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Adam Todd, PhD is Senior Lecturer in Pharmaceutical Public Health in the School of Pharmacy, Faculty of Medical Sciences, at Newcastle University, UK. He is registered pharmacist, and specializes in oncology and palliative care.
Paul W. Groundwater, PhD is Professor of Medicinal Chemistry in the Faculty of Pharmacy at The University of Sydney, Sydney, Australia.
Jason H. Gill, PhD is a Reader in Molecular Therapeutics in the School of Pharmacy, Faculty of Medical Sciences, at Newcastle University, UK.
Preface xi
Section 1: Introduction 1
1.1 The Global Burden of Cancer 3
References 11
1.2 Cancer Staging and Classification 13
1.2.1 Benign Tumour (or neoplasm) 13
1.2.2 Malignant Tumour (or cancer) 14
1.2.3 Tumour Nomenclature and Classification 14
1.2.4 Cellular Differentiation and Tumour Grade 21
1.2.5 Tumour Invasion and Metastasis 24
1.2.6 Clinical Staging of Cancer 26
References 36
1.3 Cellular and Molecular Basis of Cancer 39
1.3.1 Oncogenes 40
1.3.2 Tumour Suppressor Genes 45
1.3.3 Role of Epigenetics and Gene Promoter Regulation in Tumourigenesis 49
1.3.4 Multistage Tumourigenesis 53
1.3.5 Oncogene Addiction 54
1.3.6 Hallmarks of Cancer 55
1.3.7 Principles of Cancer Treatment 73
References 77
Section 2: The Anticancer Agents 81
2.1 Agents Which Act Directly on DNA 83
2.1.1 Nitrogen Mustards and Nitrosoureas 83
References 96
2.1.2 Temozolomide 98
References 106
2.1.3 Platinum?]containing Agents 108
References 118
2.1.4 Gemcitabine 120
References 128
2.1.5 Camptothecin and Its Analogues 128
References 139
2.1.6 Podophyllotoxins 141
References 150
2.1.7 Anthracyclines 151
References 160
2.1.8 Epigenetic Targeting Agents 162
References 177
2.2 Antimetabolites 181
2.2.1 Cytarabine 181
References 183
2.2.2 Methotrexate 184
References 195
2.2.3 5?]Fluorouracil 196
References 205
2.2.4 6?]Mercaptopurine 206
References 210
2.3 Antimicrotubule Agents 211
2.3.1 Taxanes 211
References 224
2.3.2 Vinca Alkaloids 225
References 231
2.4 Anti?]hormonal Agents 233
2.4.1 Bicalutamide 233
References 239
2.4.2 Tamoxifen 240
References 247
2.4.3 Anastrozole 248
References 254
2.5 Kinase Inhibitors 257
2.5.1 Discovery 257
2.5.2 Synthesis 262
2.5.3 Mode of Action 267
2.5.4 Mechanism of Resistance 268
2.5.5 Adverse Drug Reactions 268
References 271
Section 3: The Cancers 275
3.1 Breast Cancer 277
Key points 277
3.1.1 Epidemiology 277
3.1.2 Presentation 279
3.1.3 Diagnosis 282
3.1.4 Staging 283
3.1.5 Treatments 285
References 289
3.2 Colorectal Cancer 293
Key points 293
3.2.1 Epidemiology 293
3.2.2 Presentation 294
3.2.3 Diagnosis 296
3.2.4 Staging 298
3.2.5 Treatments 299
References 303
3.3 Leukaemia 307
Key points 307
3.3.1 Epidemiology 307
3.3.2 Presentation 310
3.3.3 Diagnosis 311
3.3.4 Staging 313
3.3.5 Treatments 314
References 319
3.4 Lung Cancer 323
Key points 323
3.4.1 Epidemiology 323
3.4.2 Presentation 327
3.4.3 Diagnosis 327
3.4.4 Staging 330
3.4.5 Treatments 330
References 337
3.5 Oesophageal Cancer 339
Key points 339
3.5.1 Epidemiology 339
3.5.2 Presentation 340
3.5.3 Diagnosis 341
3.5.4 Staging 344
3.5.5 Treatments 346
References 350
3.6 Ovarian Cancer 353
Key points 353
3.6.1 Epidemiology 353
3.6.2 Presentation 354
3.6.3 Diagnosis 356
3.6.4 Staging 357
3.6.5 Treatments 357
References 363
3.7 Pancreatic Cancer 367
Key points 367
3.7.1 Epidemiology 367
3.7.2 Presentation 368
3.7.3 Diagnosis 370
3.7.4 Staging 371
3.7.5 Treatments 373
References 375
3.8 Prostate Cancer 379
Key points 379
3.8.1 Epidemiology 379
3.8.2 Presentation 381
3.8.3 Diagnosis 382
3.8.4 Staging 384
3.8.5 Treatments 387
References 391
3.9 Skin Cancers 393
Key points 393
3.9.1 Epidemiology 393
3.9.2 Presentation 394
3.9.3 Diagnosis 395
3.9.4 Staging 396
3.9.5 Treatments 399
References 403
3.10 Testicular Cancer 405
Key points 405
3.10.1 Epidemiology 405
3.10.2 Presentation 407
3.10.3 Diagnosis 407
3.10.4 Staging 409
3.10.5 Treatments 409
References 414
Index 417
In order for us to understand cancer and its treatment it is obviously important to define what is meant by the term 'cancer'. The word is credited to Hippocrates, the Greek physician (460-370 BC), who used the words carcinos and carcinoma to describe non-ulcer and ulcer-forming growths. These words in Greek derive from the word for crab, and their use is believed to be due to the fact that the spreading nature and cellular projections of the growths observed were reminiscent of the shape of a crab. Later changes resulted in the use of the words cancer (Latin for crab) and oncos (Greek for swelling) to describe tumours, terms attributed to the Roman physicians, Celsus (28-50 BC) and Galen (130-200?AD), respectively. Interestingly, we still use all of these words to define malignancy, to discuss a tumour's histological appearance, and as a description for medical specialists in this area (oncologists).
Although described as a single condition, cancer is actually a family of hundreds of different diseases. The distinction between the different types of cancer is extremely important since their treatment, management, and outcomes for the patient are very diverse (as we shall see in the later sections). Additionally, even within a single cancer 'type' there are significant issues with regards to treatment options and patient prognosis, as individual cancers of the same type can behave very differently from one another. The same can be said for the global distribution of cancer; there are different profiles of cancer types in different geographical regions, with different causative factors, different treatment options and successes, and different prognostic and survival rates. Invariably, across the globe, some cancer types and some patients will achieve some degree of remission, and some will be cured, but others will not, with treatment in their case focusing on extending life expectancy.
Cancer is a major worldwide public health problem, as indicated by the World Health Organization (WHO) identifying cancer as one of four leading threats to human health and development (the others being cardiovascular disease, chronic respiratory diseases, and diabetes) in 2008 [1]. In 2012, cancer incidence1 was estimated at 14.1 million people, cancer mortality2 was predicted at 8.2 million deaths, and cancer prevalence3 was estimated at 32.6 million people [2]. When we just consider these numbers it is difficult to appreciate the scale of the problem, and it is therefore important to put this into context. For instance, in 2012 the estimated population of the world was 7.05 billion people, and the risk of dying4 from cancer before age 75 was 10.5% [2].
Cancer is not a modern disease, being first identified and described around 5,000 years ago. What may be unexpected is that the frequency and occurrence of cancer are higher nowadays than about a century ago despite significant advances in cancer diagnosis, treatment, and management over this period. So how can that be? Are we seeing an increase in cancer cases? Are we really making progress with the treatment of these diseases? The answers to these questions relate to the way we consider and view cancer, and have a direct relationship to factors and successes outside of the cancer field. A major contributory factor in cancer appearing to become an increasing cause of mortality over the past century is our achievements in the treatment of other life-threatening diseases. In the early 1900s cancer accounted for a small proportion of deaths, with the majority of deaths being due to infectious diseases such as pneumonia, tuberculosis, and polio. Since this time, medical progress and improvements in public health and hygiene have led to the significant reduction and elimination of infection as a major cause of death. This effect can be observed if we compare differences in cancer incidence and mortality in different regions of the world, particularly developed versus developing countries. In the developed countries of Europe, treatment for infectious diseases is highly successful and cancer appears to be a major mortality factor, for example mortality rates are greater than 150 per 100,000 and incidence rates are greater than 300 per 100,000 in Northern and Western Europe. We can compare this to the developing countries of Middle and Northern Africa, where infectious diseases are a major factor and treatment success is poor; here cancer mortality rates are below 90 per 100,000 and incidence rates are below 130 per 100,000 (Figure 1.1.1).
Figure 1.1.1 Estimated age-standardised (a) cancer incidence and (b) cancer-related mortality rates per 100,000 population in regions of the world in 2012 [3]. Northern Europe incorporates the UK and Scandinavia; South-Central Asia incorporates Iran, Iraq, Afghanistan, Pakistan, and India; Eastern Asia incorporates China, Taiwan, Japan, North Korea, South Korea, and Mongolia; South-eastern Asia incorporates Laos, Myanmar, Philippines, Thailand, Vietnam, Malaysia, Singapore, and Indonesia.
Source: Torre 2012 [3].
As we can clearly see from Figure 1.1.1, the incidence of cancer is highest in Australia/New Zealand, but is also higher than the global rate (World) in Europe and North America. The mortality rates (which are dictated by the most prevalent cancers found in each of the regions) partly reflect the incidence rates, but notable exceptions are Melanesia (Western Pacific), which has an incidence rate below the global average, but a mortality rate near the top, and its near neighbours Australia/New Zealand, which have the highest incidence per 100,000 but are below global average mortality. The most common cancer-related death in Australia is lung cancer (19%), followed by bowel cancer (11%); in Melanesia, cervical, breast, liver and lip/oral cavity cancers are the most common causes of cancer-related death (10%). Another significant factor which is related to the apparent increase in the rates of cancer in modern times is the fact that, as a population, we are living longer, with a subsequent steady increase in the global population; better lifestyles and disease management have resulted in improved life expectancy. In 1970 the median age5 of the global population was 22 years, which increased to 29 years by 2010 and is predicted to reach 38 years by 2050. Additionally, the number of people aged 60 years and over in 2050 is predicted to increase threefold, to 2 billion. With respect to cancer, by 2030 it is predicted that, annually, there could be 27 million new cancer cases and 17 million cancer-related deaths worldwide. Our extended life expectancy and improved cancer survival prevalence rates are thus an indirect consequence of the elimination of other life-threatening diseases, which has propelled cancer into the top four major health concerns.
But why are the number of cancer cases apparently rising? If we accept that the increased percentage of deaths attributable to cancer is due to a shift in the dynamic balance because of significantly reduced figures for other diseases, such as infection, then should we not just see a reduced number of total deaths reported, but with approximately the same number of cancer-related deaths? Although in principle this point should be true, what it fails to account for is the fact that, as a population, we are living longer. We know that there is a significant correlation between increasing age and the number of cancer cases, for which the underlying principles will be discussed later. Put simply, the continued growth and ageing of the World population means that people are around longer and so there is a greater opportunity for cancer to develop. Taken together, we can appreciate that these underlying factors have propelled cancer to become a major health concern globally. Nevertheless, recent studies have begun to indicate improvements in combating cancer as a consequence of improved lifestyle, earlier detection, or better treatments. For instance, the overall risk in Europe for being diagnosed with cancer has now reportedly stabilised relative to previous years (estimated at an age-standardised rate of 356 people per 100,000), and the overall risk of dying from cancer has shown a decline (estimated to be 168 per 100,000, with variations dependent on tumour type and country) [4].
We now know that cancer is a major disease, with clear global differences in terms of incidence, survival, and related-deaths. However, it is worthwhile at this point to fly a flag of caution in relation to this data, with particular reference to evaluation and interpretation. In the previous section it was identified that cancer incidence is stabilising and cancer deaths are declining in Europe, which is true based on the data presented. While this overarching change is positive, it does not identify data for specific cancers or European countries, and does not report the degree by which the risk of cancer-related mortality varies between these factors. This highlights a major consideration when evaluating or analysing cancer data, particularly in the extraction of the specific information you require. As with all things, the quality and utility of the information gained is only as good as the data entered into the system. We are by no means suggesting that this data is uninformative, misleading, or indeed incorrect, but merely indicating the caution that should be adopted when considering this task. Careful thought and consideration must be...
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