D'Arcy Little, MD, CCFP
Director of Medical Education,
York Community Services,
Toronto, ON

Munir A. Jamal, MD, FRCSC
Staff Urologist,
Credit Valley Hospital,
Mississauga, ON

Introduction

Epidemiology:
Cancer of the urinary bladder is essentially a disease of the elderly. The median age at diagnosis is 69 years for males and 71 years for females, and more than one-third of cases occur in patients over the age of 75 years of age.^1,2 The incidence of transitional cell carcinoma (TCC) of the bladder, the most common subtype of bladder cancer, accounting for over 90% of cases, is rising and currently ranks as the fourth highest new cancer diagnosis in men.³ However, the mortality rate of this disease has fallen over the last two decades.¹ The following review article will address the epidemiology, natural history, clinical presentation, and treatment of this disease, with an emphasis on issues pertaining to elderly patients. (See Figure 1)

Bladder cancer is unique among human neoplasms in that it has been associated with several distinct etiological factors.⁴ Risk factors related to the development of TCC, in addition to age, include tobacco smoking and occupational exposures in the dye, rubber, textile, and leather industries.

Shabbir M.H. Alibhai, MD, MSc, FRCPC
Senior Editor,
Geriatrics & Aging

Recently I saw a 72-year-old woman with metastatic uterine cancer in consultation. She was receiving palliative chemotherapy and our team felt she would benefit from short-term inpatient rehabilitation. Within a week of this consult, I saw an 81-year-old woman with an acute myocardial infarction. My team elected to start her on lipid-lowering therapy.

What do these two patients have to do with one another, and what does the latter patient have to do with this issue's theme of cancer? It is, simply put, a matter of life and death.

Let me explain. Many readers know that I do research in prostate cancer. In my editorial in last year's cancer issue,¹ I discussed the importance of assessing the impact of treatment on both length and quality of remaining life. Whenever clinicians make treatment decisions, we explicitly or (more commonly) implicitly consider life expectancy. For both patients that I alluded to, estimating life expectancy was fundamental to the management decision.

Several randomized trials have demonstrated improvement in survival for certain malignancies, including some gynaecologic tumours, from "palliative" (i.e. non-curative) chemotherapy. The question that clinicians and patients must struggle with is whether the expected improvement in survival (for example, two to six months) is clinically important and worth the risks of treatment. Lipid-lowering therapy has been shown in numerous large, well-designed, randomized trials to prolong survival in patients with normal or elevated lipid levels after a myocardial infarction. However, most studies suggest a survival benefit is observable after 12-18 months of therapy. Conversely, lipid-lowering therapy is generally not useful if patients have a life expectancy of less than 12 months. We estimated that our 81-year-old patient would likely survive at least a year after her infarct and thus started her on a statin.

While most of this sounds straightforward, there is a potentially flawed underlying premise--namely, that physicians can accurately estimate life expectancy. How does one do this in theory? Life expectancy can be calculated by taking age-specific annual mortality risks and modifying them by factoring in risks of dying from specific illnesses from which the patient is suffering. For example, my 81-year-old woman post infarct has an average one year risk of 9.4% of dying because of her age. This number is obtained from actuarial life tables.² Depending on her cardiac status post infarct (left ventricular function, presence of heart failure, deficits on cardiac perfusion study), she might have a 20% risk of dying from her coronary artery disease. Thus her overall risk of dying would be some combination of these two risks, assuming she is otherwise well.

So how good are we at estimating life expectancy? It is interesting to note that there are very few published studies on this subject. Yet in prostate cancer, for example, clinicians are encouraged to explicitly consider life expectancy when making treatment decisions--the so-called ten-year rule.³ This rule suggests that if patients have ten or more years of life left, excluding their prostate cancer, then curative therapy is indicated, and vice versa. There may be similar rules in other areas of cancer. Beyond these guidelines, there is little published data to guide physicians when estimating remaining life.

Two studies from the field of palliative care are provocative. The more recent one, published last year,⁴ asked a group of palliative care doctors in Chicago to estimate remaining life expectancy for 504 patients newly admitted to a hospice program. Patients were followed until they died. Patients were relatively old (mean age 69) and had advanced disease (median survival 24 days). If accuracy was defined as being within 0.5 and 2.0 times the actual survival, physicians were accurate 34% of the time, optimistic 55% of the time, and pessimistic 11% of the time. Even when we consider fairly terminal patients, physicians do not perform as well as expected.

This does not mean we should forget about estimating life expectancy. Rather, it behooves us to perform more research in this area to identify better models for predicting survival. Furthermore, we must realize that disease severity and comorbid illnesses are far more powerful predictors of life expectancy than is chronological age. Until we are far better at estimating survival, guidelines like the ten-year rule in prostate cancer do little service to ourselves and our patients.

Regular readers will realize that this is the third year we are featuring the theme of cancer in Geriatrics & Aging. Much new information continues to be published about cancer screening, diagnosis, treatment, and prognosis in the elderly. In this issue, we have chosen to focus on acute myelogenous leukemia, bladder cancer, multiple myeloma, and gastro-esophageal malignancies. As always, we hope you enjoy it.

References

1. Alibhai SMH. Oncology & Aging--Bitter Truths and Misguided Paternalism. Geriatrics & Aging 2000; 3(3):3.
2. Statistics Canada. Life tables, Canada and provinces. Health Reports 1990; 2 (4(Suppl.13)):17.
3. Walsh PA, Partin AW, Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 1994; 152:1831-1836.
4. Christakis NA, Lamont EB. Extent and determinants of error in doctors' prognoses in terminally ill patients: prospective cohort study. BMJ 2000; 320:469-473.

M.D. Minden, M.D., Ph.D., FRCPC
Princess Margaret Hospital
University Health Network
Toronto, ON

Introduction
Leukemias are malignancies of the blood and bone marrow and are classified as either acute or chronic malignancies of the myeloid--red blood cell, granulocyte, platelet lineage--or lymphoid--T or B lymphocyte. In this article we will focus on acute myeloblastic leukemias (AML) and recent advances in their classification and therapy.

In the United States, approximately 10,100 cases of AML are diagnosed each year and the yearly mortality rate from this disease is approximately 6,900 individuals. The incidence of AML is low in children (<1/100,000) and increases with age, such that by the time a person reaches the age of 80 the incidence is approximately 15/100,000 (Figure 1).¹ Over 60% of patients are 55 years of age or older, making this a significant problem in the aging population.

AML develops as the result of genetic changes in hematopoietic stem cells of the bone marrow.² These changes block the ability of the cell to undergo normal differentiation resulting in a blast-like morphology. In some cases, the patient may have large numbers of circulating leukemic blast cells compromising blood flow to vital organs.

Marilyn Schneider, Ph.D.
Executive Director,
Canadian Breast Cancer Research Initiative

Breast cancer is, in large part, a disease of aging in women. It is a disease of genes gone awry. Although a small proportion of women are born with an inherited mutant BRCA1 or BRCA2 gene that immediately puts them at very high risk for breast cancer, these inherited mutations account for only 5-10% of breast cancer cases. In most breast cancers, the woman accumulates sporadic gene mutations throughout her lifetime, and when appropriate combinations of these mutations accumulate in the woman's breast cell, she has the beginning of a breast cancer tumour.

One out of every 9.5 Canadian women is now expected to develop breast cancer sometime in her lifetime. This, however, is the lifetime risk, and this risk is known to increase with age. What is more relevant to an older woman is the probability that she will develop breast cancer over the next decade. A 60-year-old woman's probability of getting breast cancer before age 70 is 2.9% or 1 in 34; a 70-year-old woman's probability is 3.2% or 1 in 31.¹ Breast cancer is primarily a disease of older women, with only 22% of breast cancer cases occurring in women under age 50, 45% occurring in women aged 50-69, and 32% occurring in women aged 70 and over.²

On the one hand, the incidence of breast cancer has risen slowly but steadily over the past three decades, particularly for those women aged 50-69 and over the age of 70.

Jolie Ringash, MD, MSc
Department of Radiation Oncology,
Princess Margaret Hospital
University Health Network,
Toronto, ON

Background
Esophageal and gastric carcinomas are primarily diseases of older persons. Of 498 new cases of esophageal cancer in Ontario in 1997, 237 (48%) occurred in individuals aged 65 to 79, and 101 (20%) in those over the age of 80. The corresponding numbers for gastric cancer are (of a total of 1,032 cases) 492 (48%) for those aged 65 to 79, and 200 (19%) for those over 80.¹ For all age groups, gastric cancer is decreasing in incidence, with only 2, 800 cases in Canada in the year 2000. In contrast, the incidence of esophageal cancers is gradually increasing (1,350 cases in 2000).^2,3 Adenocarcinoma, primarily of the distal esophagus, has replaced squamous cell carcinoma as the most frequent histology. Tumours of the gastroesophageal junction pose a particular challenge, since management may differ depending on whether the tumour is felt to originate in esophagus or stomach.

Canadian oncologists frequently face difficult treatment decisions in the elderly. Unfortunately, since older patients are usually excluded from clinical trials, evidence for their tolerance of, and response to, therapeutic radiation is limited. Existing reports are limited to retrospective reviews and subgroup analyses, many of which originate in Japan.

Haim Cohen, Ph.D
Department of Pathology,
Harvard Medical School,
Boston, MA

The incidence of cancer increases as we age: during the last decade of life, the risk of developing cancer is a startling 50% for men and 33% for women.¹ What is the underlying link between aging and cancer? This link may be found by investigating diseases that are associated with both a high frequency of cancer and premature signs of aging. Such diseases, known collectively as RecQ syndromes, are caused by mutations in genes encoding RecQ-like proteins.² The RecQ family of proteins has a high degree of homology to the helicase domain of the RecQ helicase of E. coli. The helicase region is required for all RecQ helicases to unwind duplex DNA from 3' to 5' direction in vitro; however, the in vivo function of the eukaryotic RecQ is unknown.

At least three inherited human diseases are caused by mutations in RecQ-like genes: Werner syndrome (WS), Bloom syndrome (BS), and Rothmund-Thomson syndrome (RTS).³ These diseases share two main features: premature aging and a high level of genomic instability that manifests itself as a high incidence of cancer.

The hallmark of Bloom syndrome is an increased level of sister chromatid exchange, and patients present with sun-sensitive skin pigmentation and a predisposition to certain malignancies.

Dr. Christine I. Chen, MD, FRCPC
Princess Margaret Hospital,
University Health Network,
Toronto, ON

Introduction
Multiple myeloma arises from a malignancy of plasma cells in the bone marrow which typically produce an immunoglobulin, also referred to as a monoclonal protein (M-protein), that is detectable in the patient's blood and/or urine. Myeloma is not a common disease (incidence of 1400/year in Canada), typically affecting older individuals (median age 65 years). It is more common in blacks and slightly more prevalent in males. Since myeloma is a relatively slow-growing malignancy, many patients will have the disease for months or even years before a diagnosis is made and may continue to follow an indolent course. The pathogenesis of the disease is poorly understood.

Clinical Features
Characteristic clinical features of multiple myeloma are anemia, renal failure, bony lesions with pathologic fractures and associated pain, hypercalcemia, and recurrent infections (See Table 1). Many patients, however, will present with asymptomatic anemia or a monoclonal gammopathy, which is usually discovered during incidental lab testing.

Anna Liachenko, BSc, MSc
Managing Editor,
Geriatrics & Aging

The relationship between aging and cancer has its basis in cell cycle alterations. While multiple factors affect cell cycle progression, recent research has directed a great deal of attention to telomere length as a key factor affecting mammalian cell proliferation. This article discusses recent findings with respect to the role of telomeres and telomerase in cancer, cellular aging, and longevity.

Telomeres are short DNA repeats located at the ends of eukaryotic chromosomes. Telomeres cap chromosomal ends preventing the loss of important genes during cell division. With every cell division, the length of telomeres decreases unless it is corrected by telomerase, a ribonucleoprotein enzyme that extends the telomeres by adding hexameric nucleotide repeats to the ends of chromosomes. In humans, telomeres are short, and telomerase activity is low in many somatic tissues but is present in germ cells, activated leukocytes, and stem cells from a variety of organs. The study of telomeres has been hampered by the fact that classical animal models, such as mice, have highly active telomerase. This results in long telomeres that do not shorten enough during the animal lifespan to play a significant role in cellular aging. Recently, a genetically altered telomerase-deficient mouse model has been created by a group of researchers at Harvard.

A group of researchers from Harvard have found evidence that telomere attrition in aging telomerase-deficient mice, heterozygous for the p53 tumour suppressor gene, promotes the development of epithelial cancers.

Aged humans sustain a high rate of epithelial cancers such as carcinomas of the breast and colon, whereas mice carrying common tumour suppressor gene mutations typically develop soft tissue sarcomas and lymphomas. This difference has been attributed to the variance between species with respect to their telomere length and regulation. Unlike the situation in humans, mice have promiscuous telomerase activity and long telomeres which has been suggested as the reason why they don't develop epithelial carcinomas.

In this study, telomerase-deficient, p53-heterozygous mice were inbred for 5 to 7 generations with the resulting mice having shortened telomeres. As they aged, half of these mice developed lymphomas and sarcomas, but unexpectedly, the remaining mice developed epithelial carcinomas. These data indicate that the telomeres from these mice may have become critically short in epithelial tissues, with the malfunctioning telomeres catalyzing genomic rearrangements that initiated and sustained the development of cancer.

Cancers develop in several distinct steps, with cells of increasing aggressiveness and capability emerging over time. Cells that lack telomerase may undergo widespread genomic disarray leading them to become cancer cells. This disarray can reach a point in which the cell is no longer viable and it dies. Alternatively, the activation of telomerase can allow the addition of telomere repeats to these mutant chromosomes, which enables their survival, and the progression of the cancer.

A great deal of research has been targeted at developing pharmacological inhibitors of telomerase, with the aim of knocking out the telomerase that enables the cancer cells to survive and replicate. However, these data suggest that removing telomerase function from these cells may lead to their death in some instances, but in cells that are still not near the 'threshold for viability', the removal of telomerase may actually cause them to mutate into more aggressive forms. This suggests that telomerase inhibitors should be used in conjunction with other forms of chemotherapy to ensure the death of all cancer cells.

Jocalyn P. Clark, BSc, MSc

It is an exciting time to be involved in cancer research in Canada and Dr. Carol Sawka is helping lead the way. Over the last fifteen years Dr. Sawka has established an impressive clinical and research career in women's health, focusing on optimizing breast cancer care. Dr. Sawka's leadership roles bridge clinical, research, and policy-making activities, linking scientific research evidence to the development of clinical practice guidelines, and setting the stage for promising new treatments and outcomes for cancer patients.

Like many high profile academic physicians, Dr. Sawka wears several hats. Her eleven year involvement with the Toronto-Sunnybrook Regional Cancer Centre culminated recently in her appointment as Chief Executive Officer. Her career began at the cancer centre in 1988 as a staff oncologist, followed by her appointment in April 1998 as a Division Head. Currently she is also the CEO of the Central East Regional Cancer Centre and a Vice-President of Cancer Care Ontario. In addition, Dr. Sawka is Head of the cancer program at Sunnybrook and Women's College Health Science Centre, as well as an Associate Professor in the Departments of Public Health Sciences and Medicine at the University of Toronto and an Adjunct Senior Scientist at the Institute for Clinical Evaluative Sciences (ICES).

Dr.