© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
FDA and Accelerated Approval of Oncology Products
The U.S. Food and Drug Administration (FDA) accelerated approval regulations allow for the approval of drugs for serious or life-threatening diseases by permitting use of a surrogate endpoint, such as objective response rate, that is reasonably likely to predict clinical benefit, such as survival or symptom benefit. The regulations stipulate, however, that approval is granted pending completion of studies designed to confirm clinical benefit, which have to be conducted with due diligence. Dagher et al. (p. 1500) review the regulatory history of the accelerated approval process, summarize the FDA experience with 22 accelerated approvals in oncology, and discuss study designs and populations evaluated in the accelerated approval and confirmatory settings. The authors also stress the integration of accelerated approval into a comprehensive drug development plan.
Ductal Lavage Findings in the Presence of Breast Cancer
Ductal lavage has the potential to detect cancer by sampling breast epithelium in asymptomatic high-risk women. To test ductal lavage as a cancer diagnostic test, Khan et al. (p. 1510) investigated the association between cytologic findings from ductal lavage samples and histologic findings from tumor samples from women with known breast cancer undergoing mastectomy. They found poor agreement between ductal lavage cytologic test results and histologic test results. In breasts with cancer, ductal lavage appears to have low sensitivity and high specificity for cancer detection, possibly because cancer-containing ducts fail to yield fluid or have benign or mildly atypical cytology. They conclude that ductal lavage should not be recommended to high-risk women as a technique to detect breast cancer earlier than imaging modalities can.
In an accompanying editorial, Fabian et al. (p. 1488) notes that ductal lavage cannot be considered a sensitive screening tool given the absence of nipple aspiration fluid and/or atypical cells in a sizable proportion of women with known cancer and presumably in women with occult cancer as well. Its use as a risk assessment tool and/or as an indicator of response to intervention is still undergoing evaluation.
Reasons for Late-Stage Breast Cancer
To understand why late-stage breast cancers still occur despite high national breast cancer mammography screening rates, Taplin et al. (p. 1518) conducted a retrospective study of data from women 3 years before diagnosis of late-stage (case subjects) and early-stage (control subjects) breast cancers and categorized the women on the basis of their earliest screening mammogram during that period as absence of screening, absence of detection, or potential breakdown in follow-up. The authors found that 52% of the late-stage cases were in the absence-of-screening group and that the odds of having late-stage cancer were higher among women with an absence of screening. Among case subjects, women were more likely to be in the absence-of-screening group if they were aged 75 years or older, unmarried, or without a family history of breast cancer. The authors conclude that reaching these women should be the top priority for screening implementation to reduce late-stage breast cancer occurrence.
In an accompanying editorial, Baum (p. 1490) details three types of biases that can occur with breast cancer screening by mammography and illustrates how these biases can be used to provide an alternative explanation for the results observed by Taplin et al.
Stroke Risk and Tamoxifen Therapy
Tamoxifen, which is used widely to treat—and increasingly to prevent—breast cancer, has been associated with increased risk of stroke. Geiger et al. (p. 1528) assessed the impact of tamoxifen treatment for breast cancer on the risk of stroke in a nested case–control study of stroke after breast cancer. The authors found that tamoxifen use was not associated with risk of stroke, either overall or in subgroups defined by duration, dose, or recency of use. They did find that chemotherapy, but not a specific chemotherapy regimen, was associated with an increased risk of stroke, regardless of tamoxifen use. The authors conclude that, although tamoxifen use is not associated with an increased risk of stroke, the underlying mechanisms associated with possible increased stroke risk following chemotherapy treatment for breast cancer should be evaluated.
Combining IGFBP-3 and a Farnesyltransferase Inhibitor
Overexpression of insulin-like growth factor binding protein 3 (IGFBP-3) induces apoptosis in non–small-cell lung cancer (NSCLC) cells in vitro and in vivo. Because cells can become resistant to IGFBP-3 via activation of ras-mediated signaling pathways, Lee et al. (p. 1536) evaluated the therapeutic potential of combining IGFBP-3 (delivered as an adenoviral vector) with SCH66336, a farnesyltransferase inhibitor that blocks Ras activation, in NSCLC cell lines. The authors found that the combination of IGFBP-3 and SCH66336 had synergistic antiproliferative effects, and they identified that the signaling molecule Akt was critical in the apoptotic response to the combination of agents. The combination of IGFBP-3 and SCH66336 was associated with decreased tumor volume, increased apoptosis, and decreased Akt levels in a murine xenograft model.
Birth Weight and the Risk of Childhood Leukemia
It is believed that childhood leukemia often originates in utero. Because few prenatal risk factors have been identified for this disease, Hjalgrim et al. (p. 1549) explored the association between different prenatal risk factors, with a special emphasis on birth weight, and the risk of childhood leukemia in a population-based, case–control study in Denmark, Sweden, Norway, and Iceland. They found a statistically significant association between birth weight and the risk of childhood acute lymphoblastic leukemia (ALL) that was similar for all subtypes of ALL and all diagnostic age groups. They conclude that their results are compatible with the hypothesis that a high birth weight modifies the risk of ALL through proliferative stress (that is, an increased number of cell divisions of progenitor cells or preleukemic cells) and/or by increasing the number of cell at risk of leukemia-associated genetic aberrations.
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