© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
Trastuzumab, a humanized anti-HER2 antibody, increases the clinical benefit of first-line chemotherapy in patients with metastatic breast cancers that overexpress HER2. By using multiple drug effect/combination index isobologram analysis, Pegram et al. (p. 739) characterized interactions between trastuzumab and several chemotherapeutic agents commonly used in the treatment of breast cancer. The authors found that, at a wide range of clinically achievable drug concentrations, carboplatin, 4-hydroxycyclophosphamide, docetaxel, and vinorelbine each interacted synergistically with trastuzumab in four breast cancer cell lines, whereas doxorubicin, epirubicin, and paclitaxel each interacted additively. The authors also observed a synergistic interaction with a three-drug combination of docetaxel plus carboplatin plus trastuzumab. They conclude that trastuzumab plus carboplatin, 4-hydroxycyclophosphamide, docetaxel, or vinorelbine are rational combinations for testing in clinical trials for patients with HER2-overexpressing breast cancer.
In an accompanying article, Pegram et al. (p. 759) present the results of two phase II trials, conducted by The University of California at Los Angeles-Oncology Research Network (UCLA-ORN) and the Breast Cancer International Research Group (BCIRG), evaluating docetaxel and trastuzumab in combination with cisplatin or carboplatin for the treatment of advanced breast cancer that overexpresses HER2. Each study enrolled 62 patients. Both regimens were well tolerated and had manageable toxic effects. Responses were observed in 49 of 62 patients in the BCIRG 101 trial, with a median time to progression of 9.9 months, and in 34 of 59 evaluable patients in the UCLA-ORN trial, with a median time to progression of 12.7 months. Overall response rates were higher and the median time to progression was longer for the subset of patients whose tumors harbored HER2 gene amplification. The authors conclude that combinations of docetaxel, a platinum salt, and trastuzumab are feasible and active in patients with advanced breast cancers that overexpress HER2.
In an accompanying editorial, Sledge (p. 725) shows how the studies are important with regard to HER2-positive breast cancer, its treatment, and the style of research. He stresses how rare it is that investigators conduct translational research as well designed as that of Pegram et al.
Increasing Colorectal Cancer Screening
The rate of colorectal cancer screening in the general population is low, although screening reduces the incidence of and death from this disease. Church et al. (p. 770) conducted a randomized trial of direct mailing of fecal occult blood test (FOBT) kits to compare the 1-year change in self-reported colorectal cancer screening rates among residents of a community in which colorectal cancer screening was promoted. The 1-year rate changes in absolute percentage for self-reported adherence to FOBT use and to any colorectal cancer screening test were 1.5% and 7.8%, respectively, for the control group (no kits); 16.9% and 13.2%, respectively, for those who received kits but no reminders; and 23.2% and 14.1%, respectively, for those who received kits and reminders. The authors conclude that direct mailing of FOBT kits combined with follow-up reminders promotes more rapid increases in the use of FOBT and nearly doubles the rate of increase in overall rate of adherence to colorectal cancer screening guidelines in a general population compared with a community-wide screening promotion and awareness campaign.
Adjuvant Chemotherapy Delivery in Colon Cancer
5-Fluorouracil–based adjuvant chemotherapy after surgical resection of colon cancer is standard treatment. Which delivery route—systemic or regional—is better has been controversial. Labianca et al. (p. 750) report results of a randomized clinical trial of patients with colon cancer, in which they compared the benefits of chemotherapy delivered by both routes, individually or in combination. They found that, at a median follow-up of 99 months, overall survival and event-free survival were similar in all three groups (i.e., those receiving chemotherapy by systemic delivery only, by regional delivery only, or by a combination of both). The combined regimen was no better than either single regimen alone.
In an accompanying editorial, Grem (p. 727) discusses the need to prioritize the therapeutic regimens tested. With the present rapidly changing therapeutic landscape, she states, the paradigm must shift so that meaningful and realistic differences in outcome can be obtained in a timely fashion. She concludes that the clinical research strategy must be focused, yet flexible, to accommodate the evolving status of available, novel therapies.
Hodgkin Lymphoma and Multiple Sclerosis
Epidemiologic similarities between Hodgkin lymphoma in young adults, aged 15–44 years, and multiple sclerosis indicate that these diseases may have related etiologies. Hjalgrim et al. (p. 780) used Danish population registers to determine the risk of developing multiple sclerosis for patients with Hodgkin lymphoma and their families and the risk of developing Hodgkin lymphoma for patients with multiple sclerosis and their families. They found that families afflicted by multiple sclerosis had an increased risk of developing young-adult-onset Hodgkin lymphoma and, conversely, that families afflicted by young-adult-onset Hodgkin lymphoma had an increased risk of developing multiple sclerosis. The authors conclude that the familial clustering observed for both diseases is consistent with the hypothesis that the two conditions share environmental and/or constitutional etiologies.
Factors Influencing Melanoma Risk
Few studies have investigated the joint effects of genetic, environmental (e.g., sun exposure), and host (e.g., nevus phenotypes) factors on the risk of melanoma, and these studies have been conducted in high-risk families. To explore the role of these factors in melanoma risk, Chaudru et al. (p. 785) examined both a set of families unselected by family history and a set of families known to be melanoma prone. In both types of families, there was evidence for a dominant gene that predisposes to melanoma risk; for the melanoma-prone families, that gene was identified as CDKN2A, mutations in which are known to be associated with melanoma. The melanoma risk in both types of families was also influenced by number of nevi and/or dysplastic nevi and by sun-related covariates. The authors suggest that studies of this type will be important in improving the prediction of melanoma risk in different familial settings and in devising prevention and surveillance strategies.
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