WEBVTT 1 00:00:00.510 --> 00:00:01.620 Hi everyone. 2 00:00:01.620 --> 00:00:03.600 In this lecture, we'll be continuing our discussion 3 00:00:03.600 --> 00:00:06.000 of the epidemiology of colon cancer. 4 00:00:06.000 --> 00:00:09.390 Here we'll focus on risk factors and prevention. 5 00:00:09.390 --> 00:00:12.060 The goals of this lecture are to discuss the risk factors 6 00:00:12.060 --> 00:00:13.770 for colorectal cancer, 7 00:00:13.770 --> 00:00:16.770 to characterize trends in colorectal cancer rates, 8 00:00:16.770 --> 00:00:19.260 to discuss the chemoprevention of colorectal cancer 9 00:00:19.260 --> 00:00:21.993 and to discuss the impact of screening by colonoscopy. 10 00:00:22.950 --> 00:00:26.940 So to begin with, chronic alcohol abuse is strongly linked 11 00:00:26.940 --> 00:00:29.160 to colorectal carcinogenesis. 12 00:00:29.160 --> 00:00:31.440 Analysis of data from the US National Health 13 00:00:31.440 --> 00:00:34.530 and Nutrition Examination survey showed a 70% increase 14 00:00:34.530 --> 00:00:36.990 in colorectal cancer among individuals 15 00:00:36.990 --> 00:00:38.610 who consumed one or more drinks 16 00:00:38.610 --> 00:00:40.293 of alcoholic beverages daily. 17 00:00:41.271 --> 00:00:44.100 In a pooled analysis of eight prospective cohort studies 18 00:00:44.100 --> 00:00:46.380 performed in five countries, 19 00:00:46.380 --> 00:00:48.780 it was found that the risk increased by 40% 20 00:00:48.780 --> 00:00:51.660 at the highest level of alcohol consumption, 21 00:00:51.660 --> 00:00:54.900 greater than 45 grams of alcohol daily. 22 00:00:54.900 --> 00:00:57.210 Pooled results from five Japanese studies 23 00:00:57.210 --> 00:00:59.640 suggest that one quarter of all colorectal cancers 24 00:00:59.640 --> 00:01:01.410 in Japan are attributable 25 00:01:01.410 --> 00:01:04.653 to alcohol consumption above 23 grams daily. 26 00:01:05.700 --> 00:01:06.870 Chronic tobacco addiction 27 00:01:06.870 --> 00:01:10.710 has also been linked to colorectal cancer development. 28 00:01:10.710 --> 00:01:12.210 The epidemiologic evidence shows 29 00:01:12.210 --> 00:01:14.220 that chronic smokers of a two to threefold 30 00:01:14.220 --> 00:01:18.810 increased incidence of pre-malignant adenomas of the colon 31 00:01:18.810 --> 00:01:20.193 compared to non-smokers. 32 00:01:21.090 --> 00:01:24.270 In a meta-analysis of 106 studies, 33 00:01:24.270 --> 00:01:26.310 it was found that smoking significantly 34 00:01:26.310 --> 00:01:27.600 increases both the incidence 35 00:01:27.600 --> 00:01:30.210 and mortality of colorectal cancer. 36 00:01:30.210 --> 00:01:32.700 The existing evidence therefore supports the addition 37 00:01:32.700 --> 00:01:34.110 of colorectal cancer to the list 38 00:01:34.110 --> 00:01:36.213 of tobacco associated malignancies. 39 00:01:37.320 --> 00:01:39.780 Various mechanisms may be responsible for the effects 40 00:01:39.780 --> 00:01:42.663 of alcohol and tobacco on colorectal carcinogenesis. 41 00:01:43.530 --> 00:01:45.570 One mechanism involves the combination 42 00:01:45.570 --> 00:01:48.930 of chronic alcohol consumption and folate deficiency. 43 00:01:48.930 --> 00:01:52.030 As ethanol enters the large bowel, it's metabolized into 44 00:01:54.120 --> 00:01:57.090 acetaldehyde by anaerobic microbes. 45 00:01:57.090 --> 00:02:00.720 Acetaldehyde in terms rapidly degrades folates. 46 00:02:00.720 --> 00:02:02.340 Since folate is essential 47 00:02:02.340 --> 00:02:05.400 for normal DNA synthesis and repair, 48 00:02:05.400 --> 00:02:07.530 the fact that it's being degraded rapidly 49 00:02:07.530 --> 00:02:09.540 could readily lead to DNA instability 50 00:02:09.540 --> 00:02:12.033 and carcinogenesis in the colorectal mucosa. 51 00:02:13.260 --> 00:02:15.650 Alcohol consumption may also delay peristalsis 52 00:02:15.650 --> 00:02:17.940 in the large bowel and increase transit time 53 00:02:17.940 --> 00:02:21.660 and exposure to carcinogens and other toxic substances. 54 00:02:21.660 --> 00:02:24.480 Carcinogens from tobacco can reach the colorectal mucosa 55 00:02:24.480 --> 00:02:26.340 through the gastrointestinal tract 56 00:02:26.340 --> 00:02:28.710 or the circulatory system and may accentuate 57 00:02:28.710 --> 00:02:31.770 neurogenesis, inflammation and carcinogenesis, 58 00:02:31.770 --> 00:02:34.470 particularly in the distal colon. 59 00:02:34.470 --> 00:02:36.630 There's also speculation that tobacco and alcohol 60 00:02:36.630 --> 00:02:38.400 may synergistically heighten the risk 61 00:02:38.400 --> 00:02:39.633 of colorectal cancer. 62 00:02:41.460 --> 00:02:43.350 High levels of circulating insulin 63 00:02:43.350 --> 00:02:44.970 and insulin like growth factors 64 00:02:44.970 --> 00:02:46.800 have also been found to increase the risk 65 00:02:46.800 --> 00:02:48.573 of developing colorectal cancer. 66 00:02:51.090 --> 00:02:53.310 Individuals who manifest clinical conditions 67 00:02:53.310 --> 00:02:55.450 associated with high levels of insulin 68 00:02:56.520 --> 00:02:58.323 like type two diabetes, 69 00:02:59.220 --> 00:03:02.010 the metabolic syndrome and acromegaly, 70 00:03:02.010 --> 00:03:03.120 are at increased risk 71 00:03:03.120 --> 00:03:05.760 for the development of colorectal cancer. 72 00:03:05.760 --> 00:03:07.740 Phenotypic and lifestyle factors 73 00:03:07.740 --> 00:03:10.800 associated with hyperinsulinemia 74 00:03:10.800 --> 00:03:14.610 and high IGF one levels increase the risk. 75 00:03:14.610 --> 00:03:17.310 Components of the IGF axis, 76 00:03:17.310 --> 00:03:21.240 IGF1, IGF2, IGF cell membrane receptors 77 00:03:21.240 --> 00:03:22.710 and binding molecules 78 00:03:22.710 --> 00:03:24.990 constitute an important molecular interface 79 00:03:24.990 --> 00:03:26.460 with exposures that initiate 80 00:03:26.460 --> 00:03:28.623 and promote colorectal carcinogenesis. 81 00:03:29.940 --> 00:03:32.490 Chronic inflammation conditions of the intestinal tract 82 00:03:32.490 --> 00:03:36.240 also predispose to the development of colorectal cancer. 83 00:03:36.240 --> 00:03:39.450 Ulcerative colitis is characterized by chronic inflammation 84 00:03:39.450 --> 00:03:42.240 and ulceration of the epithelial lining of the colon 85 00:03:42.240 --> 00:03:44.970 plus other extra colonic lesions. 86 00:03:44.970 --> 00:03:46.680 The primary site of attack is usually 87 00:03:46.680 --> 00:03:48.630 in the descending or left colon, 88 00:03:48.630 --> 00:03:51.480 and approximately 1% of colorectal cancer patients 89 00:03:51.480 --> 00:03:54.510 have a history of chronic ulcerative colitis. 90 00:03:54.510 --> 00:03:57.090 Approximately 40 to 50% of individuals 91 00:03:57.090 --> 00:04:00.040 with long-standing ulcerative colitis develop colon cancer. 92 00:04:01.020 --> 00:04:04.170 Crohn's disease also increases the risk 93 00:04:04.170 --> 00:04:06.690 of colorectal cancer development. 94 00:04:06.690 --> 00:04:09.390 Both ulcerative colitis and Crohn's disease 95 00:04:09.390 --> 00:04:11.190 appear to have an autoimmune basis 96 00:04:11.190 --> 00:04:13.290 and are characterized by similar alterations 97 00:04:13.290 --> 00:04:15.333 in the IGF axis. 98 00:04:18.630 --> 00:04:22.260 The investigation of a large multi-generational family 99 00:04:22.260 --> 00:04:23.430 in the early 1900s 100 00:04:23.430 --> 00:04:27.300 identified a hereditary form of colorectal cancer. 101 00:04:27.300 --> 00:04:30.930 33 relatives with colorectal cancer were diagnosed 102 00:04:30.930 --> 00:04:33.033 among 70 members of the family. 103 00:04:34.080 --> 00:04:38.370 Hereditary nonpolyposis colorectal cancer, or HNPCC, 104 00:04:38.370 --> 00:04:40.680 was later named the Lynch syndrome, 105 00:04:40.680 --> 00:04:42.510 after Dr. Henry T. Lynch, 106 00:04:42.510 --> 00:04:44.760 who documented two large families 107 00:04:44.760 --> 00:04:47.103 with this autosomal dominant syndrome. 108 00:04:48.030 --> 00:04:51.240 Lynch and his colleagues initially designated HNPCC 109 00:04:51.240 --> 00:04:53.103 as the cancer family syndrome. 110 00:04:54.090 --> 00:04:58.080 The cause of HNPCC is an inherited germline mutation 111 00:04:58.080 --> 00:05:01.770 in at least one of a set of genes that normally repair DNA, 112 00:05:01.770 --> 00:05:04.290 the mismatch repair genes. 113 00:05:04.290 --> 00:05:07.050 In 1993, the first of these genes was discovered 114 00:05:07.050 --> 00:05:08.130 on chromosome two, 115 00:05:08.130 --> 00:05:11.400 and in 1994 the second gene was discovered 116 00:05:11.400 --> 00:05:12.723 on chromosome three. 117 00:05:13.590 --> 00:05:15.060 Mutations in these two genes 118 00:05:15.060 --> 00:05:19.020 account for 90% of the known HNPCC families. 119 00:05:19.020 --> 00:05:20.460 Carriers of either gene 120 00:05:20.460 --> 00:05:22.200 have a lifetime colon cancer risk 121 00:05:22.200 --> 00:05:24.180 approaching a hundred percent. 122 00:05:24.180 --> 00:05:26.490 The Lynch syndrome accounts for a small percentage 123 00:05:26.490 --> 00:05:28.830 of all colorectal cancer cases, 124 00:05:28.830 --> 00:05:31.860 accounting for only about one to 3% of all 125 00:05:31.860 --> 00:05:33.483 colorectal cancer cases. 126 00:05:37.110 --> 00:05:40.320 So the Amsterdam criteria 127 00:05:40.320 --> 00:05:43.390 is related to familial colon cancer 128 00:05:44.310 --> 00:05:47.850 and the criteria apply when three or more family members 129 00:05:47.850 --> 00:05:50.550 have a confirmed diagnosis of colorectal cancer 130 00:05:50.550 --> 00:05:53.703 and one of them is a first degree relative of the other two. 131 00:05:54.810 --> 00:05:59.700 This needs to apply to two successive affected generations 132 00:05:59.700 --> 00:06:02.700 and one or more of the three cases 133 00:06:02.700 --> 00:06:05.283 has to be diagnosed under age 50 years. 134 00:06:07.920 --> 00:06:11.985 In 1951, a report of a large Utah family 135 00:06:11.985 --> 00:06:15.690 containing many relatives with diffuse polyps of the colon 136 00:06:15.690 --> 00:06:17.820 and intestinal tract in multiple relatives 137 00:06:17.820 --> 00:06:19.713 with colorectal cancer was published. 138 00:06:20.820 --> 00:06:22.530 It was called Gardener's Syndrome, 139 00:06:22.530 --> 00:06:25.860 and it's a rare form of familial adenomatous polyposis, 140 00:06:25.860 --> 00:06:26.936 or FAP, 141 00:06:26.936 --> 00:06:30.240 and is characterized by the presence of multiple polyps 142 00:06:30.240 --> 00:06:32.913 in the colon together with tumors outside the colon. 143 00:06:33.840 --> 00:06:35.100 In Gardener's syndrome, 144 00:06:35.100 --> 00:06:38.340 the extra colonic tumors or tumors outside the colon 145 00:06:38.340 --> 00:06:40.590 may include osteomas of the skull, 146 00:06:40.590 --> 00:06:43.410 thyroid cancer, epidermoid cysts, 147 00:06:43.410 --> 00:06:48.300 fibromas, sebaceous cysts, and desmoid tumors. 148 00:06:48.300 --> 00:06:51.240 The countless polyps in the colon of FAP patients 149 00:06:51.240 --> 00:06:53.880 predispose to the development of colon cancer 150 00:06:53.880 --> 00:06:55.590 with a hundred percent probability 151 00:06:55.590 --> 00:06:58.080 unless the colon is removed. 152 00:06:58.080 --> 00:07:00.780 The onset of polyps occurs during the teenage years 153 00:07:00.780 --> 00:07:03.000 and the average age of diagnosis of colon cancer 154 00:07:03.000 --> 00:07:05.580 is 35 to 40 years. 155 00:07:05.580 --> 00:07:08.190 Polyps can also grow in the stomach, duodenum, 156 00:07:08.190 --> 00:07:12.297 spleen, kidneys, liver, mesentery and small bowel. 157 00:07:12.297 --> 00:07:13.620 In a small number of cases 158 00:07:13.620 --> 00:07:16.440 polyps have also occurred in the cerebellum. 159 00:07:16.440 --> 00:07:18.480 Extra colon cancers related to FAP 160 00:07:18.480 --> 00:07:21.183 commonly occur in the thyroid, liver and kidneys. 161 00:07:22.080 --> 00:07:24.990 FAP, or familial adenomatous polyposis, 162 00:07:24.990 --> 00:07:27.870 and Gardener's syndrome are caused by an autosomal dominant 163 00:07:27.870 --> 00:07:31.920 germline mutation in the adenomatous polyposis coli, 164 00:07:31.920 --> 00:07:33.990 or APC gene, 165 00:07:33.990 --> 00:07:38.430 which is located on band Q21 of chromosome five. 166 00:07:38.430 --> 00:07:41.100 The APC gene is a tumor suppressor gene 167 00:07:41.100 --> 00:07:44.700 that regulates cell adhesion, cell migration and apoptosis 168 00:07:44.700 --> 00:07:46.593 in the colorectal epithelium. 169 00:07:50.370 --> 00:07:51.330 It's important to note 170 00:07:51.330 --> 00:07:54.330 that regular intake of aspirin, ibuprofen, or other NSAIDs 171 00:07:54.330 --> 00:07:56.440 reduces the risk of polyp development 172 00:07:57.450 --> 00:08:00.660 by suppressing the formation of adenomatous polyps 173 00:08:00.660 --> 00:08:04.620 and leading to the regression of existing polyps 174 00:08:04.620 --> 00:08:06.307 in patients with FAP. 175 00:08:08.550 --> 00:08:10.530 The results of many epidemiologic studies 176 00:08:10.530 --> 00:08:12.150 provide strong evidence 177 00:08:12.150 --> 00:08:15.540 that regular intake of non-steroidal anti-inflammatory drugs 178 00:08:15.540 --> 00:08:18.150 or NSAIDs like aspirin and ibuprofen 179 00:08:18.150 --> 00:08:21.600 reduces the risk of colorectal cancer development. 180 00:08:21.600 --> 00:08:23.850 In a meta-analysis of published estimate, 181 00:08:23.850 --> 00:08:26.070 significant risk reductions were observed 182 00:08:26.070 --> 00:08:30.030 in 28 of 32 studies and regular use of NSAIDs 183 00:08:30.030 --> 00:08:32.553 produced a 43% reduction in the risk. 184 00:08:36.300 --> 00:08:39.420 It's important to note key epidemiological issues 185 00:08:39.420 --> 00:08:41.580 in chemopreventative trials. 186 00:08:41.580 --> 00:08:45.513 The first consideration is to do no harm to the patient. 187 00:08:46.920 --> 00:08:49.560 The dose also makes the poison. 188 00:08:49.560 --> 00:08:54.560 So some drugs, while non-toxic at a low dose 189 00:08:54.780 --> 00:08:57.540 may quickly become toxic at elevated doses. 190 00:08:57.540 --> 00:09:02.340 So it's important to understand the possible ramifications 191 00:09:02.340 --> 00:09:05.890 before designing a clinical trial 192 00:09:06.866 --> 00:09:11.100 of a certain chemopreventative drug. 193 00:09:11.100 --> 00:09:12.600 Trials also frequently 194 00:09:12.600 --> 00:09:15.240 run into the issue of the placebo effect. 195 00:09:15.240 --> 00:09:17.918 That is, it's important to consider the ways 196 00:09:17.918 --> 00:09:21.000 in which someone blindly receiving a placebo 197 00:09:21.000 --> 00:09:23.800 rather than an actual chemopreventative drug 198 00:09:24.690 --> 00:09:26.230 may be affected by 199 00:09:28.676 --> 00:09:30.960 the thought that they might be receiving 200 00:09:30.960 --> 00:09:33.783 a drug with an active ingredient. 201 00:09:34.740 --> 00:09:38.430 It's also important to consider the ways 202 00:09:38.430 --> 00:09:40.650 and to facilitate compliance as best 203 00:09:40.650 --> 00:09:43.170 as possible in clinical trials 204 00:09:43.170 --> 00:09:45.420 and to think about the ways that risk factors 205 00:09:45.420 --> 00:09:49.020 may or may not be matched among different treatment groups 206 00:09:49.020 --> 00:09:50.913 in chemopreventative trials. 207 00:09:52.800 --> 00:09:57.030 So if we look at the rates of colorectal cancer 208 00:09:57.030 --> 00:09:58.350 over time in the US, 209 00:09:58.350 --> 00:10:00.000 we see that rates have declined in the US 210 00:10:00.000 --> 00:10:02.130 during the past 50 years. 211 00:10:02.130 --> 00:10:04.461 In women rates began to decline in mid-century 212 00:10:04.461 --> 00:10:07.680 and have decreased by more than 50%. 213 00:10:07.680 --> 00:10:11.310 In men, rates began to decline during 1970 to 1980 214 00:10:11.310 --> 00:10:14.130 and have decreased by about 40%. 215 00:10:14.130 --> 00:10:16.770 Contributing factors including increased screening, 216 00:10:16.770 --> 00:10:18.210 more efficacious treatment, 217 00:10:18.210 --> 00:10:20.640 improvement in diet, reduction in risk factors 218 00:10:20.640 --> 00:10:24.273 and greater use of chemo preventative agents like NSAIDs. 219 00:10:25.230 --> 00:10:26.400 These declines have occurred 220 00:10:26.400 --> 00:10:28.770 in the face of concurrent epidemics of obesity 221 00:10:28.770 --> 00:10:31.263 and related conditions like type two diabetes. 222 00:10:34.110 --> 00:10:36.480 The declining pattern of colorectal cancer mortality 223 00:10:36.480 --> 00:10:38.550 in the US is most compatible 224 00:10:38.550 --> 00:10:40.950 with a relatively large contribution from screening 225 00:10:40.950 --> 00:10:43.470 and a smaller impact of risk factor reductions 226 00:10:43.470 --> 00:10:45.810 and improved treatments. 227 00:10:45.810 --> 00:10:47.910 Colonoscopy has gained greater acceptance 228 00:10:47.910 --> 00:10:49.020 in the general population 229 00:10:49.020 --> 00:10:50.940 and is the most reliable method of screening 230 00:10:50.940 --> 00:10:54.030 for the early detection of adenomatous polyps 231 00:10:54.030 --> 00:10:56.340 and cancer of the large bowel. 232 00:10:56.340 --> 00:10:59.130 In addition, visual determination of the exact location 233 00:10:59.130 --> 00:11:00.960 and size of existing tumors 234 00:11:00.960 --> 00:11:03.720 is an invaluable tool in planning and implementing 235 00:11:03.720 --> 00:11:06.630 definitive surgical resection. 236 00:11:06.630 --> 00:11:09.300 Colonoscopic imaging coupled with effective surgery 237 00:11:09.300 --> 00:11:12.750 has produced five year survival rates greater than 90% 238 00:11:12.750 --> 00:11:14.640 for patients whose tumors have not progressed 239 00:11:14.640 --> 00:11:15.873 beyond the bowel wall. 240 00:11:17.790 --> 00:11:21.990 And as I just mentioned, there's a couple different methods 241 00:11:21.990 --> 00:11:24.120 for screening for colon cancer. 242 00:11:24.120 --> 00:11:25.230 There's a blood test, 243 00:11:25.230 --> 00:11:28.713 there's sigmoidoscopy, colonoscopy and biopsy.