Carcinogenesis proceeds through a very long preclinical period. Our collective hope is that multiple opportunities exist for chemoprevention to arrest or reverse progression towards malignancy. In the hope of faster progress with fewer subjects and lower total cost, much effort is being expended on the search for reliable biomarkers to predict the likelihood of developing cancer and/or to signal the effectiveness of chemopreventive therapy. Considerable attention is paid to identifying those markers that can act as surrogate markers for cancer development, since favorable modulation of the surrogate end-point biomarker (SEBM) may demonstrate effectiveness of a putative preventive treatment. However, the complexity of the biology challenges our ability to measure the effectiveness of attempts to arrest or reverse carcinogenesis, other than through costly and time-consuming prospective trials with disease state as the endpoint. Despite much work, to date no prehistologic biological or molecular intermediate marker has been validated for sporadic cancers. Several factors accounting for the difficulties encountered in SEBM development are reviewed. Discussion is focused on the common thread of the complexity of the underlying biological changes in carcinogenesis limiting the effectiveness of any single biomarker. Additionally, the incidence of sporadic cancers is also low, further limiting the positive predictive value of any putative prognostic marker. Recent successes in development of chemopreventive agents show the concept is valid and worth pursuing, but the current strategies to develop biochemical and genetic markers to identify surrogate biomarkers is flawed, and need to be reassessed in light of the difficulties faced over the last 20 years.

Objectives. Some risk factors for cervical cancer in situ convey risk for malignancies of the cervix and other sites. We estimate risk of several malignancies following in situ cancer of the cervix for Hispanic Americans and non-Hispanic Whites. Methods. Using California Cancer Registry data (1988-1999) we identify 56,020 women with cervical cancer in situ and observe subsequent malignancies in that cohort, with over three million woman-months of follow-up, We focus on cancers of the reproductive system and cancers related to smoking. Risk estimates are standardized incidence ratios, accounting for age, time at risk, cancer type, and race/ethnicity. Results. There is elevated risk for invasive cervical cancer (SIR=4.1, 95% Cl: 3.5-4.7), which is significantly higher for Hispanics than for non-Hispanic Whites (SlRs = 5.2 and 3.2, respectively, X-2(l)=7.66, P=0.006). Excluding cervix, non-Hispanic Whites show elevated risk for a pool of reproductive cancers (SIR= 1.8, 95% Cl: 1.4-2.4). While both groups show elevated risk for a pool of smoking-related cancers, only non-Hispanic Whites show significant risk specifically for lung cancer (SIR= 1.7, 95% CI: 1.4-2.1). Non-Hispanic Whites show elevated risk for ovarian cancer (SIR = 1.8, 95% CI: 1.3-2.4). Ovarian cancer following in situ cervical cancer is disproportionately of borderline histology (G(2)(l)=7.43, P=0.006). Conclusions. These results have implications for public health planning for women, as well as better understanding of disparities in care or biologic paths to malignancies in women with in situ cancer of the cervix. (c) 2006 Elsevier Inc. All rights reserved.

Change in the area of premalignant lesions is an end point in estimating the efficacy of chemopreventive agents. When examiners round measurements of lesion length and width, they introduce variability, which perturbs the relative percent change in lesion area and, consequently, the percent of subjects showing a clinical response. We use simulations to illustrate the resulting bias when the agent under test is effective in reducing lesion area. We simulated 500 oral leukoplakia lesions per run, with 2,500 runs at each of five levels of agent effectiveness, namely, true relative percent reduction in area of 25%, 45%, 50%, 55%, and 75%. Realistic values of lesion lengths and widths were generated randomly and then rounded to the nearest multiple of five. The product is the distribution of mean relative percent change in lesion area and the corresponding percent of subjects showing a clinical response. Even the fifth percentile of the distribution of mean relative percent change in lesion area consistently underestimated the true value, by about 6 percentage points. The percent showing a clinical response was underestimated by 50%, 37%, and 11% for true values of reduction in lesion area of 50%, 55%, and 75%, respectively. This could easily double the required sample size for a modest phase II study. We suggest that it is cost-effective to train observers of lesion length and width to eschew rounding of measurements in the chemoprevention setting.

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