WEBVTT 1 00:00:00.360 --> 00:00:01.680 Hi everyone, and welcome 2 00:00:01.680 --> 00:00:04.893 to this lecture on the epidemiology of prostate cancer. 3 00:00:05.959 --> 00:00:07.350 In this lecture, we have several goals. 4 00:00:07.350 --> 00:00:09.030 We'll begin by describing the global burden 5 00:00:09.030 --> 00:00:10.590 of prostate cancer and then look 6 00:00:10.590 --> 00:00:12.840 at populations at high and low risk. 7 00:00:12.840 --> 00:00:15.270 We'll also discuss mechanisms of pathogenesis 8 00:00:15.270 --> 00:00:17.460 and studies of dietary fat, NSAIDs 9 00:00:17.460 --> 00:00:20.640 and nutritional supplements in prostate cancer. 10 00:00:20.640 --> 00:00:22.523 We'll also look at genetic risks. 11 00:00:22.523 --> 00:00:25.740 And finally, we'll look at screening 12 00:00:25.740 --> 00:00:28.740 via the prostate specific antigen test and the role 13 00:00:28.740 --> 00:00:31.563 of dietary zinc in the development of prostate cancer. 14 00:00:33.150 --> 00:00:35.250 So to begin with, during 2012, 15 00:00:35.250 --> 00:00:39.810 1,111,689 new cases were diagnosed 16 00:00:39.810 --> 00:00:44.810 and 307,471 men died of prostate cancer. 17 00:00:46.290 --> 00:00:48.660 These data reflect a marked increase 18 00:00:48.660 --> 00:00:50.613 in the global burden of prostate cancer. 19 00:00:50.613 --> 00:00:52.920 During 2000 to 2012, 20 00:00:52.920 --> 00:00:55.170 the volume of new cases more than doubled 21 00:00:55.170 --> 00:00:58.530 and the number of deaths has increased more than 50%. 22 00:00:58.530 --> 00:01:01.020 Carcinoma of the prostate is the second most common form 23 00:01:01.020 --> 00:01:03.390 of cancer in men behind only lung cancer 24 00:01:03.390 --> 00:01:06.513 and is the fifth leading cause of cancer deaths worldwide. 25 00:01:08.130 --> 00:01:11.220 In high income countries, prostate cancer is diagnosed 26 00:01:11.220 --> 00:01:13.860 more often than any other form of male cancer 27 00:01:13.860 --> 00:01:17.490 and is the third leading cause of death from cancer in men. 28 00:01:17.490 --> 00:01:19.674 Disease survival in developing countries is high 29 00:01:19.674 --> 00:01:24.000 and the ratio of incidence to mortality is 0.19 30 00:01:24.000 --> 00:01:26.850 which is primarily due to screening of asymptomatic men 31 00:01:26.850 --> 00:01:29.520 by prostate specific antigen 32 00:01:29.520 --> 00:01:32.100 and the early detection of small latent carcinomas 33 00:01:32.100 --> 00:01:35.640 of the prostate, invasive prostate cancer is diagnosed 34 00:01:35.640 --> 00:01:38.640 less often in low and middle income countries 35 00:01:38.640 --> 00:01:41.940 but tumors are usually detected after metastasis, 36 00:01:41.940 --> 00:01:45.120 resulting in a twofold higher incidence to mortality ratio 37 00:01:45.120 --> 00:01:48.033 and more than 165,000 deaths annually. 38 00:01:51.090 --> 00:01:53.340 In 2020 the age standardized incidence 39 00:01:53.340 --> 00:01:55.330 of prostate cancer was 30.7 40 00:01:56.598 --> 00:01:59.320 per 100,000 globally, and the mortality was 7.7 41 00:02:00.639 --> 00:02:01.493 per 100,000 globally. 42 00:02:02.404 --> 00:02:04.620 In the US, certain ethnic groups 43 00:02:04.620 --> 00:02:08.613 within the country have exceedingly high mortality rates. 44 00:02:09.450 --> 00:02:10.980 So African Americans living in the US 45 00:02:10.980 --> 00:02:12.660 have the highest age adjusted death rate 46 00:02:12.660 --> 00:02:14.880 from prostate cancer in the world 47 00:02:14.880 --> 00:02:19.230 and their annual rate is more than 70 deaths per 100,000. 48 00:02:19.230 --> 00:02:20.610 And this rate is more than double that 49 00:02:20.610 --> 00:02:22.102 of Caucasian or Hispanic Americans 50 00:02:22.102 --> 00:02:26.283 which have rates less than 35 deaths per 100,000 people. 51 00:02:27.510 --> 00:02:29.848 The incidence of invasive cancer 52 00:02:29.848 --> 00:02:30.810 of the prostate increases dramatically 53 00:02:30.810 --> 00:02:32.850 in men over the age of 50. 54 00:02:32.850 --> 00:02:34.590 The disease is rare until age 50, 55 00:02:34.590 --> 00:02:36.710 after which the risk increases exponentially. 56 00:02:36.710 --> 00:02:39.720 The lifetime risk of developing invasive disease 57 00:02:39.720 --> 00:02:43.143 is approximately one in six among white US men. 58 00:02:45.360 --> 00:02:47.160 Prostate cancer is often discovered 59 00:02:47.160 --> 00:02:50.250 as an incidental finding, either at postmortem exam 60 00:02:50.250 --> 00:02:52.502 or in a surgical specimen removed for other reasons 61 00:02:52.502 --> 00:02:56.223 like the treatment of benign prosthetic hypertrophy or BPH. 62 00:02:57.060 --> 00:02:58.890 Almost all such lesions are small 63 00:02:58.890 --> 00:03:02.970 and comprised only of microscopic foci malignant cells. 64 00:03:02.970 --> 00:03:05.610 This form of prostate cancer is called occult 65 00:03:05.610 --> 00:03:08.070 or latent prostate cancer. 66 00:03:08.070 --> 00:03:10.650 In postmortem studies of unselected men, 67 00:03:10.650 --> 00:03:12.450 occult prostate cancer can be identified 68 00:03:12.450 --> 00:03:16.140 in about 10% of subjects between 50 to 59 years of age 69 00:03:16.140 --> 00:03:18.270 and this number rises to a prevalence 70 00:03:18.270 --> 00:03:21.303 of 40 to 50% in those over the age of 70. 71 00:03:22.200 --> 00:03:24.840 It's noteworthy that in the vast majority of subjects, 72 00:03:24.840 --> 00:03:29.250 or 95%, these occult lesions were absolutely unexpected 73 00:03:29.250 --> 00:03:31.803 or unsuspected and clinically asymptomatic. 74 00:03:33.630 --> 00:03:37.260 To briefly discuss the anatomy of the prostate gland, 75 00:03:37.260 --> 00:03:40.200 we see that it's roughly divisible into a central region, 76 00:03:40.200 --> 00:03:42.900 the transitional zone, that's responsive 77 00:03:42.900 --> 00:03:44.940 to estrogen in a more peripheral region 78 00:03:44.940 --> 00:03:48.510 or the peripheral zone that is stimulated by androgens. 79 00:03:48.510 --> 00:03:50.940 Benign prosthetic hyperplasia or BPH, 80 00:03:50.940 --> 00:03:52.950 is an extremely common disorder that affects men 81 00:03:52.950 --> 00:03:54.540 over the age of 50. 82 00:03:54.540 --> 00:03:58.470 And in this, the hyperplastic nodules of BPH typically arise 83 00:03:58.470 --> 00:04:00.399 from the inner regions of the prostate gland 84 00:04:00.399 --> 00:04:04.500 perhaps due to the balance between androgens and estrogens. 85 00:04:04.500 --> 00:04:06.060 There's longstanding controversy 86 00:04:06.060 --> 00:04:08.973 regarding the development of cancer from BPH. 87 00:04:10.500 --> 00:04:12.360 In 1993, a large placebo 88 00:04:12.360 --> 00:04:14.070 controlled randomized clinical trial, 89 00:04:14.070 --> 00:04:15.780 the Prostate Cancer Prevention Trial 90 00:04:15.780 --> 00:04:18.630 or PCPT was initiated to determine 91 00:04:18.630 --> 00:04:22.080 if the five alpha reductase inhibitor, finasteride, 92 00:04:22.080 --> 00:04:24.420 could prevent prostate cancer. 93 00:04:24.420 --> 00:04:28.140 This study looked at nearly 20,000 men age 55 and older 94 00:04:28.140 --> 00:04:30.390 and randomized them to receive either finasteride, 95 00:04:30.390 --> 00:04:33.063 five milligrams daily or placebo. 96 00:04:33.063 --> 00:04:35.850 After seven years of follow up, 18% of men 97 00:04:35.850 --> 00:04:37.980 receiving the drug developed prostate cancer 98 00:04:37.980 --> 00:04:40.503 compared to 24% in the placebo group, 99 00:04:40.503 --> 00:04:45.503 which is a risk reduction of 25%. 100 00:04:45.570 --> 00:04:47.580 However, men who did develop prostate cancer 101 00:04:47.580 --> 00:04:49.230 while receiving the drug were more likely 102 00:04:49.230 --> 00:04:51.873 to have high grade tumors with metastatic potential. 103 00:04:52.860 --> 00:04:55.110 Final results were based upon an analysis 104 00:04:55.110 --> 00:04:58.110 of nearly 10,000 participants, which was only 105 00:04:58.110 --> 00:05:01.083 about half the men who initially enrolled in the study. 106 00:05:02.940 --> 00:05:05.160 Ecological correlation studies show a strong 107 00:05:05.160 --> 00:05:07.410 positive correlation between diets high in fat 108 00:05:07.410 --> 00:05:09.300 and calories with prostate cancer incidence 109 00:05:09.300 --> 00:05:12.610 and mortality, within countries, chronological trends 110 00:05:13.512 --> 00:05:15.540 and prostate cancer rates tend to follow in close parallel 111 00:05:15.540 --> 00:05:18.870 with per capita trends in dietary fat intake. 112 00:05:18.870 --> 00:05:20.580 Prostate cancer rates in Japan 113 00:05:20.580 --> 00:05:22.890 or Japanese men have increased nearly fivefold 114 00:05:22.890 --> 00:05:25.740 over a 50 year period since 1955, 115 00:05:25.740 --> 00:05:28.893 concurrent with rising level of fat in the Japanese diet. 116 00:05:30.300 --> 00:05:35.250 This dietary fat hypothesis was examined by a study 117 00:05:35.250 --> 00:05:38.550 in 1993, which found that men reporting fat intake 118 00:05:38.550 --> 00:05:41.640 in the highest quintile experienced a 79% increase 119 00:05:41.640 --> 00:05:43.590 in the risk of invasive prostate cancer 120 00:05:43.590 --> 00:05:46.170 compared to men in the lowest quintile. 121 00:05:46.170 --> 00:05:49.710 In another study in 2007, it was found that a high intake 122 00:05:49.710 --> 00:05:52.530 of essential N6 polyunsaturated fatty acids 123 00:05:52.530 --> 00:05:54.390 produced a 2.6 fold increase 124 00:05:54.390 --> 00:05:56.643 in the risk of invasive prostate cancer. 125 00:05:58.230 --> 00:06:01.350 Animal studies also support the ideological link 126 00:06:01.350 --> 00:06:03.420 between prostate cancer development and intake 127 00:06:03.420 --> 00:06:05.590 of specific types of dietary fat. 128 00:06:05.590 --> 00:06:10.080 And this westernized lifestyle or increase 129 00:06:10.080 --> 00:06:12.900 in consumption of fats has been linked 130 00:06:12.900 --> 00:06:15.363 to an increased risk for prostate cancer. 131 00:06:17.370 --> 00:06:19.615 Traditional non-steroidal anti-inflammatory drugs 132 00:06:19.615 --> 00:06:22.200 or NSAIDs with cyclooxygenase two 133 00:06:22.200 --> 00:06:24.510 or COX2 blocking activity 134 00:06:24.510 --> 00:06:26.100 have consistently shown potential 135 00:06:26.100 --> 00:06:27.900 in the chemo prevention of several forms 136 00:06:27.900 --> 00:06:31.170 of malignant neoplasms, including prostate cancer. 137 00:06:31.170 --> 00:06:34.320 Inter meta-analysis of 17 epidemiologic studies, 138 00:06:34.320 --> 00:06:36.480 regular intake of aspirin, ibuprofen 139 00:06:36.480 --> 00:06:39.320 or other over-the-counter NSAIDs were found 140 00:06:39.320 --> 00:06:42.026 to reduce the risk of prostate cancer by 27%. 141 00:06:42.026 --> 00:06:45.120 This primarily occurs through the reduction 142 00:06:45.120 --> 00:06:47.823 of COX-2 and the inflammatory cascade. 143 00:06:49.320 --> 00:06:51.941 Prostate cancer shows a significant familial component. 144 00:06:51.941 --> 00:06:56.760 In studies in 1982, brothers of prostate cancer cases 145 00:06:56.760 --> 00:06:57.960 had four times higher 146 00:06:57.960 --> 00:07:00.240 cumulative rates of prostate cancer 147 00:07:00.240 --> 00:07:03.300 than brothers in law or males of the general population, 148 00:07:03.300 --> 00:07:04.780 thereby reflecting existence 149 00:07:05.675 --> 00:07:06.570 of genetic factors that increased the risk 150 00:07:06.570 --> 00:07:09.720 of neoplastic development in the prostate gland. 151 00:07:09.720 --> 00:07:11.040 Recently, a mutant gene 152 00:07:11.040 --> 00:07:12.820 that altered the androgen receptor 153 00:07:13.971 --> 00:07:14.804 was developed in African American men 154 00:07:14.804 --> 00:07:16.450 with a family history of prostate cancer. 155 00:07:18.060 --> 00:07:20.250 The findings of a number of observational studies 156 00:07:20.250 --> 00:07:21.689 plus two randomized control studies 157 00:07:21.689 --> 00:07:24.570 indicate that supplemental intake of selenium 158 00:07:24.570 --> 00:07:26.010 in vitamin E might be effective 159 00:07:26.010 --> 00:07:28.775 in preventing the development of prostate cancer. 160 00:07:28.775 --> 00:07:31.110 In 2001, a large randomized placebo 161 00:07:31.110 --> 00:07:32.610 controlled clinical trial 162 00:07:32.610 --> 00:07:34.740 was initiated to determine whether selenium, 163 00:07:34.740 --> 00:07:37.533 vitamin E or both could prevent prostate cancer. 164 00:07:39.417 --> 00:07:44.417 This study was inconclusive and found no effect 165 00:07:44.490 --> 00:07:47.790 on the risk of developing invasive prostate cancer. 166 00:07:47.790 --> 00:07:49.590 Some studies have also examined the impact 167 00:07:49.590 --> 00:07:51.941 of sexual activity on prostate cancer risk. 168 00:07:51.941 --> 00:07:54.303 Though these studies are inconclusive. 169 00:07:55.980 --> 00:07:57.330 Screening for prostate cancer 170 00:07:57.330 --> 00:07:59.220 using serum prostate specific antigen 171 00:07:59.220 --> 00:08:01.050 or PSA test gained favor 172 00:08:01.050 --> 00:08:03.900 in the US and other developed countries during the 1990s. 173 00:08:04.800 --> 00:08:05.633 It is estimated 174 00:08:05.633 --> 00:08:07.770 that 20 million PSA tests are performed annually 175 00:08:07.770 --> 00:08:09.720 in North America and possibly 20 million more 176 00:08:09.720 --> 00:08:13.410 outside of North America, a high level of serum PSA 177 00:08:13.410 --> 00:08:16.770 or more than four nanograms per milliliter 178 00:08:16.770 --> 00:08:19.050 when coupled with digital rectal examination, 179 00:08:19.050 --> 00:08:20.790 ultrasonography and directed biopsy 180 00:08:20.790 --> 00:08:23.520 of suspicious prostatic tissues can be effective 181 00:08:23.520 --> 00:08:25.800 in identifying men with invasive disease 182 00:08:25.800 --> 00:08:27.720 confined to the prostate gland that can be completely 183 00:08:27.720 --> 00:08:30.344 surgically excised without recurrence. 184 00:08:30.344 --> 00:08:32.370 PSA screening is controversial 185 00:08:32.370 --> 00:08:34.680 since prostate cancer often develops so slowly 186 00:08:34.680 --> 00:08:38.160 that it will never lead to symptoms during a man's lifetime. 187 00:08:38.160 --> 00:08:40.320 Furthermore, prostatectomy for removal 188 00:08:40.320 --> 00:08:41.670 of a cancerous prostate gland 189 00:08:41.670 --> 00:08:44.490 often produces major debilitating side effects 190 00:08:44.490 --> 00:08:45.870 like urinary incontinence, 191 00:08:45.870 --> 00:08:47.793 erectile dysfunction and impotence. 192 00:08:48.810 --> 00:08:50.130 The major consideration 193 00:08:50.130 --> 00:08:51.900 for any screening protocol is to weigh the benefits 194 00:08:51.900 --> 00:08:53.700 of early detection and lifesaving treatment 195 00:08:53.700 --> 00:08:57.120 against the risk of harm from unnecessary intervention. 196 00:08:57.120 --> 00:08:59.460 Results of two large randomized clinical trials, 197 00:08:59.460 --> 00:09:01.305 a PSA screening have now been published. 198 00:09:01.305 --> 00:09:06.305 The first study did show 20% fewer deaths 199 00:09:06.840 --> 00:09:09.052 in the group that received PSA testing. 200 00:09:09.052 --> 00:09:11.310 However, the study also found that a large number 201 00:09:11.310 --> 00:09:14.160 of men who were treated unnecessarily 202 00:09:14.160 --> 00:09:17.133 resulted in a high rate of major side effects. 203 00:09:18.030 --> 00:09:22.195 Another randomized study in the US compared PSA 204 00:09:22.195 --> 00:09:24.780 to quote, unquote usual care 205 00:09:24.780 --> 00:09:27.280 in the detection and treatment of prostate cancer. 206 00:09:28.200 --> 00:09:30.590 And in this study, there were actually 13% fewer deaths 207 00:09:30.590 --> 00:09:33.510 in in the group that received quote, unquote usual care 208 00:09:33.510 --> 00:09:36.753 rather than regular prostate specific antigen tests. 209 00:09:37.590 --> 00:09:40.110 After careful for review of the scientific evidence, 210 00:09:40.110 --> 00:09:42.150 the US Preventative Service Task Force 211 00:09:42.150 --> 00:09:44.196 concluded that the data were insufficient 212 00:09:44.196 --> 00:09:46.890 to recommend screening for men under 75, 213 00:09:46.890 --> 00:09:49.923 and that men 75 and older should not be screened. 214 00:09:50.760 --> 00:09:52.500 Clinicians are now advised to use a process 215 00:09:52.500 --> 00:09:53.580 of shared decision making 216 00:09:53.580 --> 00:09:55.683 with each patient that includes candid discussion 217 00:09:55.683 --> 00:09:58.863 about the potential risks and benefits of screening. 218 00:10:00.240 --> 00:10:03.060 Finally, we turn to studies looking at the relationship 219 00:10:03.060 --> 00:10:05.820 between zinc and prostate cancer survival. 220 00:10:05.820 --> 00:10:07.290 So zinc is an essential mineral 221 00:10:07.290 --> 00:10:09.690 with known antioxidant anti-inflammatory effects 222 00:10:09.690 --> 00:10:11.490 and it's an important co-factor 223 00:10:11.490 --> 00:10:15.390 in DNA repair, apoptosis and cellular immunity. 224 00:10:15.390 --> 00:10:17.820 The concentration of zinc is higher in prostate tissue 225 00:10:17.820 --> 00:10:20.730 than in any other tissue in the human body. 226 00:10:20.730 --> 00:10:22.080 And Swedish men have one 227 00:10:22.080 --> 00:10:23.700 of the highest annual mortality rates 228 00:10:23.700 --> 00:10:25.653 from prostate cancer in the world. 229 00:10:26.719 --> 00:10:31.230 So a study was launched to examine the level 230 00:10:31.230 --> 00:10:33.060 of dietary zinc as the potential predictor 231 00:10:33.060 --> 00:10:36.300 of survival among 525 Swedish men 232 00:10:36.300 --> 00:10:38.220 diagnosed with invasive prostate cancer 233 00:10:38.220 --> 00:10:41.720 during 1989 to 1995. 234 00:10:41.720 --> 00:10:43.770 In this study, zinc intake was estimated 235 00:10:43.770 --> 00:10:45.840 based on the average content in grains, meat, 236 00:10:45.840 --> 00:10:47.040 dairy products, fruits, nuts 237 00:10:47.040 --> 00:10:49.590 and vegetables consumed by the individual patients. 238 00:10:50.481 --> 00:10:52.350 And the study found 239 00:10:52.350 --> 00:10:54.660 that high dietary zinc intake was associated 240 00:10:54.660 --> 00:10:57.930 with a reduced risk of death due to prostate cancer. 241 00:10:57.930 --> 00:11:00.900 This protective effect of high dietary zinc was stronger 242 00:11:00.900 --> 00:11:03.930 among men diagnosed with localized tumors. 243 00:11:03.930 --> 00:11:05.580 And these results suggest that high intake 244 00:11:05.580 --> 00:11:07.830 of dietary zinc has therapeutic benefit 245 00:11:07.830 --> 00:11:10.293 in men diagnosed with prostate cancer.