Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth leading cause of cancer-related death in North America. Most patients present with locally advanced or metastatic ...disease that precludes curative resection. These patients have an extremely poor prognosis. In the absence of effective screening methods, considerable efforts have been made during the past decade to identify better systemic treatments. Unfortunately most trials have not shown a survival advantage for most therapies. In tandem with this increased clinical research, there has also been an expansion of preclinical laboratory investigation. These preclinical studies revealed many of the molecular mechanisms involved in pancreatic cancer development, which has provided insights into why current therapies are ineffective. These new discoveries provide some optimism that new agents inhibiting specific targets will improve outcome and overcome the resistance of pancreatic cancer to most standard treatments. We review the current standards of care for patients with locally advanced and metastatic pancreatic carcinoma and outline some future directions for the development of new treatment strategies.
Cetuximab for the treatment of colorectal cancer Jonker, Derek J; O'Callaghan, Chris J; Karapetis, Christos S ...
The New England journal of medicine,
11/2007, Volume:
357, Issue:
20
Journal Article
Peer reviewed
Cetuximab, an IgG1 chimeric monoclonal antibody against epidermal growth factor receptor (EGFR), has activity against colorectal cancers that express EGFR.
From December 2003 to August 2005, 572 ...patients who had colorectal cancer expressing immunohistochemically detectable EGFR and who had been previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin or had contraindications to treatment with these drugs underwent randomization to an initial dose of 400 mg of cetuximab per square meter of body-surface area followed by a weekly infusion of 250 mg per square meter plus best supportive care (287 patients) or best supportive care alone (285 patients). The primary end point was overall survival.
In comparison with best supportive care alone, cetuximab treatment was associated with a significant improvement in overall survival (hazard ratio for death, 0.77; 95% confidence interval CI, 0.64 to 0.92; P=0.005) and in progression-free survival (hazard ratio for disease progression or death, 0.68; 95% CI, 0.57 to 0.80; P<0.001). These benefits were robust after adjustment in a multivariable Cox proportional-hazards model. The median overall survival was 6.1 months in the cetuximab group and 4.6 months in the group assigned to supportive care alone. Partial responses occurred in 23 patients (8.0%) in the cetuximab group but in none in the group assigned to supportive care alone (P<0.001); the disease was stable in an additional 31.4% of patients assigned to cetuximab and in 10.9% of patients assigned to supportive care alone (P<0.001). Quality of life was better preserved in the cetuximab group, with less deterioration in physical function and global health status scores (both P<0.05). Cetuximab treatment was associated with a characteristic rash; a rash of grade 2 or higher was strongly associated with improved survival (hazard ratio for death, 0.33; 95% CI, 0.22 to 0.50; P<0.001). The incidence of any adverse event of grade 3 or higher was 78.5% in the cetuximab group and 59.1% in the group assigned to supportive care alone (P<0.001).
Cetuximab improves overall survival and progression-free survival and preserves quality-of-life measures in patients with colorectal cancer in whom other treatments have failed. (ClinicalTrials.gov number, NCT00079066 ClinicalTrials.gov.).
There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the ...vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway-targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs.
We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS.
A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%).
The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.
Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human ...epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer.
Patients were randomly assigned 1:1 to receive standard gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo in a double-blind, international phase III trial. The primary end point was overall survival.
A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of 0.82 (95% CI, 0.69 to 0.99; P = .038, adjusted for stratification factors; median 6.24 months v 5.91 months). One-year survival was also greater with erlotinib plus gemcitabine (23% v 17%; P = .023). Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 (95% CI, 0.64 to 0.92; P = .004). Objective response rates were not significantly different between the arms, although more patients on erlotinib had disease stabilization. There was a higher incidence of some adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2.
To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.
Summary Background Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with ...oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma. Methods Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1:1:1) to receive FOLFOX4 (oxaliplatin 85 mg/m2 , leucovorin 200 mg/m2 , and fluorouracil 400 mg/m2 bolus plus 600 mg/m2 22-h continuous infusion on day 1; leucovorin 200 mg/m2 plus fluorouracil 400 mg/m2 bolus plus 600 mg/m2 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7·5 mg/kg plus XELOX (oxaliplatin 130 mg/m2 on day 1 every 2 weeks plus oral capecitabine 1000 mg/m2 twice daily on days 1–15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4–8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov , number NCT00112918. Findings Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab–FOLFOX4, and 952 to receive bevacizumab–XELOX. After a median follow-up of 48 months (range 0–66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab–FOLFOX4 group, and 253 (27%) in the bevacizumab–XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab–FOLFOX4 versus FOLFOX4 was 1·17 (95% CI 0·98–1·39; p=0·07), and for bevacizumab–XELOX versus FOLFOX4 was 1·07 (0·90–1·28; p=0·44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab–FOLFOX4 versus FOLFOX4 was 1·27 (1·03–1·57; p=0·02), and for bevacizumab–XELOX versus FOLFOX4 was 1·15 (0·93–1·42; p=0·21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3–5 adverse events were neutropenia (FOLFOX4: 477 42% of 1126 patients, bevacizumab-FOLFOX4: 416 36% of 1145 patients, and bevacizumab–XELOX: 74 7% of 1135 patients), diarrhoea (110 10%, 135 12%, and 181 16%, respectively), and hypertension (12 1%, 122 11%, and 116 10%, respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab–FOLFOX4: 297 26%; bevacizumab–XELOX: 284 25%) than in the FOLFOX4 group (226 20%). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab–FOLFOX4, and five receiving bevacizumab–XELOX. Interpretation Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer. Funding Genentech, Roche, and Chugai.
Asthma is prevalent in Western countries, and recent explanations have evoked the actions of the gut microbiota. Here we show that feeding mice a high-fibre diet yields a distinctive gut microbiota, ...which increases the levels of the short-chain fatty acid, acetate. High-fibre or acetate-feeding led to marked suppression of allergic airways disease (AAD, a model for human asthma), by enhancing T-regulatory cell numbers and function. Acetate increases acetylation at the Foxp3 promoter, likely through HDAC9 inhibition. Epigenetic effects of fibre/acetate in adult mice led us to examine the influence of maternal intake of fibre/acetate. High-fibre/acetate feeding of pregnant mice imparts on their adult offspring an inability to develop robust AAD. High fibre/acetate suppresses expression of certain genes in the mouse fetal lung linked to both human asthma and mouse AAD. Thus, diet acting on the gut microbiota profoundly influences airway responses, and may represent an approach to prevent asthma, including during pregnancy.
Treatment with gemcitabine provides modest benefits in patients with metastatic pancreatic cancer. The addition of erlotinib to gemcitabine shows a small but significant improvement in overall ...survival (OS) versus gemcitabine alone. Phase II results for bevacizumab plus gemcitabine provided the rationale for a phase III trial of gemcitabine-erlotinib plus bevacizumab or placebo.
Patients with metastatic pancreatic adenocarcinoma were randomly assigned to receive gemcitabine (1,000 mg/m(2)/week), erlotinib (100 mg/day), and bevacizumab (5 mg/kg every 2 weeks) or gemcitabine, erlotinib, and placebo in this double-blind, phase III trial. Primary end point was OS; secondary end points included progression-free survival (PFS), disease control rate, and safety.
A total of 301 patients were randomly assigned to the placebo group and 306 to the bevacizumab group. Median OS was 7.1 and 6.0 months in the bevacizumab and placebo arms, respectively (hazard ratio HR, 0.89; 95% CI, 0.74 to 1.07; P = .2087); this difference was not statistically significant. Adding bevacizumab to gemcitabine-erlotinib significantly improved PFS (HR, 0.73; 95% CI, 0.61 to 0.86; P = .0002). Treatment with bevacizumab plus gemcitabine-erlotinib was well tolerated: safety data did not differ from previously described safety profiles for individual drugs.
The primary objective was not met. The addition of bevacizumab to gemcitabine-erlotinib did not lead to a statistically significant improvement in OS in patients with metastatic pancreatic cancer. PFS, however, was significantly longer in the bevacizumab group compared with placebo. No unexpected safety events were observed from adding bevacizumab to gemcitabine-erlotinib.
To compare long-term survival in patients with locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium treated with gemcitabine/cisplatin (GC) or ...methotrexate/vinblastine/doxorubicin/cisplatin (MVAC).
Efficacy data from a large randomized phase III study of GC versus MVAC were updated. Time-to-event analyses were performed on the observed distributions of overall and progression-free survival.
A total of 405 patients were randomly assigned: 203 to the GC arm and 202 to the MVAC arm. At the time of analysis, 347 patients had died (GC arm, 176 patients; MVAC arm, 171 patients). Overall survival was similar in both arms (hazard ratio HR, 1.09; 95% CI, 0.88 to 1.34; P = .66) with a median survival of 14.0 months for GC and 15.2 months for MVAC. The 5-year overall survival rates were 13.0% and 15.3%, respectively (P = .53). The median progression-free survival was 7.7 months for GC and 8.3 months for MVAC, with an HR of 1.09. The 5-year progression-free survival rates were 9.8% and 11.3%, respectively (P = .63). Significant prognostic factors favoring overall survival included performance score (> 70), TNM staging (M0 v M1), low/normal alkaline phosphatase level, number of disease sites (<or= three), and the absence of visceral metastases. By adjusting for these prognostic factors, the HR was 0.99 for overall survival and 1.01 for progression-free survival. The 5-year overall survival rates for patients with and without visceral metastases were 6.8% and 20.9%, respectively.
Long-term overall and progression-free survival after treatment with GC or MVAC are similar. These results strengthen the role of GC as a standard of care in patients with locally advanced or metastatic TCC.
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