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© Oxford University Press 2007.
IN THIS ISSUE
Defining Endpoints in Trials of Colon Cancer Adjuvant TreatmentMany different outcomes are used as the primary endpoint of trials testing adjuvant treatments in cancer. The use of different endpoints—which may be defined differently by different investigators—in a single cancer type can make it difficult to compare the results of different studies. Punt et al. (p. 998) examined the endpoints and endpoint definitions used in published phase III clinical trials of adjuvant treatment for colon cancer over the last decade. A total of 52 studies were identified that used eight endpoints, most commonly disease-free survival, in addition to overall survival. Many endpoints were defined in multiple ways; for example, three different definitions of disease-free survival were used. The authors, all experts in colorectal cancer trials, identified the most appropriate definitions for each endpoint using a consensus process. They selected a uniform definition of disease-free survival as the most informative endpoint for studies of the adjuvant treatment of cancer because it includes all clinically relevant events, is unlikely to be biased, is observed earlier than overall survival, and is likely to reflect true treatment benefit. The authors suggest that the use of uniformly defined endpoints will add to the quality and comparability of studies of adjuvant treatments for cancer.
Nanocarriers and Drug Toxicity, Effectiveness
Although drug carriers have the potential to enhance tumor-specific targeting and reduce toxicity, in many cases these carriers reduce the effectiveness of drugs in killing tumor cells. Tang et al. (p. 1004) examined the ability of a nanocarrier composed of phospolipids encapsulating the cancer drug doxorubicin to increase the accumulation of the drug in tumors and its ability to inhibit tumor growth in two mouse models. It also reduced the extent of toxic symptoms in the mice. The authors suggest that the tightly packed structure of the nanocarrier may be the source of its high antitumor activity and low toxicity.
In an editorial, Chilkoti and Dreher (p. 983) suggest that, in the future, research should focus on systems that deliver a drug combination to give optimal spatial and temporal distribution within a tumor and on carriers that can undergo functional changes in the tumor environment.
Intravenous Bisphosphonate Therapy and Jaw Complications
Small studies had detected an association between bone deterioration and tissue death (osteonecrosis) in the jaw or face and treatment with intravenous bisphosphonates. Wilkinson et al. (p. 1016) investigated this association using data from the Surveillance, Epidemiology, and End Results (SEER) program linked to Medicare claims. The use of intravenous bisphosphonates was associated with an increased risk of jaw or facial bone surgery and of diagnosis with an inflammatory jaw condition or osteomyelitis of the jaw. The absolute risk of any jaw event at 6 years was 5.48 events per 100 patients who used intravenous bisphosphonates compared with 0.30 events per 100 patients not using such drugs. The authors conclude that the increased risk of these jaw conditions among bisphosphonate users may reflect an increased risk of osteonecrosis of the jaw.
In an editorial, Woo and Solomon (p. 986) point out that the increase in osteonecrosis of the jaw among individuals treated with bisphosphonates and the mode of action of this class of drugs support the view that there is a real and possibly causal relationship between bisphosphonate treatment and the disease. Studies are underway to identify risk factors and biomarkers for osteonecrosis of the jaw and to develop screening tests that detect early bone pathology. Meanwhile, they recommend that the number of skeletal-related events in cancer patients should be carefully weighed against the number of patients who develop osteonecrosis of the jaw before making decisions to continue or discontinue use of bisphosphonates.
Sexual Function Among Men in the Prostate Cancer Prevention Trial
The Prostate Cancer Prevention Trial (PCPT) was a randomized, double-blind, placebo-controlled study of finasteride's effectiveness in preventing prostate cancer in 18,882 men 55 years or older. Moinpour et al. (p. 1025) used a battery of questionnaires to prospectively assess the effects of finasteride and other covariates on sexual dysfunction in 17,313 PCPT participants during a 7-year period. Finasteride increased sexual dysfunction only slightly, and its impact diminished over time. After adjustment for all covariates, mean sexual dysfunction increased in men in both study arms from 6 months after randomization to the study's conclusion. The authors conclude that, for most men, finasteride has minimal effect on sexual function.
New Trial Design for Treatment in Biomarker-Defined Groups
Many new anticancer agents are aimed at patients with a specific molecular target, but these patients may constitute only a fraction of those with a given cancer. Ideally, a trial of the agent would be restricted to patients in whom levels of a biomarker for the target exceed a threshold level for sensitivity to the agent. However, in many cases the cutoff for sensitivity is not known, so a trial includes both insensitive and sensitive patients. As a result, any effect of the agent could be missed. To address this problem, Jiang et al. (p. 1036) have developed a phase III trial design that combines a test for a treatment effect in all randomly assigned patients with the establishment and validation of a cutoff point for a biomarker of the sensitive population. In a simulation study, the design identified a benefit both when the agent was effective in a broad patient population and when it was effective in a smaller, biomarker-defined subset of patients. The design's ability to identify a sensitive subpopulation was also illustrated using data from a prostate cancer clinical trial.
Early-Stage Breast Cancer Rates and Sentinel Lymph Node Biopsy
Incidence of stage IIA and IIB breast cancer with micro-metastatic lymph node involvement is increasing, but it may be due to changes in clinical practice. Cronin-Fenton et al. (p. 1044) used SEER data to investigate trends in breast cancer incidence according to stage. The incidence of breast cancer with micro-metastatic lymph node involvement increased during the 1990s. The rise was consistent with better detection due to widespread introduction of sentinel lymph node biopsy into routine clinical practice around 1997. The authors conclude that as the use of sentinel lymph node biopsy continues to increase, the number of breast cancer cases with lymph node involvement will also increase.
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