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IN THIS ISSUE
Competing Risks Analysis of Epirubicin CardiotoxicityPresent recommendations for maximum cumulative dosage of epirubicin during chemotherapy have been calculated based on this drug's risk of cardiotoxicity in the general population. However, a better estimate of optimum dosage can be obtained for defined patient subgroups when other factors that put them at risk of death from congestive heart failure and the competing factors that put them at risk of death from other causes, including cancer, are taken into account. Ryberg et al. (p. 1058) used data from a Danish population of patients with metastatic breast cancer to define patient characteristics that are associated with increased risk of epirubicin-mediated cardiotoxicity or increased risk of death from other causes. They present an advanced statistical method that takes into account deaths from other causes to estimate the maximum cumulative dosages of epirubicin that would confer a 5% risk of cardiotoxicity over a 2.5-year period for defined patient subgroups.
In an editorial, Hershman and Neugut (p. 1046) discuss the problems faced by physicians in predicting which patients might benefit from chemotherapy that includes anthracyclines, such as epirubicin, and which might face too much risk of congestive heart failure. The data of Ryberg et al., they say, has advantages over epidemiologic studies that used the SEER database to determine risk factors for anthracycline-induced congestive heart failure because the total dose of anthracyclines was known for each patient and congestive heart failure was ascertained more rigorously. The methods used by Ryberg et al., in addition to forms of personalized medicine, will help to contribute to future models for individualized cancer treatment.
Smoking Among Adult Survivors of Childhood Cancer in Britain
Survivors of childhood cancer are at increased risk of second malignant neoplasms, cardiovascular disease, and pulmonary complications, and cigarette smoking represents an additional source of risk. Frobisher et al. (p. 1068) examined cigarette smoking among 17,981 individuals who had been diagnosed with childhood cancer between 1940 and 1991 in Britain and had survived for at least 5 years after diagnosis and compared the survivors’ smoking habits with those of the general population. Almost 30% of the survivors were ever smokers and 20% were current smokers, rates lower than in the comparable general population. Among survivors, smoking was more prevalent among those not currently on long-term regular hospital follow-up. The authors suggest that advice on the health risks of smoking should be included in any program of clinical follow-up for survivors of childhood cancer and that smoking prevention and cessation interventions should be developed and implemented in this vulnerable group.
In an editorial, Emmons (p. 1048) discusses the need to address the impact of social disadvantage (eg, lower income and education) on smoking prevalence and to improve the role of the health care system in promoting smoking cessation in both childhood cancer survivors and the general population.
Screening Mammography: Vermont versus Norway
Most screening mammography in the United States differs from that in countries with formal organized screening programs by having a shorter screening interval and interpretation by a single reader versus independent double reading. To examine how these differences affect early detection of breast cancer, Hovfind et al. (p. 1082) compared recall, screen detection, and interval cancer rates and prognostic tumor characteristics for women aged 50–69 years who underwent opportunistic screening in Vermont (n = 45,050) with those of women who underwent organized screening in Norway (n = 194,430) from 1997 through 2003. Screening mammography detected cancer at about the same rate and at similar prognostic stages in Norway and Vermont, but the recall rate was lower in Norway. The interval cancer rate was higher in Vermont than in Norway, but the Vermont women with interval cancers were diagnosed with earlier stage tumors than the Norwegian women.
Effect of Lapatinib on Breast Cancer Metastasis to Brain
Approximately one-third of women with metastatic HER2-overexpressing breast cancer who receive trastuzumab therapy develop symptomatic brain metastases. Treatment options for brain metastases are currently limited to steroids, cranial radiotherapy, and surgical resection. Gril et al. (p. 1092) examined the efficacy of lapatinib, an inhibitor of the epidermal growth factor receptor (EGFR) and HER2 kinases, for preventing the outgrowth of breast cancer cells in the brain in a mouse xenograft model of brain metastasis. In vitro, lapatinib inhibited the phosphorylation of EGFR, HER2, and downstream signaling proteins; cell proliferation; and migration in brain-seeking human breast cancer cells (both with and without HER2 overexpression). In vivo, lapatinib inhibited the formation of large brain metastases by HER2-overexpressing brain-seeking breast cancer cells by 50%–53% and reduced phosphorylation of HER2 in the brain metastases.
mtDNA Heritability and Renal Cell Carcinoma
The extent to which the mitochondrial DNA (mtDNA) content of normal human cells is influenced by genetic factors and whether inherited variation of mtDNA content in normal cells contributes to cancer susceptibility remain unclear. Xing et al. (p. 1104) estimated the genetic contribution of mtDNA content by use of a classic twin study and investigated the association between mtDNA content and renal cell carcimona in a case–control study. They found that mtDNA content appears to have a high genetic heritability (ie, a high proportion of phenotypic variation was attributable to genetic variation among individuals). In addition, low mtDNA content appears to be associated with increased risk of renal cell carcinoma. The authors conclude that additional research into the association between mtDNA content and the risk of renal cell carcinoma and other cancers is warranted.
Inhibition of tumor growth using Salmonella expressing FasL
Usually we tend to think in terms of eliminating bacterial infections, but in some cases and under controlled conditions, bacteria could actually prove to be therapeutic. Attenuated strains of Salmonella typhimurium have been shown to home to tumor sites and to have few side effects when administered intravenously to mice. Loeffler et al. (p. 1113) used such bacteria to deliver the normally toxic pro-apoptotic, anti-tumor cytokine Fas ligand (FasL) to murine tumors implanted in mice. They found that tumor growth was greatly reduced in Salmonella FasL-treated mice by a mechanism that includes infiltration of the tumor by neutrophils and that requires host expression of Fas.
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J Natl Cancer Inst 2008 100: 1113-1116.
J Natl Cancer Inst 2008 100: 1058-1067.
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J Natl Cancer Inst 2008 100: 1104-1112.
J Natl Cancer Inst 2008 100: 1092-1103.
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J Natl Cancer Inst 2008 100: 1046-1047.
J Natl Cancer Inst 2008 100: 1048-1049.
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