Title:Attributable fraction of tobacco smoking on cancer using population-based nationwide cancer incidence and mortality data in Korea

Transcription

1 Author's response to reviews Title:Attributable fraction of tobacco smoking on cancer using population-based nationwide cancer incidence and mortality data in Korea Authors: Sohee Park Sun Ha Jee Hai-Rim Shin Eun Hye Park Seung-Sik Hwang Eun Shil Cha Young Ho Yun Aesun Shin Kyu-Won Jung Sue Kyung Park Mathieu Boniol Paolo Boffetta Version:6Date:29 April 2014 Author's response to reviews: see over

2 March 31, 2014 BMC Cancer BioMed Central 236 Gray s Inn Road London WC1X 8HB United Kingdom Dear Editor-in-Chief of BMC Cancer: Thank you very much for inviting us to submit a revised manuscript entitled Attributable fraction of tobacco smoking on cancer using population-based nationwide cancer incidence and mortality data in Korea (MS No: ) to your journal. The authors highly appreciate for valuable comments from the editor and reviewers to improve this manuscript. We have made modifications on the manuscript according to the reviewers suggestions item-by-item. Detailed information regarding the revision is provided in the attached document Authors Responses to the Editor and Reviewers Comments. We apologize that it took longer than we anticipated to revise our manuscript, but we hope that we have adequately addressed the reviewers concerns and that the revised manuscript is now acceptable for publication in BMC Cancer. We are looking forward to hearing from you regarding the journal s decision. Sincerely, Hai-Rim Shin, Ph.D. Team Leader Non Communicable Diseases and Health Promotion WORLD HEALTH ORGANIZATION Western Pacific Regional Office Manila, Philippines Tel: Fax:

3 Authors Response to the editors and reviewers Reviewer #1 (Sam Egger) 1) The log-linear model used by the authors for extrapolating second hand smoking rates is very simplistic. Consider including current smoking prevalences for 05, 06, 07 as a covariate in the log-linear model as passive smoking rates will be highly correlated with current smoking rates smoking prevalences can then be plugged into the estimated log-linear equation for what will be far more believable extrapolated results. Thank you very much for your great efforts in reviewing our manuscript. As per your comment, we further investigated the available data on passive smoking in Korea, and we were able to obtain the recent data below from Korea National Nutrition and Health Examination Survey data (KNHANES, knhanes.cdc.go.kr). Following your comment, we used the data for passive smoking prevalence from 2007 to 2012, and the prevalence of current smoking from the same period to extrapolate the passive smoking prevalence in 1989 through fitting a log-linear regression model. Also reflecting your another comment (#7), we used passive smoking prevalence in 1989 to be in concordance with the year of ever-smoking prevalence in Korea. We did not include the prevalence of passive smoking of year 2005 for extrapolation although the data were available, because it was recommended so by domestic expert committee members as the passive smoking prevalence seemed to be unstable in year 2005 when the assessment of passive smoking was attempted in KNHANES for the first time. Table 1. Prevalence of passive smoking from 2007 to 2012 in Korea and estimated prevalence in 1989 by extrapolation. Year Home Workplace Men Women Men Women

4 2) Because smoking RRs vary considerably with age, the authors should at least include the age range (or some other measure of age variation) for each study listed in Supplementary tables 1 and 2. As per your recommendation, we have revised the manuscript so that the supplementary tables include age range. 3) In this study, PAFs were applied to cancer incidence and deaths aged 20 years and older because when assuming a latency of 20 years, tobacco causes no cancers below age 20 years This seems problematic for two reasons. First, if a 20-year latency is assumed, then 20 year-olds could only develop cancers due to active smoking if they were smoking at birth (and 25 year-olds would have to have been smoking at age 5 etc. etc.). Presumably smoking prevalences are negligible before age 15 in Korea, so assuming a latency of 20 years means few cancers are attributable to smoking before age 35. Second, because smoking RRs are so dependent on age, PAFs derived from RR estimates should really only be applied to age groups that the RRs were estimated from. So if the authors want estimates of total mortality/incidence attributed to smoking then they should only include studies that cover the full range of ages in which cancer cases and deaths are due to smoking. If, for example, a study only estimated RRs for subjects aged 65 and over (and this is not clear without looking into the individual studies as age ranges are not reported), then it would be inappropriate to apply the PAFs derived from the RR estimates for 65+ year-olds to incidence and mortality data for 20+ year-olds. Studies examining only limited age ranges should be excluded from this meta-analysis. As has been done in other studies, it would be reasonable to assume that very few cancers are attributable to smoking before the age of 35 and, hence, it would be reasonable to include studies with RRs for 35+ year-olds (or 20+, 25+, 30+ etc. but not with higher minimum ages). A further complication arises from the authors use of prevalences from 20 years prior to Specifically, if cancers are attributable to the smoking exposures of 20 years prior, then, for example, the PAFs for ages 35+ should be calculated using smoking prevalences for ages 15+. Given that the category former smoker already captures prior smoking exposure to some degree, it may be easier and still appropriate to use current (2009) smoking prevalences. 3

5 Cancer site Men Women Total 20 age <35 20 age 20 age <35 20 age 20 age <35 20 age Oral cavity 51 1, ,640 Pharynx Esophagus 0 1, ,097 Stomach , , ,366 Colorectum , , ,725 Liver 98 11, , ,520 Pancreas 9 2, , ,257 Larynx 1 1, ,136 Lung 46 13, , ,878 Cervix uteri , ,695 Ovary , ,684 Kidney 84 2, , ,358 Bladder 18 2, ,140 As shown in Table 2, only 1.7% of smoking-related cancer cases were among age years, and the study population of cohort studies included for RR estimation was in the age range of 30 and above. Therefore, we consider our methodology for PAF estimation using 20-year latency period and RRs from available studies with 30+ year aged population is not problematic. Table 2. Number of cancer cases among age years for smoking-related cancers. Smokingrelated cancer 755 (1.0%)* 71,975 1,172 (3.0%)* 38,335 1,927 (1.7%)* 110,310 All cancer 2,306 96,826 6,084 91,068 8, ,894 * % in cancer cases in age 20+ years. 4) The authors state that applying PAF to cancer incidence cases and deaths, we only used the number of cases and deaths aged 20 years and older. However, it is not clear whether the total number of cases/deaths used as the denominator in calculation of PAFs of all cancers (eg. 96,826 male cases used to calculate a % of all cancer of 20.9%) is for cases/deaths aged 20+ or all ages. Please make it clear in all of the text, tables and figures which age groups estimates refer to. For example, make it clear whether 20.9% of all male cancers are attributable to smoking or whether 20.9% of all cancers aged 20+ are attributable to smoking. It is important to be clear about which age-ranges your estimates refer to, even if this means repeating information in different tables, figures and areas of text. If all PAFs relate to ages 20+ then statements such as Tobacco 4

6 smoking was responsible for.(32.9%) cancer deaths among men. in 2009 in Korea are incorrect (although I accept that the difference between all 0age and 20+ PAFs will be small because there are few cancer deaths before age 20). Yes, we only used the cancer cases aged 20 years and older for PAF calculation. Per your recommendation, we revised our manuscript to be more explicit about the fact that our PAF estimation was for adults. However, as you also mentioned, the proportion of cancer incident cases and deaths among age <20 were very small, and we believe its effect would be minimal. 5) A number of papers (including Hanley et. al. cited by the authors of the current paper) (1-3) have pointed out that the first PAF formula on page 9 is known to be inappropriate when using adjusted RRs. The appropriate PAF formula for adjusted RRs is given by equation 2C in Hanley et. al.(1) (and equation 5 in Rockhill et. al.(3)) and is based on the prevalence of exposure in the cases (these would be obtained from the individual studies). The authors should either use the appropriate formula or justify why they use an inappropriate formula (and also show that it doesn t make much difference through sensitivity analyses). Using the correct formula would also get rid of the complications arising from having 20-year prior prevalences (as pointed out in comment 3 above). We very much appreciate your valuable comments. We reviewed the three papers you referred. As we mentioned in our discussion, we purposely used the adjusted RRs to control for the potential over-estimation of PAF for smoking and alcohol. Because we could not obtain the prevalence of exposure in cases from individual studies, we could not apply the method by Hanley et al or Rockhill et al, and we used the modified Levin s formula for multiple categories instead. 6) The term active smoking could be misinterpreted at first instance (ie the term intuitively suggests current but not former smoking). Perhaps mention early on in the paper that active smokers comprise former and current smokers. Thank you for your comment. We used the term active smoking to differentiate from passive smoking second hand smoking. But we now see that it could be misinterpreted as you pointed out. Therefore, we have revised the manuscript by using the term ever-smoking to avoid the confusion. 5

7 7) Why were 1990 prevalences extrapolated for passive smoking when 1989 prevalences were used for active smoking? As we also described in the answer to your comment #1, we have re-calculated the 1989 prevalence for passive smoking as well. As per your comment, we further investigated the available data on passive smoking in Korea, and we were able to obtain the recent data below from Korea National Nutrition and Health Examination Survey data (KNHANES, knhanes.cdc.go.kr). Following your comment, we used the data for passive smoking prevalence from 2007 to 2012, and the prevalence of current smoking from the same period to extrapolate the passive smoking prevalence in 1989 through fitting a log-linear regression model as shown in Table 1. Table 1. Prevalence of passive smoking from 2007 to 2012 in Korea and estimated prevalence in 1989 by extrapolation. Year Home Workplace Men Women Men Women ) The authors state: In cases of heterogeneity, as determined by I 2 (I2#80) and Q statistics (p <0.05), I m not sure what this means as Q and I 2 are different statistics (I 2 =100% (Q-df)/Q). Did both conditions have to be satisfied for heterogeneity? This seems an usually high burden of proof. We considered both criteria to decide whether the studies are heterogeneous. Since Q statistics is known to have low statistical power to detect the heterogeneity particularly when the number of studies is small, we also considered the Higgin s I 2 value. Therefore, as a rule of thumb, we considered that there existed heterogeneity among studies if the Q 6

8 statistics was significant or I 2 value was above 75%. We revised our methods section to describe this in more detail. 9) The authors should state in the text, Table2 and Supplementary Table 3 whether the passive smoking RR for lung cancer was obtained from mortality or incidence RRs. This is not clear. Thank you very much for your valuable comment. We originally combined the data for both cancer incidence and mortality for estimating the RRs of second-hand smoking. However, reflecting your comments, we have re-analyzed the data to separately estimate the RRs for cancer incidence and cancer mortality due to second-hand smoking where possible. If a separate RR estimate for cancer mortality was not available, we used the RR for cancer incidence in place of RR for cancer mortality. We have revised our manuscript and table accordingly. 10) Step H in Supplementary Table 3 required a leap of faith for me. The authors might consider including a footnote which explains why the proportion of never smokers among lung cancer cases not attributable to smoking is the same as the proportion of never smokers in the general population. Intuitively, I would have thought never smokers would be over-represented among lung-cancers not attributable to smoking. Thank you for your helpful comment. While your intuition that never smokers would be over-represented among lung-cancers not attributable to smoking may be right, our calculation followed the formal definition of PAF calculation by assuming the proportional distribution of non-smoking-related lung cancers among ever- and neversmokers, and this is the approach that has been used by other published literature (listed below). International Agency for Research on Cancer (ed.): Attributable causes of cancer in France in the year 2000; Inoue M, Sawada N, Matsuda T, Iwasaki M, Sasazuki S, Shimazu T, Shibuya K, Tsugane S: Attributable causes of cancer in Japan in systematic assessment to estimate current burden of cancer attributable to known preventable risk factors in Japan. Ann Oncol 2012, 23(5):

9 11) The authors state: For stomach and colorectal cancer, there was no reliable RR estimates for women, hence RR of men was used for women instead. This also the case for oral cavity and pharynx mortality according to Table 1 and this should be said. Also, why wasn t the same substitution used for oral cavity and pharynx incidence (where no RRs are given for women in Table 1)? The RR estimates for oral cavity and pharyngeal cancers were for the combined cancers of two, therefore we described it in the footnote. Furthermore, due to the sample size limitation, the RR for former and current smokers in women could not be separately estimated, therefore the RRs comparing ever-smokers vs. never-smokers was used. We revised the footnotes of Table 1 to have more explicit description. 12) Please include reference numbers for the studies in the Supplementary tables so that they can be cross-referenced with the reference numbers listed in Table 1. Per your recommendation, we included reference numbers in the Supplementary tables. 13) The results section needs improving. For example the statement laryngeal cancer had the highest RR estimate is vague, it is often not clear whether the reported result refers to mortality or incidence, the RR for lung cancer mortality is 3.2 for women according to Table 1 not 3.6 as reported in the results. Thank you for your careful review. We agree that our description of results was somewhat vague and was not clear about the distinction between cancer incidence and mortality. Per your recommendation, we revised our results section to be more explicit. 14) In Figure 3, what do the intervals and shaded bars represent? Please include a legend. We included the legend for Figure 3 to describe the shaded bars and intervals. 15) The statement in the Discussion Three in ten cancer deaths among Korean men in 2009 could have been prevented had there been no smokers back in early 1990s in Korea. is at odds with the analysis. The active smoking prevalences that were used were for 1989 not the early 1990s. Also, even if there were no smokers in 1989, cancers and cancer deaths in 2009 were still attributable to ex-smoking in 1989 (otherwise you should have 8

10 excluded ex-smokers from your calculations). Hence the statement in the Conclusion Approximately one out of three lung cancer deaths in Korean men in 2009 could have been prevented had there been no smokers back in is also wrong. Thank you very much for your keen comments. Acknowledging your point, we have now revised our text not to state the exact time period for smoking exposure, for example, by getting rid of back in early 1990s in describing the results and conclusions. 16) The authors state A meta-analysis by Gandini et al. showed that smokers are at almost 10-fold elevated risk of developing lung cancer compared to never smokers in Caucasians, and 10-fold increase in African-Americans [66]. Please check that this is what this study reports. Other studies have found higher lung cancer RRs for African- Americans. Yes, in fact, according to the meta-analysis by Gandini et al, currents smokers are at 9.94 times higher risk of lung cancer in African-Americans and 10.2 times higher risk in Caucasians, hence very slightly higher in Caucasians. But what we reported in our text citing Gandini et al was correct. So we left the statement as it is. (Captured from Gandini et al. Table II. ) 9

11 Reviewer #2 (Kota Katanoda) 1) The current discussion focused too much on the comparisons with results from Western populations. Such discussion, especially on the difference in lung cancer relative risks between Western and Asian populations, has been sufficiently covered in previous literature. Authors should discuss the comparison within Asian countries in more detail. For example, why the relative risk of lung cancer in Korea was smaller than that reported from Japan or China? How about relative risk of passive smoking? There has been affluent literature on the health effect of smoking and PAF from Asian countries. Thank you for your great efforts in reviewing our manuscript. Regarding the low RR for lung cancer especially in men, we are also wondering why. In fact, the previous estimate of RR for lung cancer in 2009 using Korean studies was about 4.0, however, when we updated the literature search later in August 2012 by adding a few cohort and case-control studies conducted in Korea (e.g., KMCC cohort study), the RR estimates of current smokers for lung cancer became lower. Possible reason for lower RR in Koreans for lung cancer is that the background risk of lung cancer in non-smokers in Korea is high, therefore the relative risk for current smokers is not as high as in other countries. But further studies will have to be gathered to investigate such differences. We added more discussion comparing Korean results with other countries. 2) A part of relative risks used in this study seem to be unstable. Many values are below one, in spite of the fact that analyzed cancer sites are all causally associated with smoking. For several cancer sites, the relative risk for current smokers is smaller than that for former smokers. Several relative risks have wide confidence intervals. For cancer sites with unstable values from Korean local data, authors should consider using data from other Asian populations. Yes, we agree that the relative risk estimates for some cancer sites are unstable. However, it was important to use the Korean population data as much as possible in this study because the purpose of the study was to evaluate the Korean-specific PAF. And the error bars shown in Figure 3 are in fact not confidence intervals. It is rather showing the range of the PAF if we used the extreme lower bound and upper bound value of our RR estimates. We also had tried to estimate the 95% CI for the PAF using Delta method, but we didn t present them because such 95% CIs are known to have 10

12 problems of underestimating the interval for the PAF. Therefore, we presented the sensitivity analysis using different values of the RRs. When the estimated RR was lower than one, we replaced the RR by one. We tried to describe this procedure in more detail in the revised manuscript. 3) [Abstract; p5, 2nd paragraph] Tobacco control is important at population or policy level, as well as individual level. The corresponding sentences should be modified. Thank you for your helpful comments. We modified the sentences following your recommendation to add the term individual level. 4) [Abstract] What data showed that Korea is highest in cancer incidence and mortality in Asia? Is it crude rate or age-standardized rate? According to the GLOBOCAN 2008 (now with most updated GLOBOCAN 2012 as well), Korea had the highest age-standardized cancer incidence and mortality rates among Asian countries included in the report ( 11

13 5) [p4, the last part of 1st paragraph] As noted above, the PAF estimates have been reported from Asian countries including Japan and China. Authors should mention and cite those previous publications. We added the discussion by referencing the results from Japan and China in the Introduction and Discussion in the revised manuscript. 6) [Abstract and result] The PAF and relative risk of kidney cancer is too small, as compared with previous report from other countries (Table 4). Authors should discuss possible reasons. At this point, we do not have clear answer to why our RR estimate of kidney cancer was smaller than some of previous reports by other countries. Our estimate was RR=1.10 for men compared to RR=1.5 for Japanese men, RR=1.6 for French men, and RR=2.5 for UK men (Table 4 in the manuscript). However, for women, Japanese RR was low (RR=0.9) compared with France and UK. But the RR for UK was for kidney and renal pelvis together, and there could be some discrepancy. When we checked another result from the same study group with different follow-up period, the current smoker s RR for kidney cancer was 0.8 (95% CI, ) (as shown below; Choi et al, 2005). 12

14 Choi MY, Jee SH, Sull JW, Nam CM. The effect of hypertension on the risk for kidney cancer in Korean men. Kidney Int Feb;67(2): ) [p4, p9] Ovarian and colorectal cancers were not included in the list of sufficient evidence in the IARC Monograph Vol. 83. Authors should refer to relevant citations, if these two cancers are included. We have considered the cancer sites that were classified as carcinogen group 1 based on the most recent evaluation in the IARC Monograph Vol 100 series (reference below). Secretan B, Straif K, Baan R, Grosse Y, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L et al: A review of human carcinogens-part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 2009, 10(11): ) [p6] Authors applied a log-linear extrapolation for passive smoking prevalence data, but the observed data were available only for two years. Is it valid method? At least, authors should present actual data in the main text or supplement, and add relevant discussion. Per your and other reviewer s comments, we further investigated the available data on passive smoking in Korea, and we were able to obtain the recent data below from Korea National Nutrition and Health Examination Survey data (KNHANES, knhanes.cdc.go.kr). Following your comment, we used the data for passive smoking prevalence from 2007 to 2012, and the prevalence of current smoking from the same period to extrapolate the passive smoking prevalence in 1989 through fitting a loglinear regression model. As per reviewer #1 s comment as well, we used passive smoking prevalence in 1989 to be in concordance with the year of ever-smoking prevalence in Korea. We did not include the prevalence of passive smoking of year 2005 for extrapolation although the data were available, because it was recommended so by domestic expert committee members as the passive smoking prevalence seemed to be unstable in year 2005 when the assessment of passive smoking was attempted in KNHANES for the first time. 13

15 Table 1. Prevalence of passive smoking from 2007 to 2012 in Korea and estimated prevalence in 1989 by extrapolation. Year Home Workplace Men Women Men Women ) [Tables] How about exchanging Table 2 and Table 3? The result of active smoking had better be shown consecutively. Thank you for your comment. We have exchanged the order of Table 2 and Table 3. 10) [p11] Authors should clearly mention lung cancer, when showing the result of passive smoking. Thank you for your comment. We revised our text to be explicit about lung cancer when showing the results of passive smoking. 11) [Discussion] Readers may be interested in comparisons between the present results and the WHO Global report: mortality attributable to tobacco (2012). Thank you for your comment. We reviewed the WHO Global report: mortality attributable to tobacco (2012), and added a few sentences discussing the results in WHO Global report. 12) [Table 3] It would be helpful if the result of all cancers combined is included in this table. 14

16 Per your recommendation, we added the proportion of second-hand-smoking-related cancers from all cancers combined to the Table 3 (now Table 2 in the revised manuscript). 13) [p15, 2nd paragraph] one out of three lung cancer -> one out of three cancer? Thank you for your careful review. We corrected the typo in our text. 15