© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 19, 1545,
October 4, 2000
© 2000 Oxford University Press
IN THIS ISSUE |
Breast carcinomas that overexpress HER2, a membrane receptor with tyrosine kinase activity, are associated with poor prognosis. Inhibition of HER2 activity with anti-HER2 antibodies can reduce growth of tumors overexpressing HER2; however, the objective response rate is low. The antibiotic geldanamycin can also reduce HER2 activity, but it is highly toxic in vivo. To enhance the inhibitory activity of the antibody and to decrease the toxicity of free geldanamycin, Mandler et al. (p. 1573) coupled an anti-HER2 monoclonal antibody (MAb), e21, to geldanamycin to form an immunoconjugate. The e21 monoclonal antibody can be internalized by HER2-positive cells. They found that the immunoconjugate inhibited proliferation of HER2-overexpressing cells and reduced the levels of HER2 much better than the free antibody or than a noninternalizing monoclonal antibody conjugated to geldanamycin. The authors conclude that conjugating geldanamycin to an internalizing anti-HER2 antibody enhances the inhibitory effect of the antibody.
In an accompanying editorial, Mendelsohn (p. 1549) notes that the promise of antibodies as mediators of effective targeted anticancer therapy is beginning to be fulfilled. In a bold step, Mandler et al. have specifically delivered geldanamycin to one of its best characterized targets, HER2, by coupling it to an anti-HER2 antibody. This promising immunoconjugate, he concludes, must now be subjected to extensive testing to determine whether it eventually can be moved into clinical trials.
Health Outcomes After Prostate Cancer Treatment
Men who receive aggressive therapy for clinically localized prostate cancer often experience complications in urinary, bowel, and sexual function that persist long after treatment. To determine how these complications differ with respect to treatment, Potosky et al. (p. 1582) compared health outcomes in a large and diverse group of men who had received either radical prostatectomy or radiotherapy. The authors found that men who had received radical prostatectomy were more likely to experience incontinence, whereas men who had received radiotherapy experienced greater declines in bowel function. Although men in both treatment groups reported large declines in sexual function, men who had received radical prostatectomy experienced statistically significantly higher rates of impotence. The men in both treatment groups reported similar general quality-of-life outcomes. The authors conclude that treatment choice, baseline function, and age affect changes in disease-specific outcomes.
"These results provide comprehensive and representative information about long-term complications of the two treatments to help guide and inform treatment decisions."
—Potosky et al.
Precursors of Gastric Cancer
Gastric cancer appears to arise through a defined series of precursor lesions; the disease is common in certain parts of the world, but the reasons for locally elevated incidence rates are not well understood. You et al. (p. 1607) prospectively examined a cohort of residents of Linqu County, China, a population with very high rates of gastric cancer. The investigators evaluated the presence of gastric lesions by means of endoscopic biopsies, measured baseline micronutrient levels and antibodies to Helicobacter pylori in blood samples, and questioned subjects on smoking habits and other lifestyle factors. The authors found that H. pylori infection, low levels of serum vitamin C, and smoking were the most important risk factors for progression of gastric precursor lesions. They also estimated that infection with H. pylori—present in approximately 70% of residents of Linqu County—is likely to account for a large proportion of gastric cancer in that region.
Insulin-Related Proteins and Risk of Colorectal Cancer
Recent theories propose that an increased risk of colorectal cancer is mediated by increases in circulating insulin levels and in the bioactivity of insulin-like growth factor (IGF)-I. Kaaks et al. (p. 1592) tested this hypothesis in a nested case–control study of women in New York in which 102 women who developed colorectal cancer were matched with 200 who did not. In blood samples collected from these women, they measured C-peptide (a marker for the secretion of insulin), IGF-I, and IGF-binding proteins (IGFBPs)-1, -2, and -3. They found that risk increased with increasing levels of C-peptide, IGF-I, and IGFBP-3 but decreased with increasing levels of IGFBP-1 and IGFBP-2. They conclude that chronically high levels of insulin may increase colorectal cancer risk by decreasing the level of IGFBP-1 and thus increasing the bioactivity of IGF-I.
Selecting Regimens for Phase III Trials for SCLC
Phase II clinical studies assess patient response rates to chemotherapy, and phase III trials assess whether a new chemotherapy regimen prolongs patient survival compared with the standard treatment. Previous studies have shown little correlation between the success of phase II and phase III trials that test the same chemotherapy regimen. Using patient survival data from phase II studies, Chen et al. (p. 1601) developed a statistical model to predict whether a particular chemotherapy regimen is likely to increase patient survival in a subsequent phase III trial for patients with extensive stage small-cell lung cancer (SCLC). The authors conclude that the model may be beneficial in deciding whether to proceed with subsequent phase III trials.
In an accompanying editorial, Pazdur (p. 1552) discusses the link between response rates and increased patient survival, noting that for a variety of reasons response rates may not predict clinical benefit, a regulator end point used in traditional drug approval. With the availability of accelerated drug approval by the U.S. Food and Drug Administration based on surrogate end points, he points out, the controversy over the relationship between response rates and clinical benefits has become increasingly complicated.
"We believe that survival data from phase II studies can be better utilized to help decide which regimens should be brought to phase III trial."
—Chen et al.
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