Virtually every review of the cytogenetics of cancer begins with a reference to Boveri (1914), and this is certainly not inappropriate. He anticipated a relationship between aneuploidy and malignancy several decades before a relation between aneuploidy and any human disease was first established. His principal ideas, as quoted by Hauschka (1961), were the following:

The required improvements in techniques did not occur for over forty years, but when they did, the validity of Boveri's insight was finally established. As viewed by Sager (1983), “Boveri's contribution to clear thinking about cancer ranks nearly with Mendel's contribution to clear thinking about genes. Written close to 70 years ago, Boveri's view of the origin of cancer anticipates much of what we know today.” What still remains to be accomplished, as will be discussed in this chapter, is to discover the meaning of the relationship between aneuploidy and malignancy.

Cancer is one of the leading causes of mortality and morbidity in the developed world. Age is a primary risk factor for developing cancer, and geriatric oncology is a rapidly emerging field that aims to address the specific needs of older patients with cancer. All clinicians who treat elderly patients should have knowledge of cancer risks, screening, and management principles. This chapter will review the principles of geriatric oncology, including geriatric assessment in the oncology population. We will then discuss the four most common solid tumors encountered in elderly patients: breast, prostate, colorectal, and lung cancer. Each section will include risk factors, screening and prevention, presentation, staging, prognosis, and multidisciplinary management of early- and late-stage disease.

In January 1994, the journal Scientific American published a review essay on cancer that opened with a quotation from John Bailar III, a famous epidemiologist at McGill University, claiming that the “war on cancer” had not been won. Bailar was referring to the anticancer campaign launched by President Richard Nixon in 1971 as a civilian alternative to the Vietnam War and as a Republican follow-up to President Lyndon Johnson’s War on Poverty. Bailar’s argument rested on statistical data from the National Cancer Institute suggesting that U.S. cancer death rates, adjusted for the aging population, went up seven percent during the twenty-five years of a war that was waged by means of research investments – both biological and clinical.

That article reminds us that cancer remains the visible, frightening, and “scientific” disease it has been for more than a century. More than tuberculosis or syphilis, which were considered conquered after World War II, cancer was the scourge of the twentieth century. From the late nineteenth century, the growing incidence of various types of tumors, as well as the limitations of existing therapies, have been at the center of Western medical discourses increasingly concerned with relatively wealthy and aging populations. Since then, experts have viewed the formation of tumors as a problem of unlimited multiplication of cells, a process that might be controlled by physical or chemical means derived froma better understanding of cell growth and cell division.

Overview

Cancer, a group of genetic diseases, is development gone wrong in a clone of somatic cells – a tumor. If a tumor destroys adjacent tissue it is malignant. Tumor cells:

• Accumulate mutations and become genetically unstable

• Grow in an unregulated manner

• Lose contact inhibition; i.e., growth is not inhibited by adjacent cells

• Lose the potential to undergo apoptosis

• May metastasize – migrate and establish subclones in other body locations

Characteristics of Cancer

The hallmark of tumors is uncontrolled cell proliferation. Cancer cells proliferate exponentially because they have gained the ability to self-stimulate cell cycling and have lost the ability to respond to extrinsic growth inhibitors. A tumor's potential to be lethal principally depends on its uncontrolled growth. The growth of normal cells is inhibited by contact with adjacent cells, whereas cancer cells have lost contact inhibition. The morphology of cancer cells changes and telomerase synthesis (not present in normal somatic cells) resumes. Cancer cells become immortal – they can go through an indefinite number of cell division cycles – and gain the ability to be cultured; a normal somatic clone can survive for a limited time, ~102 cell division cycles. Cancer cells often lose the ability to undergo apoptosis. Solid tumors may stimulate angiogenesis, the growth of blood vessels supplying the tumor. Many cancer cells metastasize – move into the blood and migrate to other locations in the body. Cancer cells may evolve the ability to evade the immune system.

Introduction

So stark a chapter title befits the subject. Even today, with the outlook for many malignancies dramatically improved, the word ‘cancer’ can strike fear into many hearts. Any attempt to over-simplify the subject would be facile, but there are a few basic rules. Cancer implies a malignant growth or tumour, although the word ‘tumour’ actually means a swelling or lump, and many tumours are benign, the majority (but not all) remaining so. For a tumour to be malignant (cancerous) its method of cell division and replication becomes disordered and goes out of control, a cellular Sorcerer's Apprentice. Human tissues are living and shed old cells to replace them with new ones but in an orderly, even pre-ordained, fashion.

Two definitive features of cancer are, firstly, that it invades neighbouring tissues and structures and, secondly, that it spreads to remote organs by the blood or the lymphatic systems to cause secondary deposits (metastases). The detailed classification of malignant tumours is complex. It is reasonable to simplify it. Malignant tumours arising from lining surfaces are carcinomas, and those from connective tissues such as fat or bone are sarcomas. To subdivide again, lining tissues are the epithelium (e.g. skin, mouth, gullet) and endothelium, including the lining of the gastrointestinal tract from stomach to rectum. Then there are cancers arising from more specialised tissues, particularly the nervous system. A survival rate is the percentage of patients still alive years after treatment for that growth. Achieving these benchmarks often reassures patients enormously. There are sarcomas for which a survival of two years after therapy almost behoves a cure. For other tumours that may be achieved within five.

Treatment can readily be classified. Surgery may involve just a local excision, or removal of part or all of an organ and lastly of the total structure, plus a more extensive dissection, removing surrounding tissues. Modern scanning techniques (e.g. CT, MRI and PET) now enable doctors to accurately define the edges of a growth and plan treatment accordingly. Surgery is often supplemented or even supplanted by radiation (radiotherapy) and/or by anti-cancer drugs (chemotherapy). These are sometimes given in conjunction with one another.

Cancer is not exclusively a modern disease, and paleopathological evidence of many of its forms has been found in ancient human remains. Even so, the evidence from thousands of prehistoric and ancient remains, such as fossils, mummies, and skeletons, suggests neoplasms were not common until after the medieval period in Europe. Investigation of Egyptian mummies suggests malignancies were rare, although multiple melanoma cases have been well documented, and also nasopharyngeal carcinoma, which is readily identifiable through damage to the skull. Hippocrates made the distinction between malignant and benign cancers in the fifth century BC. Although malignant cancers are now usually referred to as malignant neoplasms, the term cancer is used here as it has a longer history in the research literature. At the end of the 18th century in England, there were early references to cancer as a form of “tubercle,” and only a few deaths were recorded in the “cancer” category in the London Bills of Mortality. In some cases the wasting may have been difficult to distinguish from the effects of tuberculosis for the purposes of recording cause of death. When national registration began in England and Wales, the term malignant tumors was already in use, although “carcinoma” was not formally distinguished from “genuine crude tubercle” until 1855. Pathologists sought to define the difference between cancer and tuberculosis, which occur in many of the same sites in the body, and the idea of an inverse relationship developed despite both occurring at the same time in a few cases. It is now usual to regard cancers as a group of diseases, differing widely in etiology, frequency of occurrence, and site of manifestation.

The underlying processes in cancer have long been regarded as linked with the cumulative effects of irritants and carcinogens. Burnet suggested that errors in the repair of DNA could explain associations between carcinogens and particular sites of cancer, such as radiation and skin cancer, cigarette smoking and lung cancer, naphthylamines and bladder cancer, radium salts in paints and bone sarcoma, and many others. The molecular-level process in “environmental cancer” could involve a carcinogenic agent entering cells and causing damage to the DNA, which can be repaired but with an increased risk of informational error and abnormal cells that can replicate out of control.

Introduction

It has been known for many years that two or more independent primary tumors can arise in the same patient. Schoenberg (1977), who surveyed multiple cancers in Connecticut between 1935–1964, appears to have been the first to make a comprehensive quantitative analysis of the risk of developing a second tumor through the investigation of 120, 195 cancer patients from a well-defined population.

Second cancers may arise in the same individual for a number of reasons (Table 59.1). The major issue is usually whether an excess risk represents a common causal factor or some degree of genetic susceptibility. Among relevant issues are the following: (i) the recognition of syndromes of associated sites which may suggest a common etiology; (ii) identification of the regions of the body to which special attention should be paid when following up individuals with the first cancer; (iii) assessment of the carcinogenicity of treatments used for a first cancer.

Common etiological factors

The combined effects of tobacco and alcohol largely account for the constellation of cancers arising in the oral cavity, larynx and oesophagus. In contrast the association between retinoblastoma and osteosarcoma is most likely to reflect the influence of common hereditary factors. The interplay of both exogenous and endogenous factors in multiple cancers of the breast, uterine corpus, ovary and colon has long intrigued investigators. Both reproductive factors and dietary habits are believed to be involved. Biilow et al. (1990) report metachronous colorectal cancers can be as high as 30% after 40 years.

Chapter 4 introduced the concept of information transfer to cells whereby chemical signals (hormones and cytokines) transmit information across the outer, plasma membrane via protein receptors that, in turn, activate relays of proteins converging on the nucleus to direct appropriate patterns of gene expression. Prominent components of such signalling networks in the context of cancer are receptor tyrosine kinases (RTKs) that signal via RAS, a molecular switch, to the mitogen-activated protein kinase (MAPK) pathway and other protein relays that control aspects of normal cell growth. These networks show aberrant behaviour in most human tumours due to activating mutations in RAS or other components. Oncogenic RAS signalling frequently combines with abnormal activity of MYC, a central regulator of cell growth and proliferation, in tumour development.