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© Oxford University Press 2008.
IN THIS ISSUE
High-dose Chemotherapy for Small Cell Lung CancerSmall cell lung cancers often become resistant to chemotherapy and recur. To determine whether increasing the dose intensity of treatment with ifosfamide, carboplatin, and etoposide (ICE) would improve survival outcomes of patients with small cell lung cancer, Leyvraz et al. (p. 533) performed a randomized phase III clinical trial in which they compared 3-year survival rates of patients who were treated with high-dose (High-ICE, n = 69) vs standard-dose (Std-ICE, n = 71) therapy and the subsequent toxic effects of treatment. The median relative intensity of the treatment dose in the High-ICE arm was almost three times that in the Std-ICE arm, but 3-year survival rates were similar in both arms (18% with High-ICE vs 19% with Std-ICE). Toxic effects were observed in both arms: three (4%) and five (8%) patients died from treatment toxicity in the Std-ICE and High-ICE arms, respectively. The authors conclude that a threefold increase in treatment dose intensity does not improve the long-term outcome of patients with small cell lung cancer and that this strategy should be abandoned.
In an editorial, Bunn (p. 520) expresses hope that the results of this trial and other studies will end the "desperate" treatment of small cell lung cancer patients with high doses of toxic drugs and urges that new targeted therapies be moved to the clinic as soon as possible.
Conjugated Equine Estrogen and Risk of Benign Breast Disease
In 2002, after a mean follow-up of 5.2 years, a Women's Health Initiative (WHI) randomized controlled trial found a 1.26-fold increased risk of breast cancer among healthy postmenopausal women using a combination of conjugated equine estrogen (CEE) and progesterone as hormone replacement therapy. In 2004, after a mean follow-up of 6.8 years, the WHI randomized controlled CEE trial did not find an increase in risk of breast cancer among postmenopausal women with hysterectomy using CEE alone. However, given that estrogens stimulate the breast epithelium, Rohan et al. (p. 563) used the WHI randomized controlled CEE trial to identify and study cancer-free breast biopsy specimens. Biopsies from women taking CEE were more than twice as likely as biopsies from women taking a placebo to show evidence of benign proliferative breast disease (BPBD). Whether an increase in BPBD risk due to CEE would lead to increased risk of breast cancer is not yet known.
Neoadjuvant Chemotherapy Strategies in Early Breast Cancer
Among patients with early breast cancer, nonresponse to initial neoadjuvant chemotherapy is associated with unfavorable outcome. In the phase III randomized GeparTrio study, 2090 women were assigned to two initial cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC). von Minckwitz et al. (p. 514) randomly assigned the 622 patients who did not respond to these two initial TAC cycles to an additional four cycles of TAC or to four cycles of vinorelbine and capecitabine (NX) to investigate the non-inferiority of NX. The two arms had similar response rates, demonstrating the non-inferiority of NX treatment. Although the efficacy of NX was similar to that of TAC, NX was better tolerated. The authors conclude that new biological agents, preferably those with a mechanism of action that induces drug sensitivity, should be developed for use in neoadjuvant chemotherapy in these patients with poor prognosis.
By contrast, patients with early breast cancer who have an early response to neoadjuvant chemotherapy have chemosensitive tumors and a high probability for a pathological complete response at surgery. von Minckwitz et al. (p. 552) investigated the relationship between extended chemotherapy and pathological complete response at surgery in the 1390 patients in the GeparTrio study who responded to two initial cycles of TAC. These patients were randomly assigned to four or six additional cycles of TAC. The rate of pathological complete response in the arm with eight cycles in total was moderately but not statistically significantly better than that in the arm with six cycles in total. The authors conclude that other approaches to improve the response to neoadjuvant chemotherapy should be explored in adequately powered and controlled randomized trials.
In an editorial, Esteva and Hortobagyi (p. 521) recommend that uniform criteria be developed to define a pathological complete response. They also suggest that clinical trials be conducted to validate the use of new imaging techniques, for example, to assess whether a pathological complete response has occurred.
Risk of Cancer in Blood Donors: Donation Frequency and Iron Loss
Blood donors have low risks of cancer and mortality, but it is unclear whether their healthy lifestyle may mask deleterious long-term effects of blood donation. To examine risks of cancer overall and of cancers that have been associated with high iron levels among frequent blood and plasma donors, Edgren et al. (p. 572) performed a nested case–control study within a cohort of Swedish and Danish blood donors (more than 10,000 blood donors who developed cancer and more than 107,000 matched control subjects). No associations were observed between overall cancer risk and number of blood donations. However, among men who had donated blood 3–7 years earlier, the authors observed a trend of decreasing risks of cancers of the liver, lung, colon, stomach, and esophagus with increasing estimated levels of iron loss. They also observed an increased risk of non-Hodgkin lymphoma among frequent plasma donors. The authors conclude that the trend they observed with iron loss is questionable due to inconsistencies across latency periods and that the association between plasma donation and risk for non-Hodgkin lymphoma needs further study.
Synergistic Cytoxicity of Retinoid and Bcl-2 Inhibitor in Leukemia
The pan-Bcl-2 inhibitor ABT-737 is cytotoxic to acute lymphoblastic leukemia (ALL) cell lines and xenografts. In some cancers, resistance to ABT-737 is associated with expression of myeloid cell leukemia 1 (Mcl-1), an antiapoptotic Bcl-2 family member. Kang et al. (p. 580) conducted molecular studies in seven human ALL cell lines to study the mechanisms of resistance to ABT-737 and the synergistic effects of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) on the cytotoxicity of ABT-737. In ABT-737–resistant ALL cell lines, Mcl-1 protein levels increased with ABT-737 treatment and decreased with 4-HPR treatment. 4-HPR–induced inhibition of Mcl-1 expression occurred via c-Jun kinase phosphorylation downstream of reactive oxygen species generation. ABT-737 plus 4-HPR enhanced the mitochondrial apoptotic cascade and caused caspase-dependent synergistic multilog cytotoxicity in all seven ALL cell lines, but the combination had minimal cytotoxicity for normal lymphocytes.
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Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2008 100: 563-571.
J Natl Cancer Inst 2008 100: 580-595.
J Natl Cancer Inst 2008 100: 520-521.
J Natl Cancer Inst 2008 100: 572-579.
J Natl Cancer Inst 2008 100: 542-551.
J Natl Cancer Inst 2008 100: 533-541.
J Natl Cancer Inst 2008 100: 552-562.
J Natl Cancer Inst 2008 100: 521-523.
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