© Oxford University Press 2006.
IN THIS ISSUE
Risk of Serious Side Effects of Breast Cancer ChemotherapyMany clinical trials are not designed to accurately estimate the risks of important side effects posed by new treatments. To better assess the risks of serious adverse effects experienced by women with breast cancer treated with chemotherapy outside of clinical trials, Hassett et al. (p. 1108) analyzed medical insurance claims of matched breast cancer patients who did or did not receive chemotherapy but who were otherwise very similar. Chemotherapy recipients were more likely than non-recipients to experience each of eight serious side effects of chemotherapy, and the frequencies of several side effects were higher than had been reported in clinical trials. The authors estimate that the annual incremental cost of serious side effects due to breast cancer chemotherapy was $1271 per chemotherapy recipient, or approximately $45 million nationwide. They suggest that a more accurate assessment of the risks associated with cancer therapies would aid decision making by clinicians and patients.
In an editorial, Lau and Erban (p. 1096) suggest that, as we enter an era of targeted therapeutics and drugs with fewer acute toxicities, there will be a strong tendency to push them to market before adequate long-term toxicity studies have been performed. They argue that the validity of estimates of the risk of side effects based on trial data should be viewed with healthy skepticism and that diligent reporting of potential toxicities should continue once an agent enters general use.
Effects of Bortezomib on Human Neuroblastoma
Combination chemotherapy is the standard treatment for pediatric neuroblastoma, the most common solid tumor in children. However, patients develop chemoresistance over time, and the disease is eventually fatal. Bortezomib is a selective reversible inhibitor of the 26S proteasome, and it has potent antitumor activity against several adult cancers. Brignole et al. (p. 1142) examined the effects of bortezomib on the growth and survival of neuroblastoma cell lines and primary neuroblastoma cells from patients. They found that bortezomib was an effective inhibitor of neuroblastoma cell growth and angiogenesis and that it extended the survival of mice in two animal models of human neuroblastoma. The authors conclude that further clinical investigation of bortezomib in neuroblastoma patients is warranted.
Modeling Extravascular Transport and Activity of Drugs
For an anticancer drug to be effective, it must penetrate through the extravascular compartment of the tumor. However, the poor vasculature of tumors means that drugs must diffuse over long distances. If this process is inefficient, the therapeutic activity of the drug will be reduced. In this issue, Hicks et al. (p. 1118) determined the pharmacokinetic and pharmacodynamic parameters of analogs of the small-molecule, hypoxia-activated drug tirapazamine and used these to develop a spatially resolved model of extravascular transport of these compounds in a tumor. They then used this model to predict the drugs' antitumor activity in vivo. The model showed low drug concentrations in the most hypoxic regions of the tumor, leading to a much lower level of cell death than would be expected if there were no barrier to diffusion. The model-predicted level of cell death was strongly correlated with actual cell death as measured in xenograft tumors.
In an editorial, Sausville (p. 1098) writes that researchers have often lacked the tools to characterize and optimize the pharmaceutical features of new anticancer drugs. He notes that the observations of Hicks et al. incorporating drug diffusing capacity are of great importance because they offer a clear method for selecting compounds with the most desirable features. Similar models might optimize the selection of agents with other mechanisms of action.
Effect of Finasteride on Sensitivity of the PSA Test
In the Prostate Cancer Prevention Trial (PCPT), finasteride reduced the risk of prostate cancer by 25%. However, men in the finasteride group had more high-grade tumors than men in the placebo group, which reduced enthusiasm for the use of finasteride for prostate cancer prevention. Because some evidence indicated that the increased detection of high-grade disease with finasteride may have resulted from detection bias rather than from a change in the biology of the disease, Thompson et al. (p. 1128) analyzed the effects of finasteride on the performance of the prostate-specific antigen (PSA) test. PSA had statistically significantly better sensitivity for detecting both prostate cancer and high-grade prostate cancer in the finasteride arm of the PCPT than in the placebo arm. The authors conclude that finasteride is the first single factor found to enhance the performance of the PSA test and that it may improve the performance of PSA screening in the general population. They also conclude that its effect on PSA sensitivity may in part explain the increased detection of high-grade cancers with finasteride in the PCPT.
Initial Local Therapy Use In Lower-Risk Prostate Cancer
Many researchers are concerned about overtreatment of prostate cancer because many prostate cancers grow slowly and radical prostatectomy prolongs survival primarily among men younger than 65 years. Miller et al. (p. 1134) quantified the incidence of initial curative therapy (i.e., surgery or radiation therapy) among a population-based sample of men with lower-risk cancers as defined by their low likelihood of either dying from expectantly managed prostate cancer or achieving a survival benefit from local therapy. Of 24,420 men with lower-risk prostate cancers, 55% received initial curative therapy, and 81% of those men received radiation therapy. Assuming that initial expectant management is appropriate for all lower-risk cancers, the authors estimate that 10% of the men were overtreated with radical prostatectomy and 45% with radiation therapy.
Carbonated Soft Drinks and Esophageal Adenocarcinoma
The intake of carbonated soft drinks and the incidence of esophageal adenocarcinoma have both increased during the past several decades. To determine whether there is a direct association between intake and risk, Lagergren et al. (p. 1158) analyzed data from a nationwide study of Swedish residents collected between 1995 and 1997 that included 189 patients with esophageal adenocarcinoma and 820 control subjects. The authors found no association between the frequency of intake of carbonated soft drinks or low-alcohol beer and risk of esophageal adenocarcinoma.
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