WEBVTT 1 00:00:00.780 --> 00:00:02.850 Hi everyone and today's lecture 2 00:00:02.850 --> 00:00:05.580 will be beginning our discussion of the epidemiology 3 00:00:05.580 --> 00:00:07.050 of colon cancer, 4 00:00:07.050 --> 00:00:08.790 by talking about the biology, 5 00:00:08.790 --> 00:00:11.760 global trends and pathogenesis. 6 00:00:11.760 --> 00:00:12.930 The goals of this lecture 7 00:00:12.930 --> 00:00:17.010 are to describe the global burden of colorectal cancer. 8 00:00:17.010 --> 00:00:20.970 Describe the anatomic pattern of colorectal cancer. 9 00:00:20.970 --> 00:00:24.930 Define the high fat, low fiber hypothesis of Burkitt 10 00:00:24.930 --> 00:00:28.650 and to discuss mechanisms of pathogenesis. 11 00:00:28.650 --> 00:00:29.883 So to begin with, 12 00:00:30.840 --> 00:00:34.320 we see that colorectal cancer is more common 13 00:00:34.320 --> 00:00:36.240 in high income countries 14 00:00:36.240 --> 00:00:39.330 compared to low and middle income countries. 15 00:00:39.330 --> 00:00:40.530 In high income countries, 16 00:00:40.530 --> 00:00:42.780 colorectal cancer mortality ranks third 17 00:00:42.780 --> 00:00:45.390 behind only lung cancer and breast cancer. 18 00:00:45.390 --> 00:00:47.733 Whereas in developing nations, it ranks sixth. 19 00:00:50.880 --> 00:00:53.520 We also see this pattern repeated 20 00:00:53.520 --> 00:00:55.728 when looking at mortality rates 21 00:00:55.728 --> 00:00:59.460 being particularly high in parts of Eastern Europe 22 00:00:59.460 --> 00:01:02.463 and Western Europe and Northern Asia. 23 00:01:04.260 --> 00:01:07.110 In the United States, colon cancer in 2020 24 00:01:07.110 --> 00:01:12.110 was responsible for 11.4 cases per 100,000, 25 00:01:12.190 --> 00:01:16.050 with a slightly higher incidence rate in men than in women. 26 00:01:16.050 --> 00:01:21.017 Overall, there were 5.4 colorectal cancer deaths per 100,000 27 00:01:21.900 --> 00:01:26.580 in the US in 2020, with again, the mortality rate for men 28 00:01:26.580 --> 00:01:28.830 being slightly higher than that of for women. 29 00:01:30.150 --> 00:01:32.790 As with most other solid cancerous tumors, 30 00:01:32.790 --> 00:01:35.550 colorectal cancer evolves over a period of years 31 00:01:35.550 --> 00:01:37.350 and even decades. 32 00:01:37.350 --> 00:01:40.530 Approximately 65 to 70% of large bowel cancers 33 00:01:40.530 --> 00:01:43.560 develop in the descending sigmoid colon and rectum 34 00:01:43.560 --> 00:01:46.080 and the remainder developed in the transverse 35 00:01:46.080 --> 00:01:48.063 and ascending portions of the colon. 36 00:01:48.990 --> 00:01:50.802 More than 95% of colorectal cancers 37 00:01:50.802 --> 00:01:54.513 are denso carcinomas and many of them secrete mucin. 38 00:01:55.350 --> 00:01:57.720 Carcinomas of the sigmoid colon and rectum 39 00:01:57.720 --> 00:02:00.780 often grow, grow in an annular fashion, 40 00:02:00.780 --> 00:02:03.660 producing so-called napkin ring constrictions 41 00:02:03.660 --> 00:02:05.730 and obstruction of the bowel. 42 00:02:05.730 --> 00:02:07.470 Carcinomas of the ascending colon 43 00:02:07.470 --> 00:02:09.570 tend to extend along the bowel wall 44 00:02:09.570 --> 00:02:12.093 and are much less likely to cause obstruction. 45 00:02:12.930 --> 00:02:14.670 Colorectal cancer often develops 46 00:02:14.670 --> 00:02:16.740 as a sequential series of steps, 47 00:02:16.740 --> 00:02:19.350 beginning with focal dysplasia and hyperplasia 48 00:02:19.350 --> 00:02:20.730 of the epithelial lining 49 00:02:20.730 --> 00:02:25.110 and progressing to the formation of a adenomatous 50 00:02:25.110 --> 00:02:26.490 and villous polyps. 51 00:02:26.490 --> 00:02:30.150 Carcinoma in situ and ultimately invasive cancer. 52 00:02:30.150 --> 00:02:33.148 Colon carcinogenesis invariably 53 00:02:33.148 --> 00:02:37.113 progresses in the presence of inflammation. 54 00:02:39.360 --> 00:02:41.280 Risk factors for colorectal cancer 55 00:02:41.280 --> 00:02:45.390 include both lifestyle factors and genetic syndromes. 56 00:02:45.390 --> 00:02:47.370 The comprehensive epidemiologic evidence 57 00:02:47.370 --> 00:02:48.510 suggests that colorectal cancer 58 00:02:48.510 --> 00:02:51.570 is largely influenced by these lifestyle factors. 59 00:02:51.570 --> 00:02:53.400 So the risk of colorectal cancer development 60 00:02:53.400 --> 00:02:56.340 is increased by diets high in fat and low in fiber, 61 00:02:56.340 --> 00:03:00.030 sedentary lifestyles, obesity, alcohol and tobacco use, 62 00:03:00.030 --> 00:03:02.490 and deficiencies in vitamin D, calcium, 63 00:03:02.490 --> 00:03:04.650 and possibly selenium. 64 00:03:04.650 --> 00:03:07.560 Genetic syndromes involving mutant mismatch repair genes 65 00:03:07.560 --> 00:03:08.610 and tumor suppressor genes 66 00:03:08.610 --> 00:03:11.673 account for only a small percentage of of cases. 67 00:03:15.030 --> 00:03:18.810 Denis Burkitt formulated the high fat, low fiber hypothesis 68 00:03:18.810 --> 00:03:20.490 of colon cancer. 69 00:03:20.490 --> 00:03:22.920 This hypothesis is based upon the low incidence 70 00:03:22.920 --> 00:03:25.080 of colon cancer and other intestinal diseases 71 00:03:25.080 --> 00:03:27.450 in the African continent, 72 00:03:27.450 --> 00:03:30.330 where Burkitt conducted his surgical practice. 73 00:03:30.330 --> 00:03:33.210 In populations consuming a high fiber low fat diet, 74 00:03:33.210 --> 00:03:35.970 Burkitt observed virtually none of the large bowel diseases 75 00:03:35.970 --> 00:03:38.370 that are commonplace in westernized societies 76 00:03:38.370 --> 00:03:43.370 such as hemorrhoids, diverticulosis, diverticulitis, 77 00:03:45.780 --> 00:03:49.650 ulcerative colitis, Crohn's disease, and colorectal cancer. 78 00:03:49.650 --> 00:03:51.990 His recommendations for prevention of colon cancer 79 00:03:51.990 --> 00:03:54.960 specify high levels of intake throughout life. 80 00:03:54.960 --> 00:03:58.293 40 grams of fiber daily with a high proportion of brand. 81 00:03:59.169 --> 00:04:02.400 Protective mechanisms of fiber within the large bowel 82 00:04:02.400 --> 00:04:05.250 can be broadly divided into that for soluble 83 00:04:05.250 --> 00:04:07.290 and insoluble fiber. 84 00:04:07.290 --> 00:04:09.300 Increasing the level of insoluble fiber 85 00:04:09.300 --> 00:04:12.660 increases fecal bulk, thereby reducing transit time 86 00:04:12.660 --> 00:04:14.256 and diluting the concentration of toxic 87 00:04:14.256 --> 00:04:16.770 and carcinogenic compounds. 88 00:04:16.770 --> 00:04:19.295 Soluble fiber binds to bile acids and bile salts 89 00:04:19.295 --> 00:04:22.680 that may irritate the colorectal mucosa. 90 00:04:22.680 --> 00:04:25.110 Furthermore, soluble fiber is fermented 91 00:04:25.110 --> 00:04:28.440 to single chain fatty acids, such as beauty rate 92 00:04:28.440 --> 00:04:31.260 that maintain homeostasis of cell proliferation 93 00:04:31.260 --> 00:04:32.313 and apoptosis. 94 00:04:33.330 --> 00:04:34.200 Animal studies, 95 00:04:34.200 --> 00:04:37.200 suggests that colorectal protection depends on the type 96 00:04:37.200 --> 00:04:40.620 and level of fiber and wheat brand 97 00:04:40.620 --> 00:04:42.570 and that wheat brand inhibits tumor development 98 00:04:42.570 --> 00:04:45.900 more consistently than other sources of fiber. 99 00:04:45.900 --> 00:04:47.970 The totality of evidence generated thus far 100 00:04:47.970 --> 00:04:50.427 remains compatible with Burkitt's original hypothesis. 101 00:04:50.427 --> 00:04:53.910 The diet's high in fiber, particularly wheat brand fiber 102 00:04:53.910 --> 00:04:55.290 provides significant protection 103 00:04:55.290 --> 00:04:57.540 against the development of colorectal cancer. 104 00:04:59.970 --> 00:05:02.430 Marked increases in the rates of colorectal cancer 105 00:05:02.430 --> 00:05:03.750 in some developing countries 106 00:05:03.750 --> 00:05:06.990 have also been linked to higher levels of fat intake. 107 00:05:06.990 --> 00:05:09.510 A striking example is the Japanese population 108 00:05:09.510 --> 00:05:12.570 wherein rates have risen from the lowest to the highest 109 00:05:12.570 --> 00:05:14.790 in the world over the past 50 years. 110 00:05:14.790 --> 00:05:15.900 In close parallel, 111 00:05:15.900 --> 00:05:18.723 with the increase in per capita fat calories. 112 00:05:21.750 --> 00:05:24.240 There's a hypothesis that colon cancer development 113 00:05:24.240 --> 00:05:26.880 is linked to high intake of dietary fat 114 00:05:26.880 --> 00:05:30.210 that upsets the balance of gut flora. 115 00:05:30.210 --> 00:05:32.880 This hypothesis was based upon the historic low rates 116 00:05:32.880 --> 00:05:34.350 of colorectal cancer in Japan 117 00:05:34.350 --> 00:05:36.330 compared to high rates in the US, 118 00:05:36.330 --> 00:05:39.663 corresponding to their low and high fat diets respectively. 119 00:05:40.710 --> 00:05:43.009 Many subsequent epidemiologic investigations 120 00:05:43.009 --> 00:05:45.900 have consistently found that the risk of colorectal cancer 121 00:05:45.900 --> 00:05:50.310 increases with high intake of saturated fat in animal fat 122 00:05:50.310 --> 00:05:53.220 and reciprocally that the risk is reduced 123 00:05:53.220 --> 00:05:55.503 with increased intake of fish and fish oil. 124 00:05:56.850 --> 00:05:59.010 Willie and colleagues found that American women 125 00:05:59.010 --> 00:06:03.240 who ate beef, pork or lamb daily had a 2.5 fold higher risk 126 00:06:03.240 --> 00:06:06.513 compared to women reporting little or no consumption. 127 00:06:07.470 --> 00:06:10.680 In an investigation conducted in 24 European nations, 128 00:06:10.680 --> 00:06:13.620 increasing the intake of omega-3 fatty acids from fish 129 00:06:13.620 --> 00:06:16.230 and fish oil conferred significant protection 130 00:06:16.230 --> 00:06:18.063 against colon cancer development. 131 00:06:20.010 --> 00:06:21.810 Animal studies are in general agreement 132 00:06:21.810 --> 00:06:23.130 with the epidemiologic evidence 133 00:06:23.130 --> 00:06:26.370 in finding that a high amount of omega-6 fatty acids 134 00:06:26.370 --> 00:06:29.215 from beef, corn oil or lard in the diet 135 00:06:29.215 --> 00:06:32.040 enhances chemically induces tumor development 136 00:06:32.040 --> 00:06:34.860 in lab animals and reciprocally 137 00:06:34.860 --> 00:06:36.600 that the increasing the intake 138 00:06:36.600 --> 00:06:40.290 of omega-3 fatty acids from fish, fish oil and olive oil, 139 00:06:40.290 --> 00:06:41.943 decreases carcinogenesis. 140 00:06:46.710 --> 00:06:50.250 In studies of migrants from low risk to high risk regions, 141 00:06:50.250 --> 00:06:53.400 the rates of colon cancers show dramatic increases 142 00:06:53.400 --> 00:06:55.200 after single generation, 143 00:06:55.200 --> 00:06:57.300 suggesting that the risk for tumor development 144 00:06:57.300 --> 00:07:00.570 in the large bowel increases rapidly with transition 145 00:07:00.570 --> 00:07:02.043 to a high fat diet. 146 00:07:03.060 --> 00:07:05.850 Mechanistically, it's theorized that diet's high in fat 147 00:07:05.850 --> 00:07:08.190 promotes secretion of bile acids from the liver 148 00:07:08.190 --> 00:07:09.960 and biliary tree. 149 00:07:09.960 --> 00:07:12.810 These bile acids are dehydrogenated 150 00:07:12.810 --> 00:07:15.033 to form the carcinogenic metabolites. 151 00:07:16.740 --> 00:07:20.160 In addition, diet's high in fat typically contains steriles 152 00:07:20.160 --> 00:07:22.260 which have mitogenic activity. 153 00:07:22.260 --> 00:07:27.153 A key high risk enzyme is beta glucanase 154 00:07:28.650 --> 00:07:32.220 which is responsible for hydrolysis of sterile conjugates 155 00:07:32.220 --> 00:07:34.173 so that they may be recirculated. 156 00:07:36.780 --> 00:07:38.430 It's also been noticed 157 00:07:38.430 --> 00:07:40.728 that a gradient of colorectal cancer rates 158 00:07:40.728 --> 00:07:42.690 is associated with latitude. 159 00:07:42.690 --> 00:07:44.880 That is rates become higher in populations 160 00:07:44.880 --> 00:07:47.253 that are further away from the equator. 161 00:07:48.480 --> 00:07:50.820 It's been hypothesized that colon cancer development 162 00:07:50.820 --> 00:07:52.800 may be related to a lack of vitamin D 163 00:07:52.800 --> 00:07:55.020 due to decreased exposure to sunlight 164 00:07:55.020 --> 00:07:58.260 and populations further away from the equator. 165 00:07:58.260 --> 00:08:00.120 Activated vitamin D is necessary 166 00:08:00.120 --> 00:08:01.860 for the absorption of dietary calcium 167 00:08:01.860 --> 00:08:04.147 and important mineral for the maintenance 168 00:08:04.147 --> 00:08:06.420 of physiologic homeostasis in the human body, 169 00:08:06.420 --> 00:08:08.520 particularly the regulation and control 170 00:08:08.520 --> 00:08:10.200 of cell division and the cell cycle. 171 00:08:10.200 --> 00:08:12.300 In proliferating cell populations 172 00:08:12.300 --> 00:08:13.863 like the colorectal mucosa. 173 00:08:15.090 --> 00:08:17.520 Higher levels of vitamin D and calcium intake 174 00:08:17.520 --> 00:08:18.570 have also been found 175 00:08:18.570 --> 00:08:20.430 to reduce the risk of colorectal cancer 176 00:08:20.430 --> 00:08:23.100 in several epidemiologic studies. 177 00:08:23.100 --> 00:08:25.380 The relationship of vitamin D and cancer mortality 178 00:08:25.380 --> 00:08:26.580 was examined in the third 179 00:08:26.580 --> 00:08:29.343 National Health and Nutrition Examination Survey. 180 00:08:32.511 --> 00:08:36.300 Baseline levels of serum 25 hydroxylated vitamin D 181 00:08:36.300 --> 00:08:39.240 were measured in more than 16,000 participants 182 00:08:39.240 --> 00:08:41.340 aged 17 years and older. 183 00:08:41.340 --> 00:08:44.550 Individuals with serum vitamin D levels 184 00:08:44.550 --> 00:08:47.280 of 80 animals per liter or higher at baseline 185 00:08:47.280 --> 00:08:50.910 experience a 72% reduction in colorectal cancer mortality 186 00:08:50.910 --> 00:08:52.470 compared to individuals with levels 187 00:08:52.470 --> 00:08:54.573 lower than 50 animals per liter. 188 00:08:55.740 --> 00:08:57.960 Despite the beneficial impact of vitamin D 189 00:08:57.960 --> 00:09:00.750 in calcium observed in epidemiologic studies, 190 00:09:00.750 --> 00:09:03.690 a randomized clinical trial involving postmenopausal women 191 00:09:03.690 --> 00:09:07.560 of the Women's Health Initiative failed to show any benefit. 192 00:09:07.560 --> 00:09:10.890 In at study daily supplementation of calcium and vitamin D 193 00:09:10.890 --> 00:09:12.480 for seven years had no effect 194 00:09:12.480 --> 00:09:15.060 on the incidence of colorectal cancer. 195 00:09:15.060 --> 00:09:16.590 The long latency associated 196 00:09:16.590 --> 00:09:18.000 with the development of colorectal cancer 197 00:09:18.000 --> 00:09:19.980 in the limited seven year duration of the trial 198 00:09:19.980 --> 00:09:22.203 may have contributed to this null finding. 199 00:09:25.200 --> 00:09:30.200 Finally, so as we just noted some studies show mixed results 200 00:09:34.080 --> 00:09:37.690 regarding the high fat, low fiber hypothesis of colon cancer 201 00:09:38.700 --> 00:09:40.650 and considering what we know 202 00:09:40.650 --> 00:09:44.070 about Hill's criteria of causality, 203 00:09:44.070 --> 00:09:47.818 it's important to conduct further independent studies 204 00:09:47.818 --> 00:09:52.818 and to look at the total available evidence 205 00:09:53.910 --> 00:09:58.910 when trying to conclude what factors might be risk factors 206 00:10:00.060 --> 00:10:02.430 or protective factors for colon cancer. 207 00:10:02.430 --> 00:10:05.716 I also want to point out that studies 208 00:10:05.716 --> 00:10:07.680 may have been hampered by the difficulty 209 00:10:07.680 --> 00:10:10.560 of conducting randomized control trials, 210 00:10:10.560 --> 00:10:12.600 which can be expensive. 211 00:10:12.600 --> 00:10:15.090 They can last a long time 212 00:10:15.090 --> 00:10:17.460 and it can be difficult to recruit participants 213 00:10:17.460 --> 00:10:19.323 for such studies.