Fred Hutchinson Cancer Research Center, Public Health Sciences Division, 1100 Fairview Avenue North, Box 19024, Seattle, WA 98109, USA.
Math Biosci. 2012 Nov;240(1):20-34. doi: 10.1016/j.mbs.2012.05.008. Epub 2012 Jun 15.
It is currently not known whether most lung cancers detected by computerized tomography (CT) screening are aggressive and likely to be fatal if left untreated, or if a sizable fraction are indolent and unlikely to cause death during the natural lifetime of the individual. We developed a longitudinal biologically-based model of the relationship between individual smoking histories and the probability for lung cancer incidence, CT screen detection, lung cancer mortality, and other-cause mortality. The longitudinal model relates these different outcomes to an underlying lung cancer disease pathway and an effective other-cause mortality pathway, which are both influenced by the individual smoking history. The longitudinal analysis provides additional information over that available if these outcomes were analyzed separately, including testing if the number of CT detected and histologically-confirmed lung cancers is consistent with the expected number of lung cancers "in the pipeline". We assume indolent nodules undergo Gompertz growth and are detectable by CT, but do not grow large enough to contribute significantly to symptom-based lung cancer incidence or mortality. Likelihood-based model calibration was done jointly to data from 6878 heavy smokers without asbestos exposure in the control (placebo) arm of the Carotene and Retinol Efficacy Trial (CARET); and to 3,642 heavy smokers with comparable smoking histories in the Pittsburgh Lung Screening Study (PLuSS), a single-arm prospective trial of low-dose spiral CT screening for diagnosis of lung cancer. Model calibration was checked using data from two other single-arm prospective CT screening trials, the New York University Lung Cancer Biomarker Center (NYU) (n=1,021), and Moffitt Cancer Center (Moffitt) cohorts (n=677). In the PLuSS cohort, we estimate that at the end of year 2, after the baseline and first annual CT exam, that 33.0 (26.9, 36.9)% of diagnosed lung cancers among females and 7.0 (4.9,11.7)% among males were overdiagnosed due to being indolent cancers. At the end of the PLuSS study, with maximum follow-up of 5.8 years, we estimate that due to early detection by CT and limited follow-up, an additional 2.2 (2.0,2.4)% of all diagnosed cancers among females and 7.1 (6.7,8.0)% among males would not have been diagnosed in the absence of CT screening. We also find a higher apparent cure rate for lung cancer among CARET females than males, consistent with the larger indolent fraction of CT detected and histologically confirmed lung cancers among PLuSS females. This suggests that there are significant gender differences in the aggressiveness of lung cancer. Females may have an inherently higher proportion of indolent lung cancers than males, or aggressive lung cancers may be brought into check by the immune system more frequently among females than males.
目前尚不清楚通过计算机断层扫描（CT）筛查发现的大多数肺癌是否具有侵袭性，如果不治疗，是否很可能致命，还是相当一部分是惰性的，在个体的自然寿命内不太可能导致死亡。我们开发了一种基于个体吸烟史与肺癌发病、CT 筛查检出、肺癌死亡率和其他原因死亡率之间关系的纵向生物学模型。该纵向模型将这些不同的结果与一个潜在的肺癌疾病途径和一个有效的其他原因死亡率途径联系起来，这两个途径都受到个体吸烟史的影响。与这些结果分别进行分析相比，纵向分析提供了更多信息，包括测试 CT 检测到和组织学确认的肺癌数量是否与预期的“管道中”肺癌数量一致。我们假设惰性结节呈 Gompertz 生长并且可通过 CT 检测到，但不会生长到足以对基于症状的肺癌发病率或死亡率产生重大影响的程度。似然模型校准是针对 Carotene and Retinol Efficacy Trial（CARET）的对照组（安慰剂）中 6878 名无石棉暴露的重度吸烟者和 Pittsburgh Lung Screening Study（PLuSS）中 3642 名具有可比吸烟史的重度吸烟者的数据进行的；PLuSS 是一项用于诊断肺癌的低剂量螺旋 CT 筛查的单臂前瞻性试验。使用来自另外两个单臂前瞻性 CT 筛查试验的纽约大学肺癌生物标志物中心（NYU）（n=1,021）和莫菲特癌症中心（Moffitt）队列（n=677）的数据检查了模型校准。在 PLuSS 队列中，我们估计在基线和第一年 CT 检查后第二年结束时，女性中诊断出的肺癌中有 33.0%（26.9%，36.9%）和男性中有 7.0%（4.9%，11.7%）是由于惰性癌症而过度诊断的。在 PLuSS 研究结束时，最长随访时间为 5.8 年，我们估计由于 CT 的早期检测和有限的随访，在没有 CT 筛查的情况下，女性中所有诊断出的癌症中有 2.2%（2.0%，2.4%）和男性中有 7.1%（6.7%，8.0%）将不会被诊断出来。我们还发现 CARET 女性的肺癌表观治愈率高于男性，这与 PLuSS 女性中 CT 检测和组织学确认的肺癌中惰性部分较大一致。这表明肺癌的侵袭性存在显著的性别差异。女性可能比男性具有更高比例的惰性肺癌，或者女性的免疫系统更频繁地阻止侵袭性肺癌的发展。
