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Surrogate Biomarkers (surrogate + biomarker)
Selected AbstractsA Phase II study of gemcitabine and cisplatin in advanced biliary tract cancerCANCER, Issue 6 2006Seung Tai Kim M.D. Abstract BACKGROUND The authors performed a Phase II study of combination chemotherapy with gemcitabine and cisplatin in patients with inoperable biliary tract cancer to evaluate efficacy and toxicity of this combination. In addition, the correlation between the CA 19-9 response and clinical outcome was analyzed. METHODS The eligibility criteria for this study were 1) histologically or cytologically confirmed inoperable biliary tract cancer in patients with metastatic or recurrent disease; 2) age between 18 and 70 years; 3) at least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria; 4) an Eastern Cooperative Oncology Group (ECOG) performance status , 2; 5) a life expectancy of at least 3 mos; and 6) adequate bone marrow, hepatic, and renal function. The patients received gemcitabine (1250 mg/m2, Days 1 and 8) and cisplatin (60 mg/m2, Day 1) every 3 weeks. Tumor response was assessed by RECIST criteria every 2 cycles of chemotherapy. Treatment was continued until progression of disease was documented. RESULTS Twenty-nine patients were enrolled. The median age of these patients was 52 years (range, 37 to 69 yrs), and the median ECOG performance status was 1. No complete response was observed, and 10 of 29 patients had partial responses. The overall response rate was 34.5% (95% confidence interval [CI], 17.9,54.3) for the intent-to-treat analysis. Stable disease was observed in 4 (13.8%) patients and progressive disease in 13 (44.8%) patients. The median follow-up time was 10.0 months (95% CI, 7.2,12.8). The median time to progression (TTP) was 3.0 months (95% CI, 2.12,3.88), and the median overall survival was 11 months (95% CI, 5.49,16.5). Although these results showed a better response rate (57.1 % vs. 27.3%) and survival (12 vs. 10 mos) in patients with a decline in CA 19-9 of at least 25%, these data were statistically not significant. In addition, there was a significant positive correlation between the increment in CA 19-9 values and tumor progression as determined with RECIST criteria (r = 0.96, P < 0.01). However, there was no definite correlation between the CA 19-9 response and the response according to RECIST criteria (P = 0.087). National Cancer Institute (NCI) common toxicity criteria (CTC) Grade 3 or 4 hematologic toxicities included neutropenia in 4 (14%) patients and anemia in 1 (3%) patient. Two of 4 patients with Grade 3 or 4 neutropenia had febrile episodes (7%) and required hospital admissions. NCI-CTC Grade 3 or 4 nonhematologic toxicity included nausea in 1 (3%) patient. There were no treatment-related deaths. CONCLUSION The combination chemotherapy with gemcitabine and cisplatin in inoperable biliary tract cancer was tolerable for most patients and showed modest response rates. The role of CA 19-9 monitoring as a surrogate biomarker in patients with BTC treated with gemcitabine chemotherapy should be further investigated. Cancer 2006. © 2006 American Cancer Society. [source] Systemic concentrations of antioxidants and biomarkers of macromolecular oxidative damage in horses with grass sicknessEQUINE VETERINARY JOURNAL, Issue 2 2003B. C. McGORUM Summary Reasons for performing study: The aetiopathogenesis of equine grass sickness (EGS) is unknown. The role of free radical-mediated neuronal damage has not previously been investigated in this condition. Objectives: To investigate the potential contribution of oxidative damage and antioxidant status to neurodegeneration in EGS. Methods: Systemic levels of surrogate biomarkers were determined in 10 horses with acute EGS and in 2 control populations; 10 healthy horses co-grazing with the 10 EGS horses at the onset of clinical disease, and 10 healthy mares grazing where EGS has not been reported. Results: EGS horses had alterations in levels of several antioxidants, consistent with oxidative stress, the acute phase response and/or the secondary metabolic complications of EGS. EGS horses had elevated plasma dihydroxyphenylalanine (DOPA) levels. Conclusions: The elevated DOPA levels probably reflected a generalised disturbance of catecholamine metabolism rather than increased DOPA production via free radical-mediated oxidation of tyrosine. However, there was no evidence of systemic macromolecular oxidative damage. Potential clinical relevance: Further work is required to determine whether macromolecular oxidative damage occurring at the neuronal level contributes to EGS. [source] Endpoints of therapy in chronic hepatitis B,HEPATOLOGY, Issue S5 2009Jordan J. Feld Because clearance of hepatitis B virus (HBV) infection is rarely, if ever, achievable, the goals of therapy necessarily focus on prevention of bad clinical outcomes. Ideally, therapies would be shown to prevent tangible clinical endpoints like development of cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, these endpoints typically take years or decades to occur and are therefore impractical targets for clinical trials which last only 1-2 years. As a result, surrogate biomarkers that are believed to correlate with long-term outcome are used to evaluate therapy. Of the clinical, biochemical, serological, virological, and histological endpoints that have been evaluated, none has been shown to be ideal on its own. Symptoms are uncommon and aminotransferase levels fluctuate spontaneously. Loss of hepatitis B e antigen (HBeAg) has been the traditional therapeutic endpoint; however, the indefinite durability off treatment and the emergence of HBeAg-negative disease have made it inadequate as the sole goal of therapy. Loss of hepatitis B surface antigen is associated with improved clinical outcomes, but it is rarely achieved with current therapies. Suppression of viral replication, as measured by serum HBV DNA levels, has become the major goal of therapy, particularly if maintained off therapy. Although useful, the significance of viral levels depends on the stage of disease, degree of liver damage, and the type of therapy. Finally, liver biopsy, often considered the gold standard, is invasive, prone to sampling error, and may take years to change significantly. At present, there is no ideal biomarker for evaluation of therapies for hepatitis B. Future research should be directed at development and validation of surrogate markers that accurately predict or reflect clinically relevant outcomes of chronic hepatitis B. (HEPATOLOGY 2009;49:S96,S102.) [source] Challenges of antiangiogenic cancer therapy: trials and errors, and renewed hopeJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2007Miguel Ángel Medina ,,Introduction ,,What can we learn from the previous failures? ,,Signs of hope ,,Another turn of the screw: a surrogate marker, at last ,,Future avenues for the vascular therapy of cancer Abstract Angiogenesis inhibition has been proposed as a general strategy to fight cancer. However, in spite of the promising preclinical results, a first generation of antiangiogenic compounds yielded poor results in clinical trials. Conceptual errors and mistakes in the design of trials and in the definition of clinical end-points could account for these negative results. In this context of discouraging results, a second generation of antiangiogenic therapies is showing positive results in phases II and III trials at the beginning of the twenty-first century. In fact, several combined treatments with conventional chemotherapy and antiangiogenic compounds have been recently approved. The discovery and pharmacological development of future generations of angiogenesis inhibitors will benefit from further advances in the understanding of the mechanisms involved in human angiogenesis. New styles of trials are necessary, to avoid missing potential therapeutic effects. Different clinical end-points, new surrogate biomarkers and methods of imaging will be helpful in this process. Real efficacy in clinical trials may come with the combined use of antiangiogenic agents with conventional chemotherapy or radiotherapy, and combinations of several antiangiogenic compounds with different mechanisms of action. Finally, the existing antiangiogenic strategies should include other approaches such as vascular targeting or angioprevention. [source] | ||||||||||