitment ran from January 2004 until May 2007, and the last follow-up concluded in December 2012. Overall, 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF). Patients were stratified according to the presence of metastases, duration of first-line therapy, and Karnofsky performance status.
Median follow-up was 54.1 months, and 160 patients were eligible for the primary analysis. The median overall survival in the OFF group (5.9 months; 95% CI, 4.1 to 7.4) versus the FF group (3.3 months; 95% CI, 2.7 to 4.0) was significantly improved (hazard ratio HR, 0.66; 95% CI, 0.48 to 0.91; log-rank P = .010). Time to progression with OFF (2.9 months; 95% CI, 2.4 to 3.2) versus FF (2.0 months; 95% CI, 1.6 to 2.3) was significantly extended also (HR, 0.68; 95% CI, 0.50 to 0.94; log-rank P = .019). Rates of adverse events were similar between treatment arms, with the exception of grades 1 to 2 neurotoxicity, which were reported in 29 patients (38.2%) and six patients (7.1%) in the OFF and FF groups, respectively (P < .001).
Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer.
Background: Current guidelines recommend screening colonoscopy in first-degree relatives of patients with colon cancer. The aim of this state-wide study was to investigate the compliance for ...colonoscopic in first-degree relatives, who were younger than 60 years of age. Methods: A total of 602 patients were identified from the tumor registry of the public health insurance of Lower Saxony. A questionnaire was sent to these patients, which included a number of different questions regarding their knowledge about the risk of colon cancer for their family members, as well as their participation in screening colonoscopy. Results: Data from 442 patients and their first-degree relatives (1005 siblings and 354 parents) were available; 178 parents had undergone screening colonoscopy and 344 siblings. Interestingly, the percentage of siblings who underwent screening colonoscopy was significantly higher (27%) among those siblings where the index patients were aware of the increased risk for the first-degree relatives, in contrast to the siblings of the index patients who were not aware of this risk (20%). Conclusion: This study demonstrates that only a minority of first-degree relatives undergo screening colonoscopy and that informing patients about the potential risk for their relatives will increase participation in screening colonoscopy in first-degree relatives of the patients.
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