Dr. Carol Townsley, Clinical Research Fellow, Princess Margaret Hospital,
University Health Network, Toronto, ON.
Dr. David Hedley, Staff Medical Oncologist, Princess Margaret Hospital,
University Health Network, Toronto, ON.

Pancreatic cancer is the fourth leading cause of cancer-related death for both men and women in North America (following lung, colon and prostate/breast), and is responsible for 5% of all cancer-related deaths. At two to three percent, pancreatic adenocarcinoma has the worst overall five-year survival rate of any cancer. Due to the extreme difficulty in diagnosing pancreatic cancer when it is still surgically resectable, and because of the lack of effective systemic therapies, incidence rates are, unfortunately, virtually equal to mortality rates. Although the overall survival is quite poor, there is a subgroup of patients with slow growing tumours who may survive for several years with good symptom control.

Epidemiology and Risk Factors
An increased incidence of pancreatic cancer is seen in patients of male gender, advanced age and black race. The risk of developing pancreatic cancer is low in the first three to four decades of life but increases sharply after the age of 50 years, with most patients being between the ages of 60 and 80 at the time of diagnosis. Although exact risk factors for pancreatic cancer are not well defined, there appears to be a clear association with smoking and possibly with chronic pancreatitis.

At the time of the writing of this editorial, there is a 'high profile' inquest going on in Toronto concerning driving and the elderly. Two years ago, an elderly woman making a right hand turn struck and killed a young woman. The young woman was then dragged under the car for almost a kilometre with the driver apparently unaware. There was no suggestion that the elderly driver had any physical or cognitive impairment that affected her driving. However, despite the absence of cognitive impairment, this was felt to be a case that could raise the profile of cognitive impairment and the aging driver. The inquest has not concluded, but fortunately initial testimony has stressed that most elderly drivers are competent to drive.

The same day that my testimony at this inquest was reported in the papers, another story was reported, more gruesome than the first. A 25-year-old Texas woman struck a homeless man, impaled him on her windshield, and then locked him and the car in the garage while he slowly bled to death over two or three days. She and her friends then removed the body and 'dumped' it in a garbage bin. For some reason, the first case has sparked an intense interest in whether or not the elderly should drive, but I have not read or heard any musing about restricting the driving privileges of 25-year-olds. Perhaps all young people should have random drug testing to maintain their driving privileges (a presumed factor in the Texas incident)!

Clearly, the difference in the two cases from a geriatrician's perspective is as follows: The incident with the elderly driver is immediately generalized to reflect all the elderly, whereas the incident with the young driver is a reflection of her actions, and her actions alone. In the first case, the trial judge last year pronounced that the woman's ability to drive was 'impaired by age.' I have yet to identify any evidence that shows age is an independent risk factor for driving. Rather, it is the morbidity that accompanies aging that impairs driving. I suspect that any slowing of reaction time and reflexes in the elderly is more than compensated by better judgment and increased caution. Even though we know that a large number of the over 80 population has cognitive impairment, we do not have accurate information on how many still drive, vital information to have if any screening endeavours are considered.

This issue focuses on cancer and the elderly and, as I have discussed in the past, the presumption is often made that the elderly should be treated less aggressively than should younger patients, even though comorbidity is a more important factor than age alone. The lesson, brought home once again by this inquest, is that management must be tailored to the individual and based on comprehensive assessment, not just a single factor such as age.

Fortunately, in this issue we feature articles by experts who do not fall prey to age bias. Dr. Townsley and Dr. Hedley discuss pancreatic cancer in the elderly, and other articles address the issues of cardiac tumours (Desai and Butany), ovarian cancer (Gould and McMeekin), male breast cancer (Glück and Friedenreich), and screening for colorectal cancer (Rossos and Yeung). As well, we have our usual assortment of other articles, including a special piece on estrogen and the aging brain by Elise Levinoff and Dr. Howard Chertkow, one of Canada's leading investigators in the field of cognitive impairment.

Enjoy this issue.

Diagnosis and Management in the Elderly

Deirdre A. Jenkins, MD
Richard C. Woodman, MD
Division of Hematology and Hematological Malignancies,
University of Calgary and Tom Baker Cancer Centre, Calgary, AB.

Introduction
Chronic lymphocytic leukemia (CLL) is a monoclonal disorder of long-lived, mature lymphocytes. It is the most common leukemia in North America with an incidence of 2.7 cases per 100,000. CLL is primarily a disease of the elderly, with a median age of 70 at diagnosis and a slight male predominance. In patients older than 85 years, the incidence rises to 30.6 per 100,000.¹ There are no clear hereditary patterns; however, increased incidence is noted in families with other lymphoproliferative disorders. The etiology is unknown, and typical risk factors for other cancers (like viruses, radiation and chemicals) have no clear role in CLL. The importance of understanding the diagnosis and treatment of this disorder lies in the chronic nature of the disease, as patients may live years to decades after diagnosis. Knowing your treatment goals, and anticipating complications are fundamental for managing patients with CLL.

Diagnosis
While there has been a growing number of patients serendipitously diagnosed on routine blood tests, the majority of patients will present with symptoms referable to their disease (Table 1).

Researchers at Yale University have come up with a new take on an old problem: how to cut off blood supply to a tumour. Previously, it was believed that we might be able to eradicate cancer by preventing tumour angiogenesis--a theory that worked well in animal models, but had disappointing results in humans. The new twist on the method developed by Hu and Garen is to destroy tumours by killing the blood vessels that supply them, rather than trying to prevent their development in the first place.

The researchers developed an immunoconjugate molecule (icon), composed of a mutated mouse factor VII (mfVII) targeting domain and the Fc effector domain of an IgG1 Ig (mfVII/Fc icon), and tested its efficacy in mouse models of human and mouse prostate cancer, and human melanoma. Mice were injected subcutaneously with a human prostatic tumour line, forming a skin tumour that produces a high blood titer of prostate-specific antigen and metastasizes to bone. The icon was encoded in a viral vector that was injected directly into the tumour. Tumour cells infected with the vector synthesize more of the icon molecule and secrete it into the blood where it binds to mouse tissue factor expressed on endothelial cells lining the lumen of the tumour vasculature and to human tissue factor on the tumour cells. One part of the icon then activates an immune attack against any cell that is capable of binding it--which means that the immune attack is only directed against cells that show 'tumour' characteristics. Injection with icon resulted in long-term regression of the injected human prostatic tumour, and also of the uninjected tumour (a model for a metastasis), without any toxicity to the mouse. The same results were obtained for the mouse model of human melanoma.

The researchers are hoping to begin clinical trials in humans next spring, although they caution that it is far too early to predict how well the technique will work in humans.

Source

1. Hu Z and Garen A. Targeting tissue factor on tumor vascular endothelial cells and tumor cells for immunotherapy in mouse models of prostatic cancer. Proc. Natl. Acad. Sci. USA, 10.1073/pnas.201420298.

When I started my residency program in internal medicine, one of my favourite rotations was in hematology/oncology. Not only did one care for sick patients and make a positive contribution to their care, there was the added bonus of blood film and bone marrow examination. The teaching sessions at the microscope were highly educational and incredibly fun. It made me feel like a 'real doctor' to peer down the eyepieces, even though I was pretty weak at interpreting what I saw.

My first presentation on the service was on Preleukemia. In those pre-computer times, I labouriously hunted down references by hand, including Block's original article in the 1953 volume of JAMA (1953:152:1018-29). Today, we would call these preleukemic states myelodysplastic syndromes, and the science and taxonomy has progressed tremendously. However, the fascination with blood remains. Since my internship days, I have learned that this fascination with blood is endemic in medicine, and in society as a whole. This topic is particularly well covered in Professor Jacalyn Duffin's wonderful text on medical history, entitled: History of Medicine: A Scandalously Short Introduction. Not surprisingly, Professor Duffin is a hematologist, as well as a historian. My personal involvement with the 'preleukemic syndrome' continued in 1990 when my mother-in-law developed a myelodysplastic syndrome that rapidly evolved into fatal acute myelogenous leukemia. In an incredible bit of foreshadowing, my initial presentation in internship turned out to be on a topic that is predominantly geriatric, and one that would have a significant impact on my personal life.

In the United States, the predominance of the elderly in the field of oncology has resulted in the insertion of geriatric teaching modules in hematology/oncology training programs. One hopes that Canada will soon follow suit. In any event, there is no shortage of important hematology or oncology topics to discuss in the elderly. As noted in a previous editorial by our Senior Editor, Shabbir Alibhai, there may be many explanations for the poorer outcome for cancer in the elderly. Some of these are failure to correct for comorbidity, inadequate treatment, delay in diagnosis, and presentation at a later stage of disease. Another concern is that the elderly are prone to complications arising from cancer therapy that may not be well managed. Dr. Jeffrey Zonder and Dr. Ulka Vaishampayan, both of Wayne State University School of Medicine, address this issue in their article. Dr. D'Arcy Little covers the issue of thrombocytopenia in the elderly, and Dr. Ahmed Galal and Dr. Jeffrey Lipton from Princess Margaret Hospital discuss the topic of chronic myelogenous leukemia. Our understanding and treatment of this disease has certainly changed dramatically in the past few years. Living with cancer can be enormously stressful, and Dr. Jennifer Jones and Dr. Gary Rodin, also from Princess Margaret Hospital, discuss psychological adjustment to cancer: normative responses as well as psychopathology and treatment.

We also have articles on management of venous ulcers (Dr. Morris Kerstein and Dr. Ernane Reis from Mount Sinai School of Medicine, in New York), genetic counselling and testing for Alzheimer disease (Dr. Wendy Meschino, Toronto), rehabilitation of unilateral neglect (Dr. Gail Eskes and Dr. Beverly Butler, Dalhousie University), the impact of clinical pharmacy in nursing homes (Professor Michael Roberts, University of Queensland, Australia), and the impact of caloric restriction in the aging process (Dr. Isao Shimokawa, Nagasaki University School of Medicine, Japan).

Life is a risky business, and may become even riskier as we age. Many health care providers are intent on making sure our patients are completely 'risk free' in their living arrangements, clearly an impossibility. Harold Parker and Dr. Laura Diachun from the University of Western Ontario look at caregiver responses to the elderly living at risk.

Please do not take any risk that you might miss something important in this issue! Read and enjoy all of the articles.

Jennifer M. Jones, PhD
Research Scientist,
Psychosocial Oncology Program,
Princess Margaret Hospital, University Health Network,
Toronto, ON.

Gary Rodin, MD, FRCP(C)
Head, Psychosocial Oncology,
Princess Margaret Hospital & Psychiatrist-in-Chief,
University Health Network,
Toronto, ON.

Psychological Response to Illness: Coping with a Diagnosis of Cancer
The diagnosis of cancer is inevitably experienced as a traumatic event, although the individual response to it depends upon the nature and stage of the disease, the associated disability, the life stage of the individual affected, its personal meaning and the sociocultural context in which the individual is situated. In the elderly, who commonly experience concerns about self-sufficiency, the onset of a serious medical illness such as cancer may trigger intolerable feelings of helplessness and dependence.

Most patients experience shock when they first learn of their diagnosis of cancer. In some cases, there may be profound anxiety with symptoms of hyperarousal and vigilance arousal, and an oscillation between intrusive thoughts of the cancer and avoidance of the frightening reality. These symptoms represent a stress response syndrome, which may be reactivated following a recurrence of the cancer, which can be even more traumatic than the original diagnosis.

Ahmed Galal, MD, MSc, FRCPC
Fellow in Allogeneic Bone Marrow Transplant,
University Health Network
Princess Margaret Hospital,
Toronto, ON.

Jeffrey Lipton, PhD, MD, FRCPC
Chief, Allogeneic Bone Marrow Transplant Program,
Princess Margaret Hospital,
Head, Chronic Myeloid Leukemia Group,
Associate Professor of Medicine,
University of Toronto,
Toronto, ON.

Introduction
Chronic myelogenous leukemia (CML), in addition to polycythemia rubra vera and essential thrombocytosis, are the most commonly diagnosed forms of the myeloproliferative disorders.^1-5 These diseases share several distinct features:

• They are clonal disorders of hema-topoiesis that arise in a hematopoietic stem or early progenitor cell;
• They are characterized by the dysregulated production of a particular lineage of mature myeloid cells with fairly normal differentiation;
• They exhibit a variable tendency to progress to acute leukemia.

Cytogenetic studies of bone marrow and peripheral blood in the benign myeloproliferative disorders are usually normal. However, CML is invariably associated with an abnormal chromosome known as the Philadelphia chromosome.⁶ CML accounts for 15-20% of adult leukemias. It has an annual incidence of 1 to 2 cases per 100,000, with a slight male predominance.

Anna Gagliardi, MSc, MLS
Program Manager
Surgical Oncology, Cancer Care Ontario,
Toronto, ON.

A. Denny DePetrillo, MD, FRCSC
Division of Gynecological Oncology,
University Health Network-Princess Margaret Hospital Site,
Toronto, ON.

A projected 134,100 new cases of cancer and 65,300 deaths from cancer will occur in Canada in 2001.¹ Forty percent of men and 35% of women will develop cancer during their lifetime and just over 25% of men and 20% of women will die of cancer. Given better and more widely used screening tests such as mammography for breast cancer and the PSA blood test for prostate cancer, more cases of cancer are being detected. Moreover, mortality from these cancers has decreased because they are being caught at an earlier, more treatable stage.

The incidence of most cancers increases with age and it is estimated that 55% of human cancer occurs in individuals 65 years of age and older. The literature on cancer treatment for the elderly is limited but it has been suggested that this demographic may be subject to underscreening, understaging, less aggressive therapy, lack of participation in clinical trials, or no treatment at all.^2,3 It has been demonstrated that older adults desire curative surgical treatment as much as younger patients, but they believe more strongly that doctors should make treatment decisions, making them more vulnerable to possible age bias.

Oral cancer is the most common neoplasm of the head and neck and the ninth most common cancer worldwide. A simple, novel genetic test may now help with early diagnosis of this disease. The most common premalignant lesion of the oral cavity is oral leukoplakia, the presence of white patches in the mouth. Leukoplakia is recognized as an increased risk for cancer but there are no reliable clinical or histologic features that can be used to predict whether it will progress to cancer.

Researchers measured the DNA content (ploidy) of 150 patients with oral leukplakia, classified as epithelial dysplasia. What they found was that ploidy could be used to predict outcome. Patients with leukoplakia containing the normal 46 chromosomes were unlikely to progress to cancer. However, a startling 84% of patients with aneuploid lesions developed squamous cell carcinoma. The test was 97% accurate in its ability to predict that a patient would not develop cancer, and 84% accurate in its ability to predict that one would.

Unfortunately, a single molecular marker or class of markers cannot be used to predict the outcome of every case of oral leukoplakia because oral cancers develop along complex molecular pathways. Further studies are needed to support these data.

Sources

1. Sudbo J, Kildal W, Risberg B, Koppang H, Danielsen HE, Reith A. New England Journal of Medicine. 2001;344:1270-8.

Is there a Role for Primary and Secondary Prevention Strategies?

Ruth E Heisey, MD, CCFP, FCFP
Assistant Professor,
University of Toronto,
Family physician and Clinical Associate,
Department of Surgical Oncology,
Sunnybrook and Women's Health Science Centre, and
Princess Margaret Hospital Site,
University Health Network,
Toronto, ON.

H Lavina A Lickley, MD, PhD, FRCSC, FACS
Professor of Surgery and Physiology,
University of Toronto,
Surgeon (special interest in Breast Disease),
Women's College Campus of Sunnybrook and Women's College Health Science Centre,
Toronto, ON.

"Old age is like everything else. To make a success of it, you've got to start young."¹ Fred Astaire

Breast cancer is the most common cause of cancer death in women over the age of 65.² Between the ages of 30 and 80 years, the annual incidence of breast cancer rises from 1:5900 to 1:290.^3,4 It has been estimated that by the year 2030, almost two-thirds of women with a diagnosis of breast cancer will be 65 years of age or older.⁵

The incidence of breast cancer among Canadian women has been rising steadily over the past decade, probably due in part to improved detection with mammographic examinations.