WEBVTT 1 00:00:00.450 --> 00:00:01.440 Hi, everyone. 2 00:00:01.440 --> 00:00:02.460 In today's lecture, 3 00:00:02.460 --> 00:00:06.330 we will continue discussing the epidemiology of lung cancer 4 00:00:06.330 --> 00:00:10.380 by digging into the Surgeon General's 1964 Report 5 00:00:10.380 --> 00:00:13.710 and the history of tobacco control in the US. 6 00:00:13.710 --> 00:00:16.620 So our two aims of this presentation 7 00:00:16.620 --> 00:00:20.610 are to review the early studies of smoking and lung cancer 8 00:00:20.610 --> 00:00:24.660 and to describe the Surgeon General's 1964 Report. 9 00:00:24.660 --> 00:00:27.270 So before we begin, I just wanna circle back 10 00:00:27.270 --> 00:00:30.510 and remind everyone about Hill's criteria of judgment. 11 00:00:30.510 --> 00:00:34.770 And these were the criteria that was promulgated 12 00:00:34.770 --> 00:00:37.440 by Bradford Hill, a British statistician, 13 00:00:37.440 --> 00:00:39.183 in the mid 20th century. 14 00:00:40.290 --> 00:00:43.740 The key components of the criteria of judgment 15 00:00:43.740 --> 00:00:46.950 are the consistency of independent studies. 16 00:00:46.950 --> 00:00:49.290 That being that consistent findings observed 17 00:00:49.290 --> 00:00:51.600 by different people in different places 18 00:00:51.600 --> 00:00:54.180 with different samples are all pointing 19 00:00:54.180 --> 00:00:55.500 to the same conclusions. 20 00:00:55.500 --> 00:00:58.110 That is, the studies are reproducible. 21 00:00:58.110 --> 00:00:59.650 The strength of association 22 00:01:00.600 --> 00:01:03.600 is another important aspect to look at 23 00:01:03.600 --> 00:01:05.160 when trying to determine 24 00:01:05.160 --> 00:01:07.650 whether something is a causal relationship. 25 00:01:07.650 --> 00:01:12.650 And that means that if there's only a small association 26 00:01:12.720 --> 00:01:15.360 between a proposed cause and proposed effect, 27 00:01:15.360 --> 00:01:18.450 that does not mean that there's not a causal effect, 28 00:01:18.450 --> 00:01:20.580 but the larger the association, 29 00:01:20.580 --> 00:01:22.323 the more likely that it is causal. 30 00:01:23.550 --> 00:01:25.170 The biological gradient, 31 00:01:25.170 --> 00:01:27.990 or the dose response relationship, 32 00:01:27.990 --> 00:01:31.050 says that greater exposure should generally lead 33 00:01:31.050 --> 00:01:33.060 to greater incidence of the effect. 34 00:01:33.060 --> 00:01:34.440 However, in some cases, 35 00:01:34.440 --> 00:01:37.500 the mere presence of the factor can trigger the effect. 36 00:01:37.500 --> 00:01:39.423 So there may be no gradient. 37 00:01:40.710 --> 00:01:42.870 Specificity is also important. 38 00:01:42.870 --> 00:01:45.630 Causation is likely if there is a very specific population 39 00:01:45.630 --> 00:01:47.760 at a specific site and disease 40 00:01:47.760 --> 00:01:50.250 with no other likely explanation. 41 00:01:50.250 --> 00:01:52.590 The more specific an association between a factor 42 00:01:52.590 --> 00:01:54.510 and an effect is, 43 00:01:54.510 --> 00:01:55.770 the bigger the probability 44 00:01:55.770 --> 00:01:57.273 of a causal relationship. 45 00:01:58.320 --> 00:02:01.560 Next, we have the importance of temporality. 46 00:02:01.560 --> 00:02:05.340 So that states that the effect has to occur after the cause 47 00:02:05.340 --> 00:02:06.960 and if there's an expected delay 48 00:02:06.960 --> 00:02:09.210 between the cause and the expected effect, 49 00:02:09.210 --> 00:02:12.033 then the effect must occur after the delay. 50 00:02:13.770 --> 00:02:15.090 Finally, we have coherence. 51 00:02:15.090 --> 00:02:17.340 So there should be a coherence 52 00:02:17.340 --> 00:02:19.690 between epidemiological and laboratory findings 53 00:02:20.790 --> 00:02:23.130 in order to determine that there's an effect. 54 00:02:23.130 --> 00:02:24.960 However, at the same time, 55 00:02:24.960 --> 00:02:29.070 the lack of such laboratory evidence cannot nullify 56 00:02:29.070 --> 00:02:32.340 the possibility or the presence of an epidemiological effect 57 00:02:32.340 --> 00:02:33.573 on an association. 58 00:02:34.800 --> 00:02:36.960 So keeping this criteria of judgment in mind, 59 00:02:36.960 --> 00:02:40.770 we move to the state of smoking in 1964. 60 00:02:40.770 --> 00:02:43.770 There were 70 million smokers in the US 61 00:02:43.770 --> 00:02:48.770 and the per capita cigarette use had increased from 50 62 00:02:50.439 --> 00:02:54.753 in 1910 to almost 4,000 in 1962. 63 00:02:56.070 --> 00:03:00.990 Next, there's significant proportions of smokers in 1955. 64 00:03:00.990 --> 00:03:04.770 So in 1955, it's projected that 68% of men smoked 65 00:03:04.770 --> 00:03:06.933 and 38% of women smoked. 66 00:03:08.700 --> 00:03:11.613 Next, we see too that there's an increase, 67 00:03:12.990 --> 00:03:17.990 or an increased concentration of tobacco in cigars 68 00:03:19.710 --> 00:03:20.910 and chewing tobacco. 69 00:03:20.910 --> 00:03:24.820 So the tobacco that was present in 117 cigars in 1920 70 00:03:25.860 --> 00:03:29.580 is equivalent to 55 in 1962. 71 00:03:29.580 --> 00:03:32.580 Similarly, the amount of tobacco in two to four pounds 72 00:03:32.580 --> 00:03:35.130 of chewing tobacco in 1900 could be found 73 00:03:35.130 --> 00:03:38.703 in only a half pound of chewing tobacco in 1962. 74 00:03:40.050 --> 00:03:43.680 So the Surgeon General's report 75 00:03:43.680 --> 00:03:45.810 that was published in 1964 used 76 00:03:45.810 --> 00:03:47.340 a number of different kinds of evidence. 77 00:03:47.340 --> 00:03:48.810 There were animal studies, 78 00:03:48.810 --> 00:03:50.550 there were clinical and autopsy studies, 79 00:03:50.550 --> 00:03:52.710 and there were population studies. 80 00:03:52.710 --> 00:03:55.443 So both cohort and case control studies. 81 00:03:56.730 --> 00:03:59.250 The report found that there were three main classes 82 00:03:59.250 --> 00:04:02.910 of carcinogens in tobacco smoke, heterocyclic amines, 83 00:04:02.910 --> 00:04:06.663 nitrosamines, and polycyclic aromatic hydrocarbons. 84 00:04:08.370 --> 00:04:11.610 The report drew upon seven prospective cohort studies 85 00:04:11.610 --> 00:04:14.070 involving more than a million men. 86 00:04:14.070 --> 00:04:15.840 These studies looked at the smoking history 87 00:04:15.840 --> 00:04:18.450 and other characteristics of participants, 88 00:04:18.450 --> 00:04:20.550 and there were 10 years of follow up. 89 00:04:20.550 --> 00:04:23.730 Over that time period, there were almost 40,000 deaths, 90 00:04:23.730 --> 00:04:27.480 and mortality rates in smokers and non-smokers were compared 91 00:04:27.480 --> 00:04:30.840 to determine the excess deaths in smokers. 92 00:04:30.840 --> 00:04:33.093 The study also adjusted for age. 93 00:04:36.120 --> 00:04:40.140 So one category of study was autopsy studies, 94 00:04:40.140 --> 00:04:43.530 and these studies looked at 63 men, 95 00:04:43.530 --> 00:04:46.947 or 63 individuals who died from lung cancer 96 00:04:46.947 --> 00:04:50.370 and 339 who died from causes other than lung cancer 97 00:04:50.370 --> 00:04:52.110 at the Veterans Administration Hospital 98 00:04:52.110 --> 00:04:53.613 in East Orange, New Jersey. 99 00:04:54.930 --> 00:04:57.540 Smoking history were ascertained from the family 100 00:04:57.540 --> 00:04:59.760 and the frequencies of histological changes observed 101 00:04:59.760 --> 00:05:02.613 in smokers and non-smokers were compared. 102 00:05:03.540 --> 00:05:05.520 Lung tissues from smoking cases 103 00:05:05.520 --> 00:05:09.150 had significantly higher frequencies of carcinoma in situ, 104 00:05:09.150 --> 00:05:11.820 squamous metaplasia, hyperplasia, 105 00:05:11.820 --> 00:05:13.590 and loss of cilia than lung tissues 106 00:05:13.590 --> 00:05:15.720 from non-smoking patients. 107 00:05:15.720 --> 00:05:18.180 Furthermore, the frequency of lesions increased 108 00:05:18.180 --> 00:05:19.503 with the level of smoking. 109 00:05:20.400 --> 00:05:23.566 Among 65 men who never smoked regularly, 110 00:05:23.566 --> 00:05:28.080 16.8% of 3,324 specimens showed 111 00:05:28.080 --> 00:05:31.380 at least one histological change in the epithelium, 112 00:05:31.380 --> 00:05:33.960 whereas one or more epithelial changes were found 113 00:05:33.960 --> 00:05:38.960 in 98% of the 13,689 specimens 114 00:05:39.510 --> 00:05:42.300 from 274 men who regularly smoked cigarettes 115 00:05:42.300 --> 00:05:45.090 and diet of causes other than lung cancer, 116 00:05:45.090 --> 00:05:50.090 and in 99.8% of the 2,784 specimens from the 63 men who died 117 00:05:52.200 --> 00:05:53.223 of lung cancer. 118 00:05:54.150 --> 00:05:58.080 Most notably, the frequency of carcinoma in situ, 119 00:05:58.080 --> 00:06:01.590 or lung cancers, was 0% in non-smokers, 120 00:06:01.590 --> 00:06:03.480 20% in those who smoked less 121 00:06:03.480 --> 00:06:05.430 than one pack of cigarettes per day, 122 00:06:05.430 --> 00:06:08.727 48% in those who smoked one to two packs per day, 123 00:06:08.727 --> 00:06:11.550 and 75% in those who smoked more than two packs 124 00:06:11.550 --> 00:06:12.807 of cigarettes per day, 125 00:06:12.807 --> 00:06:16.650 and 83% in those who died from lung cancer. 126 00:06:16.650 --> 00:06:18.030 Based on these results, 127 00:06:18.030 --> 00:06:20.647 the investigators concluded the following. 128 00:06:20.647 --> 00:06:22.230 "In our opinion, 129 00:06:22.230 --> 00:06:23.340 the histologic evidence 130 00:06:23.340 --> 00:06:25.230 from this study greatly strengthens 131 00:06:25.230 --> 00:06:28.950 the already overwhelming body of epidemiologic evidence 132 00:06:28.950 --> 00:06:31.170 that cigarette smoking is a major factor 133 00:06:31.170 --> 00:06:33.963 in the causation of bronchogenic carcinoma. 134 00:06:36.030 --> 00:06:39.000 So the Surgeon General's report came out 135 00:06:39.000 --> 00:06:41.790 with some conclusions about smoking and health. 136 00:06:41.790 --> 00:06:45.150 Overall, smoking leads to a 1.7 fold increase 137 00:06:45.150 --> 00:06:47.400 in all cause mortality 138 00:06:47.400 --> 00:06:51.390 and a tenfold increase in lung cancer mortality. 139 00:06:51.390 --> 00:06:52.950 For heavy smokers, 140 00:06:52.950 --> 00:06:56.580 there's a 20 fold increase in lung cancer mortality. 141 00:06:56.580 --> 00:07:00.060 There's also increases in mortality 142 00:07:00.060 --> 00:07:03.720 from other types of cancer and other chronic conditions. 143 00:07:03.720 --> 00:07:05.400 So laryngeal cancer, 144 00:07:05.400 --> 00:07:06.960 smokers had a fivefold increase 145 00:07:06.960 --> 00:07:09.210 in mortality when compared to non-smokers. 146 00:07:09.210 --> 00:07:11.430 For COPD, it's a sixfold increase, 147 00:07:11.430 --> 00:07:14.913 and for CBD it's a twofold increase. 148 00:07:18.240 --> 00:07:20.610 So in the wake of the Surgeon General's report, 149 00:07:20.610 --> 00:07:22.650 several steps were taken to control tobacco 150 00:07:22.650 --> 00:07:24.780 and tobacco use in the US. 151 00:07:24.780 --> 00:07:28.530 Smoking prevalence peaked at 42% in 1964 152 00:07:28.530 --> 00:07:32.193 and has dropped to 18% in 2013 in the US. 153 00:07:33.420 --> 00:07:34.590 And tobacco control 154 00:07:34.590 --> 00:07:38.400 has been prevented 8.3 million premature deaths in the US 155 00:07:38.400 --> 00:07:40.950 since the 1964 report. 156 00:07:40.950 --> 00:07:43.320 Clearly, the cause and effect patterns of smoking 157 00:07:43.320 --> 00:07:45.810 and lung cancer are clearly visible 158 00:07:45.810 --> 00:07:50.460 on examinations of ecologic time trend data in the US. 159 00:07:50.460 --> 00:07:53.280 Here, we see that there's close parallels 160 00:07:53.280 --> 00:07:56.190 of lung cancer mortality in cigarette use in the US 161 00:07:56.190 --> 00:07:58.830 that has persisted since 1930. 162 00:07:58.830 --> 00:08:01.080 The time interval between the exposure curve 163 00:08:01.080 --> 00:08:02.460 and the mortality curve reflects 164 00:08:02.460 --> 00:08:04.710 an approximate age development, 165 00:08:04.710 --> 00:08:06.750 or an approximate average development time 166 00:08:06.750 --> 00:08:10.020 of 20 years or more for lung carcinogenesis. 167 00:08:10.020 --> 00:08:13.530 Overall, cigarette smoking accounts for 85 to 90% 168 00:08:13.530 --> 00:08:16.050 of all lung cancer risk in the US 169 00:08:16.050 --> 00:08:18.273 and most other developed countries. 170 00:08:20.370 --> 00:08:23.010 Here too we see that there's different kinds 171 00:08:23.010 --> 00:08:26.310 of carcinoma in the lung. 172 00:08:26.310 --> 00:08:28.680 So people can be afflicted by a adenocarcinoma 173 00:08:28.680 --> 00:08:31.323 or squamous cell carcinoma of the lung. 174 00:08:34.260 --> 00:08:39.260 One causal factor that determines which cancer 175 00:08:40.050 --> 00:08:42.840 that people become diagnosed with 176 00:08:42.840 --> 00:08:46.860 is the kind of cigarette or tobacco that one is consuming. 177 00:08:46.860 --> 00:08:49.260 So right now in the US, 178 00:08:49.260 --> 00:08:51.480 filter brands now dominate the market 179 00:08:51.480 --> 00:08:53.670 and currently comprise over 85% 180 00:08:53.670 --> 00:08:56.730 of all cigarettes manufactured in the US. 181 00:08:56.730 --> 00:08:58.410 Compared to non-filtered cigarettes, 182 00:08:58.410 --> 00:09:01.533 filter brands deliver less tar and nicotine per cigarette. 183 00:09:02.670 --> 00:09:04.050 And among smokers in the US, 184 00:09:04.050 --> 00:09:08.850 about 96% of women and 92% of men smoke filter cigarettes. 185 00:09:08.850 --> 00:09:13.170 Despite this transition to filter or low yield cigarettes, 186 00:09:13.170 --> 00:09:14.850 smokers tend to inhale deeper 187 00:09:14.850 --> 00:09:17.970 and compensate by smoking more cigarettes, 188 00:09:17.970 --> 00:09:20.060 which may account for the drastic increase 189 00:09:20.060 --> 00:09:23.310 in lung adenocarcinomas among cigarette smokers 190 00:09:23.310 --> 00:09:24.273 in recent years. 191 00:09:25.140 --> 00:09:27.150 Major changes have occurred in the profile 192 00:09:27.150 --> 00:09:30.060 of histologic cell types of lung cancer being diagnosed 193 00:09:30.060 --> 00:09:31.560 during the past several decades, 194 00:09:31.560 --> 00:09:34.230 as evidenced by this chart, 195 00:09:34.230 --> 00:09:36.730 and the increase in odds of adenocarcinoma 196 00:09:37.770 --> 00:09:39.723 over squamous cell carcinoma. 197 00:09:41.280 --> 00:09:43.950 So we can say that the changing histologic profile 198 00:09:43.950 --> 00:09:47.400 of lung cancer is due to the transition from non-filtered 199 00:09:47.400 --> 00:09:49.413 to filter cigarettes. 200 00:09:50.340 --> 00:09:53.190 Finally, among men and women who smoked 30 201 00:09:53.190 --> 00:09:54.720 or more cigarettes daily, 202 00:09:54.720 --> 00:09:57.270 the odds of developing either squamous cell carcinoma 203 00:09:57.270 --> 00:10:00.720 or small cell carcinoma were four to five times higher 204 00:10:00.720 --> 00:10:03.750 than the odds of developing adenocarcinoma. 205 00:10:03.750 --> 00:10:06.120 There were also differences in the histologic profile 206 00:10:06.120 --> 00:10:07.680 of lung cancer in men and women 207 00:10:07.680 --> 00:10:10.380 and among smokers versus non-smokers. 208 00:10:10.380 --> 00:10:14.160 Among men, the majority of tumors, or 53%, 209 00:10:14.160 --> 00:10:15.900 were squamous cell carcinomas, 210 00:10:15.900 --> 00:10:18.330 and 20% were small cell carcinomas, 211 00:10:18.330 --> 00:10:21.420 and 27% were adenocarcinomas. 212 00:10:21.420 --> 00:10:24.630 Among women, the majority of tumors were adenocarcinomas, 213 00:10:24.630 --> 00:10:27.720 and 28% were squamous cell carcinoma, 214 00:10:27.720 --> 00:10:30.603 and 22 were small cell carcinoma. 215 00:10:32.070 --> 00:10:34.710 So here we see that the odds ratio 216 00:10:34.710 --> 00:10:38.040 of men having squamous cell carcinoma 217 00:10:38.040 --> 00:10:42.410 is nearly 100 times higher among men who smoke 30 218 00:10:42.410 --> 00:10:43.920 or more cigarettes per day 219 00:10:43.920 --> 00:10:46.743 than those who don't smoke cigarettes per day.