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作者：Nick Mulcahy  
出處：WebMD醫學新聞

　　December 4, 2009 — 現在還不清楚使用電腦斷層(CT)篩檢肺癌是否有助於改善死亡率，許多臨床試驗正著手研究此一議題。
　　
　　其中一個由來自荷蘭和比利時研究者進行的研究，報告指出對於死亡率沒有幫助，但是在技術上帶來臨床挑戰：如何在偵測到非鈣化肺結節病患進行。
　　
　　研究者在登載於12月3日新英格蘭醫學期刊(New England Journal of Medicine)的報告中指出，使用體積倍數時間(volume-doubling time)測量，是確認這些結節有哪些可分類為陰性、以及非臨床意義肺癌的高度準確方法。
　　
　　「Nederlands-Luevens Longanker Screening Onderzoek (NELSON)」試驗的研究者報告指出，體積計算是使用一個適用於任何CT系統的非專利軟體，在本研究中，對於陰性掃描可以提供99.7%的陰性預測值 (95%信心區間為99.6-99.8)。
　　
　　體積倍數時間是一個結節體積加倍時所估計花費的時間。
　　
　　該研究中，7,557名高風險肺癌病患接受CT掃描，結節體積倍數時間超過400天者被視為緩慢，也被歸類為陰性；掃描發現沒有結節的視為陰性。
　　
　　這些高風險病患中，第一次掃描時為CT陰性的7,361名病患中，在追蹤的兩年期間只有偵測到20名肺癌－相當高的陰性預測值。
　　
　　荷蘭鹿特丹Erasmus醫學中心的Rob J. van Klaveren博士等作者指出，第一次檢測陰性之後一年和兩年發現有肺癌的機率分別是仟分之一和仟分之三。
　　
　　【可能的疼痛與節省費用】
　　編輯評論中，兩位美國肺癌專家對於體積測量的幫助感到印象深刻。
　　
　　伊利諾州芝加哥Rush大學醫學中心的James L Mulshine醫師和加州大學舊金山癌症中心的David M. Jablons醫師寫道，研究結果認為，將肺結節體積測量整合為臨床有意義的肺癌指標之一，可改善肺癌的診斷與效率，而新增的費用有限、診斷步驟也無傷害。
　　
　　研究作者寫道，轉診進行後續診斷評估－可能包括肺切片－是醫師們發現直徑大於5mm非鈣化結節時的現行實務。
　　
　　研究作者寫道，藉由測量體積與體積加倍的時間，他們可以提供便宜又簡單的追蹤過程，也不會增加篩檢的偽陰性比率。
　　
　　如同編輯們所指出的，結節的體積增加在以前即被視為惡性腫瘤的一個規範(Radiology. 2000;217:251-256)。編輯們指出，本研究的貢獻是，確認CT篩檢這個方法的效果，此方法須在例行性臨床實務進行後續確認。
　　
　　【研究細節】
　　研究作者表示，多中心NELSON試驗的目標，是確認在隨機分組10年之後，與無篩檢相較，CT掃描是否可以使肺癌死亡率減少達至少25%。
　　
　　隨機分組的研究對象都有肺癌高風險，未接受篩檢或在開始時(第一次)、一年後和三年後篩檢。使用LungCare軟體來確認體積，之後測量任何一個非鈣化肺結節的體積加倍時間。
　　
　　結節體積成長的定義是，兩次掃描之間體積至少增加25%。他們寫道，第一次掃描時結節體積小於50 mm3、體積為50-500 mm3但是在三個月追蹤CT時體積沒有成長、體積雖有成長但是估計體積加倍時間超過400天者，則被視為陰性。
　　
　　接受篩檢的7,557名參與者中，在開始時，1,451人的非鈣化結節為50-500 mm3，這些人之中，根據三個月時的追蹤掃描，有518人的結節估計體積加倍時間超過400天。
　　
　　這些體積加倍時間緩慢者，和那些開始時的掃描為陰性者一起分組，對合併組追蹤兩年後，如前述，僅發現20例肺癌。
　　
　　Roche Diagnostics提供部分資助予本研究。van Klaveren博士報告接受Eli Lilly、Roche Pharmaceuticals與Roche Diagnostics等的諮詢費用、演講費用以及資金支持。Mulshine醫師報告接受Savara Pharmaceutical的顧問費用；Optical Society of America — Kitware的資金支持；和部份與肺癌診斷之分子方法有關的專利費用。
　　
　　N Engl J Med. 2009;361:2221-2229, 2281-2282.  


Is That CT-Detected Noncalcified Nodule Lung Cancer or Not?

By Nick Mulcahy
Medscape Medical News

December 4, 2009 — It is not yet known whether lung cancer screening with computed tomography (CT) provides a mortality benefit. A number of clinical trials are ongoing to address that unknown.

Investigators from one of those trials, from the Netherlands and Belgium, report not on mortality benefit, but on a clinical challenge presented by the technology: how to proceed with patients in whom noncalcified pulmonary nodules are detected.

The investigators, in a report published in the December 3 issue of the New England Journal of Medicine, explain that the use of a "volume-doubling time" measurement is a highly accurate method for determining which of these nodules can be categorized as a "negative" scan result and not a clinically significant lung cancer.

This volumetric measurement, which is made with the help of nonproprietary software that can be used with any CT system, helped provide a negative predictive value of 99.7% (95% confidence interval, 99.6 to 99.8) among the negative scans in the study, report the investigators from the Nederlands-Luevens Longanker Screening Onderzoek (NELSON) trial.

Volume-doubling time refers to the estimated amount of time it takes for a nodule to double its volume.

In this study of 7557 high-risk lung cancer patients who underwent CT screening, a nodule with a doubling time of more than 400 days was considered slow and, therefore, the scan was considered negative; scans that showed no nodules were also considered negative.

Among the 7361 negative CT scans detected by an initial round of scanning of these high-risk patients, only 20 lung cancers were detected during 2 years of follow-up — yielding the high negative predictive value.

"The chances of finding lung cancer 1 and 2 years after a negative first-round test were 1 in 1000 and 3 in 1000, respectively," note the authors, led by Rob J. van Klaveren, MD, PhD, from the Erasmus Medical Center in Rotterdam, the Netherlands.

Potential Pain and Money Saver

In an editorial that accompanies the study, a pair of American lung cancer experts were impressed by helpfulness of the volumetric measurements.

"The results suggest that the efficiency of the diagnostic workup for lung cancer can be improved by integrating the measurement of volume growth of lung nodules as an indicator of clinically significant lung cancer while limiting the need for additional costly or potentially harmful diagnostic procedures," write James L Mulshine, MD, from the Rush University Medical Center in Chicago, Illinois, and David M. Jablons, MD, from the University of California, San Francisco Cancer Center.

Referral for additional diagnostic evaluation — which potentially includes a lung biopsy — is the current practice when clinicians find a noncalcified nodule larger than 5 mm in diameter in this setting, write the study authors.

By measuring volume and volume-doubling time, the investigators write, they were able "to provide an inexpensive and simple follow-up process without increasing the false-negative rate of the screening test."

As the editorialists point out, volume growth of a nodule has been previously proposed as a criterion for malignancy (Radiology. 2000;217:251-256). The contribution of this study is to validate a methodology for this CT-screening workup, say the editorialists. This approach must be further validated in the setting of routine clinical practice, they add.

Study Details

The purpose of the multicenter NELSON trial is to determine whether or not, at 10 years after randomization, CT screening will have reduced mortality from lung cancer by at least 25%, compared with no screening, say the study authors.

The randomized participants, all at high risk for lung cancer, undergo either no screening or screening at baseline (the first round), 1 year, and 3 years from baseline. LungCare software was used to determine the volume and then the volume-doubling time of any noncalcified lung nodule.

Growth of a nodule was defined as an increase in volume of at least 25% between 2 scans. The first round of screening was considered negative "if the nodule volume was less than 50 mm3, if it was 50 to 500 mm3 but had not grown by the 3-month follow-up CT, or if, in the case of those that had grown, the volume-doubling time was [an estimated] 400 days or more," they write.

Among the 7557 participants who underwent screening, a noncalcified nodule between 50 mm3 and 500 mm3 was found in 1451 individuals at baseline. Among those, 518 had nodules with an estimated volume-doubling time of more than 400 days according to the follow-up scan at 3 months.

The participants with these slow volume-doubling times were grouped with those who had negative scans at the baseline screening. The combined group was followed for 2 years and, as noted above, 20 lung cancers were subsequently detected.

The study was partly funded by a grant from Roche Diagnostics. Dr. van Klaveren reports receiving advisory board fees, lecture fees, and grant support from Eli Lilly, Roche Pharmaceuticals, and Roche Diagnostics. Dr. Mulshine reports receiving consulting fees from Savara Pharmaceutical; grant support from the Optical Society of America — Kitware; and royalties from patents, some of which involve with molecular methods of lungncancer diagnosis.

N Engl J Med. 2009;361:2221-2229, 2281-2282.