BMC Cancer. 2013 Apr 9;13:189. doi: 10.1186/1471-2407-13-189.

Indirectly estimated absolute lung cancer mortality rates by smoking status and histological type based on a systematic review.

Lee PN, Forey BA.

P N Lee Statistics and Computing Ltd, Sutton, Surrey, UK.



BACKGROUND: National smoking-specific lung cancer mortality rates are unavailable, and studies presenting estimates are limited, particularly by histology. This hinders interpretation. We attempted to rectify this by deriving estimates indirectly, combining data from national rates and epidemiological studies.

METHODS: We estimated study-specific absolute mortality rates and variances by histology and smoking habit (never/ever/current/former) based on relative risk estimates derived from studies published in the 20th century, coupled with WHO mortality data for age 70-74 for the relevant country and period. Studies with populations grossly unrepresentative nationally were excluded. 70-74 was chosen based on analyses of large cohort studies presenting rates by smoking and age. Variations by sex, period and region were assessed by meta-analysis and meta-regression.

RESULTS: 148 studies provided estimates (Europe 59, America 54, China 22, other Asia 13), 54 providing estimates by histology (squamous cell carcinoma, adenocarcinoma). For all smoking habits and lung cancer types, mortality rates were higher in males, the excess less evident for never smokers. Never smoker rates were clearly highest in China, and showed some increasing time trend, particularly for adenocarcinoma. Ever smoker rates were higher in parts of Europe and America than in China, with the time trend very clear, especially for adenocarcinoma. Variations by time trend and continent were clear for current smokers (rates being higher in Europe and America than Asia), but less clear for former smokers. Models involving continent and trend explained much variability, but non-linearity was sometimes seen (with rates lower in 1991-99 than 1981-90), and there was regional variation within continent (with rates in Europe often high in UK and low in Scandinavia, and higher in North than South America).

CONCLUSIONS: The indirect method may be questioned, because of variations in definition of smoking and lung cancer type in the epidemiological database, changes over time in diagnosis of lung cancer types, lack of national representativeness of some studies, and regional variation in smoking misclassification. However, the results seem consistent with the literature, and provide additional information on variability by time and region, including evidence of a rise in never smoker adenocarcinoma rates relative to squamous cell carcinoma rates.

PMID: 23570286

A commentary:

            National lung cancer mortality rates are readily available by age, sex and time period, but are not available by smoking habits.  While numerous epidemiological studies report risks of lung cancer for current and former smokers relative to never smokers, they rarely present absolute risks by smoking habit. Indeed case-control studies, the most commonly conducted type of epidemiological study, cannot directly quantify absolute risks.

            The lack of available data on absolute risks inhibits the ability to draw all the inferences that one would like to.  In an attempt to rectify this omission, we estimated absolute risks by an indirect method: combining national estimates of the overall lung cancer rate with relative risk data from epidemiological studies conducted in the same country at the same time.  These absolute risks were derived separately for never smokers and also for former, current and ever smokers. They were calculated not only for overall lung cancer, but also for the two major histological types – squamous cell carcinoma and adenocarcinoma.  The estimates could be used to study variations by sex, period and region.

Though the indirect method we used to estimate the rates may be open to question for various reasons which we discuss in the paper, a number of clear conclusions can be drawn from the set of estimates that we derived, which covered 10 major regions of the world and a time period stretching from 1930 to 1999, the period covered by the epidemiological database of 287 studies that we used.  I refer below to some of the more interesting conclusions.

First, there is a clear tendency for rates to be higher in men than women.  This is most clearly seen in smokers, where it is evident not only for overall lung cancer but also for both the histological types studied, and can be attributed partly to the greater average cigarette consumption and duration of smoking in men.  However, it can also be seen in never smokers, except for adenocarcinoma where rates are similar in men and women.  Although we did not use data from studies conducted specifically in occupationally exposed groups, the higher rates in never smokers of squamous cell (and overall) lung cancer in men than in women may still be associated with their increased occupational exposure to carcinogens.

Our results also helped clarify why relative risks for lung cancer are much lower in China than in America and Europe.  Our results suggest this is not because in China rates are similar to those in America and Europe in never smokers, but much lower in ever smokers.  Rather it is due to never smoker rates being much higher in China, with rates in ever smokers in China quite similar to those in the West.  One reason for the high rates in Chinese never smokers may be common household use of poorly-vented stoves in various regions of China.

Another interesting result is the highly statistically significant rise in rates of adenocarcinoma in never smokers over the period studied, with the estimated rates (per 100,000 per year at age 70-74) being 6.9, 17.0, 18.1, 29.0 and 33.9 for, respectively, 1930-60, 1961-70, 1971-80, 1981-90 and 1991-1999.  These results clearly show that the large upward trend in adenocarcinoma rates seen in many countries cannot be explained by changes in the type of cigarette smoked, as recently claimed in the latest US Surgeon General Report1. That report argues that rates in adenocarcinoma in never smokers have not risen, based on changes in rates reported in the first two years of follow-up in the two large American Cancer Society CPS-I and CPS-II studies, starting in 1959 and 1982. However,  this comparison2 is based on very few adenocarcinoma deaths, the data actually being consistent statistically with at least a 2-fold rise in the rate over this period (from 1959-1961 to 1982-1984).

We feel that the set of indirect estimates we present in the paper will be helpful to researchers and allow extra insight into relationships with smoking.  Consideration could be given to the use of a similar approach for other diseases and risk factors.



1.   US Surgeon General. The health consequences of smoking – 50 years of progress: a report of the Surgeon General. Atlanta, Georgia: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014.

2.   Thun MJ, Lally CA, Flannery JT, Calle EE, Flanders WD, Heath CW, Jr.  Cigarette smoking and changes in the histopathology of lung cancer.  J Natl Cancer Inst 1997;89:1580-6.


Date:  13th February 2014

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