新预测模型可揭示肺结节的癌变风险

根据《新英格兰医学杂志》（NEJM）9月4日在线发表的一篇报告，对于在使用小剂量计算机断层扫描（LDCT）筛查高危患者时发现的肺结节，可以使用一种新型的具有“极佳”精准性的统计学模型来预测哪些结节有发生癌变的可能；该模型结合了风险计算，这使得快速简单地根据患者及结节的特征算出肺癌风险成为可能，进而可指导临床方案的制订，并由此减少LDCT筛查项目中发病和死亡的风险和成本(N. Engl. J. Med. 2013;369:910-9)。

之前有几项研究报告称参与LDCT筛查项目的人中有超过20%被查出有至少1个需要进一步检查的肺结节，但最终只有很小比例的肺结节被诊断为恶性。在一项大规模筛查试验中，根据初步LDCT扫描提示需要进行手术治疗的病例中，有25%的结节被证实是良性的，这意味着很多患者承受了不必要的有创诊断手术。

温哥华全科医院及不列颠哥伦比亚省癌症诊疗机构的Annette McWilliams医生及其合作者建立这种模型的第一步是，针对LDCT检查中发现的已经癌变或将会癌变的结节采集大量的详细数据。为此，他们分析了 “泛加拿大肺癌早期检测研究”这项多中心群体性试验的数据，所采集的样本包括2,537名年龄介于50~75岁、无肺癌病史但在近3年内有2%以上患病风险的当前及既往吸烟者。其中，1,871人（74%）在初步扫描时被查出肺结节，共7,008个。中位随访时间为3.1年，每隔3~12个月使用LDCT复查1次，具体间隔时间视最大结节的大小而定。肺癌的诊断依据是切除标本的组织病理学评估和细针穿刺抽吸活检样本的细胞病理学检查。总共查出102个恶性结节（5.5%）。

与恶变有强相关性的肿瘤特征包括结节尺寸较大、部分实变型（相对于那些非实变型、完全实变型或肺裂周围型的结节而言）、结节位于上肺叶、结节数量少（而非大量结节）以及毛刺征。与恶变呈强相关的患者特征是女性、老年人、有肺癌家族史以及肺气肿。研究者们使用这些特征建立了预测模型，然后，在确证队列中对这个模型进行了验证，该队列包括1,090名50~74岁的当前及既往吸烟者，他们均接受了LDCT检查，这也是不列颠哥伦比亚省癌症诊疗机构在10年间进行的多项化学预防试验的一部分。从这些受试者体内共发现了5,021个肺结节。在中位随访8.6年中，从这些患者中查出了42例肺癌。利用LDCT从以上2个队列中发现的571个肺裂周围结节中无一证实为恶性结节。对这两项研究的数据进行汇总分析发现，肺裂周围结节发展为肺癌的概率是0。这些结节很可能不需要利用CT检查进行纵向随访。

研究者表示，其模型展示了极佳的预测精准性，明确地把研究对象中已经患上肺癌或发展为肺癌的患者与未患肺癌者区分开来。该模型即使应用在10 mm或更小的结节上，也能有很好的表现，而这样的小结节在临床上最具挑战性，数量也最大。该模型不适用于低危人群，目前不建议对这部分人进行LDCT检查。另外，该模型也不适用于肺门或纵膈淋巴结病患者，对于这些人来说，不论结节大小，都应该做进一步的检查。

本研究得到了特里·福克斯研究所、加拿大抗癌合作组织、美国公共卫生服务部和国家癌症研究所的支持。McWilliams医生未报告任何财务利益冲突；其合作者报告与康尔福盛、礼来、葛兰素史克、Med Biogene、奥林巴斯、辉瑞、罗氏、西门子和东芝公司有联系。

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By: MARY ANN MOON, Internal Medicine News Digital Network

New statistical models can be used to predict with "excellent" accuracy which lung nodules found on screening low-dose computed tomography scans of high-risk patients are likely to be cancerous, according to a report published online Sept. 4 in the New England Journal of Medicine.

"Our models are coupled with risk calculators, which make possible the rapid and easy calculation of lung-cancer risk given the characteristics of the person and the nodules," said Dr. Annette McWilliams of Vancouver General Hospital and the British Columbia Cancer Agency, and her associates (N. Engl. J. Med. 2013;369:910-9).

Several previous studies have reported that more than 20% of people who participate in low-dose computed tomography (LDCT) screening programs are found to have at least one lung nodule that requires further investigation. Yet only a small percentage of these nodules turn out to be malignant.

In one large screening trial, 25% of the surgical procedures that were prompted by an initial LDCT scan were performed on nodules that proved to be benign. That means that many patients were needlessly exposed to invasive diagnostic procedures, Dr. McWilliams and her colleagues said.

They developed models that would accurately predict the likelihood that such nodules are malignant, so as to guide clinical decision making and thereby reduce the risks and the costs of morbidity and mortality in LDCT screening programs.

The first step was to collect a large amount of detailed data regarding nodules identified on LDCT that were either cancerous when detected or later developed into cancers. To do that, the researchers analyzed data from the multicenter Pan-Canadian Early Detection of Lung Cancer Study, a population-based sample of current and former smokers aged 50-75 years who had no history of lung cancer but had a 3-year risk of at least 2% of developing the disease.

A total of 1,871 of the 2,537 participants in that study (74%) were found to have 7,008 lung nodules on initial scanning. They were followed for a median of 3.1 years using repeat LDCT at 3- to 12-month intervals, depending on the size of the largest nodule.

Lung cancer was diagnosed on the basis of histopathologic assessment of resection specimens or cytopathologic examination of needle-aspiration biopsy samples. A total of 102 nodules (5.5%) were found to be malignant.

Tumor characteristics that strongly correlated with malignancy were larger nodule size, partially solid type (as opposed to nonsolid, fully solid, or perifissural types), location of the nodule in the upper lung lobes, a small number of nodules (rather than numerous nodules), and the presence of spiculation.

Patient characteristics that strongly correlated with malignancy were female sex, older age, family history of lung cancer, and emphysema.

Dr. McWilliams and her associates used these traits to develop prediction models. They then tested the models in a validation cohort: 1,090 current and former smokers aged 50-74 years who underwent LDCT as part of several chemoprevention trials conducted by the British Columbia Cancer Agency over a 10-year period.

Those study subjects were found to have 5,021 lung nodules. Forty of those patients were found to have 42 lung cancers during a median follow-up of 8.6 years.

"Our models showed excellent predictive accuracy," clearly differentiating study subjects who had or developed lung cancer from those who did not. "The models performed well even when applied to nodules 10 mm or smaller, which are the most clinically challenging and most numerous nodules," the investigators noted.

None of the 571 perifissural nodules found on LDCT in those two cohorts proved to be malignant. "When the data from the two studies were pooled, the probability of lung cancer in perifissural nodules was 0," Dr. McWilliams and her associates said.

Such nodules "probably do not require longitudinal follow-up with CT," they added.

Their models are not intended for use in low-risk people for whom LDCT is not currently recommended. The models also "do not apply to persons with hilar or mediastinal lymphadenopathy, for whom further investigations are warranted irrespective of the nodule size," the researchers added.

The Terry Fox Research Institute, the Canadian Partnership Against Cancer, the U.S. Public Health Service, and the National Cancer Institute supported the study. Dr. McWilliams reported no financial conflicts of interest; her associates reported ties to CareFusion, Eli Lilly, GlaxoSmithKline, Med Biogene, Olympus, Pfizer, Roche, Siemens, and Toshiba.