Strauss G M, Dominioni L
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Cancer. 2000 Dec 1;89(11 Suppl):2422-31. doi: 10.1002/1097-0142(20001201)89:11+<2422::aid-cncr16>3.3.co;2-5.
In less than a century, lung cancer has progressed from a medical curiosity to the most deadly of all malignant diseases on our planet. Because cigarette smoking is responsible for the existing global lung cancer epidemic, policy initiatives have focused almost exclusively on primary prevention. There is no question that smoking prevention is the most effective method of reducing future lung cancer mortality rates among children, adolescents, and young adults. However, smoking cessation has limited effectiveness as a lung cancer prevention strategy among long term smokers, particularly in the short term.
Conventional wisdom maintains that screening for lung cancer is ineffective. This is because no randomized trial has demonstrated a significant reduction in lung cancer mortality. Indeed, mortality was higher in two of four randomized trials focusing on chest X-ray (CXR) screening for lung cancer. Accordingly, the recommendation against CXR screening is believed to be based upon powerful and direct evidence from randomized trials that CXR screening is ineffective.
Because lung cancer is almost uniformly fatal, a plausible explanation for the ineffectiveness of lung cancer screening, at least with CXR, is readily apparent. Coventional widsom maintains that in lung cancer, the asymptomatic preclinical interval is so short that apparently localized cancers are already metastatic when they are detected at an apparently localized stage. Accordingly, "early" lesions are not truly amenable to cure through surgical resection. The problem with this interpretation, however, is that it pays no heed to what the data actually show. While mortality reductions have not been observed, significant stage and long term survival advantages have consistently been demonstrated in populations randomized to screening. Interpretation of existing trials within the strict constraints of our accepted paradigm lends support to the hypothesis that CXR screening detects and labels as cancer a substantial number of early stage lesions that are clinically unimportant in that they would never have become clinically evident during the life of the patient. The paradox is that this hypothesis, known as overdiagnosis, is biologically implausible and is not supported by any epidemiologic or clinical evidence.
Based upon our accepted paradigm, a reduction in cause specific mortality in a population-based randomized trial is accepted without question as an unbiased and definitive measure of screening effectiveness. The mortality paradigm is dependent upon two assumptions, which relate first, to the randomization process, and second, to the confounding influence of screening biases on other endpoints. The fundamental problem, however, is that these assumptions, which should always have been the focus of investigation rather than supposition, are invalid. Reconsideration of our assumptions is imperative to a proper understanding of the effect of interventions in population-based research. Indeed, reexamination of our paradigm is key to reducing the global burden of lung cancer mortality.
在不到一个世纪的时间里，肺癌已从一种医学上令人好奇的病症发展成为地球上最致命的恶性疾病。由于吸烟是当前全球肺癌流行的罪魁祸首，政策举措几乎完全集中在一级预防上。毫无疑问，预防吸烟是降低儿童、青少年和年轻人未来肺癌死亡率的最有效方法。然而，对于长期吸烟者而言，戒烟作为一种肺癌预防策略，其效果有限，尤其是在短期内。
传统观念认为肺癌筛查无效。这是因为没有随机试验表明肺癌死亡率有显著降低。事实上，在四项聚焦于胸部X光（CXR）肺癌筛查的随机试验中，有两项试验中的死亡率更高。因此，反对CXR筛查的建议被认为是基于随机试验的有力直接证据，即CXR筛查无效。
由于肺癌几乎无一例外是致命的，肺癌筛查无效（至少对于CXR而言）的一个看似合理的解释显而易见。传统观念认为，在肺癌中，无症状的临床前期间隔非常短，以至于在看似局限期被检测到的明显局限性癌症实际上已经发生转移。因此，“早期”病变实际上无法通过手术切除治愈。然而，这种解释的问题在于它没有关注实际数据所显示的情况。虽然未观察到死亡率降低，但在随机接受筛查的人群中，始终显示出显著的分期优势和长期生存优势。在我们公认的范式的严格限制内对现有试验进行解读，支持了这样一种假设，即CXR筛查检测到并标记为癌症的大量早期病变在临床上并不重要，因为它们在患者的一生中永远不会变得临床上明显。悖论在于，这种被称为过度诊断的假设在生物学上看似不合理，且没有任何流行病学或临床证据支持。
基于我们公认的范式，在基于人群的随机试验中，特定病因死亡率的降低无疑被视为筛查效果的无偏且确定的衡量标准。死亡率范式依赖于两个假设，第一个假设与随机化过程有关，第二个假设与筛查偏倚对其他终点的混杂影响有关。然而，根本问题在于，这些假设本应一直是研究的重点而非臆断，实际上却是无效的。重新审视我们的假设对于正确理解基于人群的研究中干预措施的效果至关重要。事实上，重新审视我们的范式是减轻全球肺癌死亡率负担的关键。
