Urologic Oncology: Seminars and Original Investigations
Seminar articleBladder cancer in the elderly☆
Introduction
Men and women aged 65 years and older represent approximately 12% (36.8 million) of the U.S. population, a number expected to double by the year 2030 [1], [2], [3], [4], [5], [6], [7], [8], [9]. Data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program for the most recent 5-year period (1998–2002) indicate that 56% of newly diagnosed cancers and 71% of cancer deaths occur in individuals who are 65 years and older [10]. Regarding increase in life expectancy, the fastest growing segment of the population is the 85 years and older; this age group is projected to increase in number from 3.7 million in 1996, to 5.7 million in 2010, and to 18.2 million by 2050 [1].
Age is now widely accepted as the greatest single risk factor for developing cancer, and cancer is considered as primarily a disease of the elderly. Approximately 60% of all incident malignancies in the U.S. occur in adults aged ≥65 years; 16% of those aged ≥65 years have a history of cancer [5], [8], [9]. Although cancer is the second leading cause of death among men and women aged ≥65 years, [5], [8] many older adults are surviving cancer. In the U.S. alone, it is estimated that 6.5 million of the 10.8 million cancer survivors are aged ≥65 years, with those ≥85 years comprising 15% of this 6.5 million. Approximately 43% of these elderly men and women with cancer survive over 10 years, and approximately 17% survive over 20 years from the time of their initial diagnosis [1], [5], [8]. Because of the close link between age and incidence of cancer, it can be expected that cancer will become an enormous challenge with the growth of our aging population in the years ahead.
These cancer and aging trends are a major public health challenge that healthcare professionals will face in caring for this growing population. Unfortunately, evidence-based practice guidelines regarding the short-term and long-term management of urothelial carcinoma of the bladder (UCB) are sparse for this group. Moreover, it is inappropriate to extrapolate from studies on younger populations because older adults are physiologically, psychologically, and socially different from younger adults [11]. For many older adults, cancer appears to be joining the ranks of other age-related chronic diseases, but the post-treatment burden of the disease (e.g., loss of physical function, permanent disability, fatigue, insomnia, depression, anxiety, and economic devastation) is relatively unknown or at best poorly defined in this growing population [9].
Several theories have been proposed to explain the interactions between carcinogenesis in general and the aging process. First, as individuals age, they experience increasing exposure to carcinogens and the potential accumulation of cellular events that can lead to neoplastic transformation. Second, environmental exposure to carcinogens occurs cumulatively over time (particularly with cigarette smoking and with exposure to carcinogens in the workplace and/or in highly polluted living conditions). Third, the existence of a lag time between these exposures, the accumulation of cellular events, and the clinical expression of malignancy may account for the first appearance of bladder cancer in an older population. Also potentially contributing to this association is the increasingly prolonged contact of carcinogen-containing urine with the urothelium with aging, particularly in men with enlarged prostates and the development of increasing urine residuals with increased concentration of urinary contents. Of additional importance may be the decreased ability to detoxify potential carcinogens as the result of organ system deterioration with aging.
In recent years, there has been a small but steadily growing recognition that the link between aging and cancer is more complex than the simple passage of time to which age-dependence of cancer has traditionally been ascribed. Research on changes in the growth regulatory function of genes and proteins with advancing age and cancer has led to a better understanding of biological relationships between cancer development and aging and has introduced new possibilities for intervention [12]. Certain genes may be activated while others may be suppressed with advancing age. This can lead to an increase in the activation of oncogene activity, leading to the genesis of a cancer cell, or a decrease in tumor-suppressor gene activity with inability to suppress or clear an organ of transformed neoplastic cells. Further, an aged cell may have a decreased capacity for repair of mutations in its DNA. In UCB, multiple genes have been found to fulfill the roles of both oncogenes and tumor-suppressor genes [13], [14], [15]. These may then be associated with the development of different types of UCB with individualized and distinctive intrinsic biologic potentials [13], [15].
In considering UCB and aging, it is also important to consider the phenomenon of aging itself and how it affects both the function and the physiologic reserve of different organ systems that may be important not only in the development of different forms of UCB but also in their specific treatment. Miller has defined aging as “the process that converts healthy adults into frail ones with diminished reserves in most physiologic systems and an exponentially increasing vulnerability to disease and death” [16]. The vulnerability that accompanies this process can affect various organ systems in different ways. It can also increase a host's vulnerability to the carcinogenic process. The development of a cancer itself as well as the treatments required can then affect organ systems in which limitations in physiologic reserve make an individual even more vulnerable to the cancer as well as to the potential risks and side effects of its treatment [17], [18].
In this article, we discuss normative physiologic changes associated with aging. In addition, we review the molecular pathways linking age and cancer. Third, we review the literature regarding the risk factors that contribute to the vulnerability of individuals to develop UCB, and the ability to deliver various forms of treatment (for both non-muscle-invasive and muscle-invasive bladder cancer) in the elderly population in the context of their overall physiologic function and reserve.
Section snippets
Physiologic changes that occur with aging
Nearly all organ systems show a progressive physiologic decline in function beginning at age 30 [17], [19], [20]. The degree and timeline of this decline vary among different individuals and organ systems. Although these changes are generally imperceptible over the years, they can be unmasked through various internal and external stressors. Furthermore, even without the presence of actual disease, aging itself results in a gradual, progressive loss in the biologic reserve necessary for the body
Molecular pathways linking cancer and aging
Many of the mechanisms that may account for the aging process have also been shown to influence carcinogenesis. In turn, those mechanisms affecting carcinogenesis may influence aging. Indeed, the incidence of cancer is closely linked to age because molecular pathways of aging and cancer are intertwined [12], [57], [58]. On the cellular level, aging and carcinogenesis are both believed to be associated with the accumulation of damage, senescence, and disruption of the replicative capacity of a
Age and development of bladder cancer
Age has been found to be an independent risk factor for the development of UCB [80]. Various demographic studies have shown that individuals age 65 and older have an 11-fold increase in the incidence of cancer in general and a 15-fold increase in cancer mortality when compared with individuals less than age 65 [80]. Correspondingly, the incidence of UCB is 28.6% in patients under 65 years and 71.4% in those over 65 years with a clear increase in those above the age of 50 years [81]. The
Cancer-specific outcomes
Treatments for non-muscle-invasive UCB are generally well tolerated by the elderly. Surgical procedures and the anesthetic support they require are not particularly intrusive or disruptive. Neither creates scenarios where there are major fluid shifts or pressures imposed on the cardiovascular, pulmonary, renal, or liver system.
For UCBs with a low risk proliferative diathesis, disease recurrence, and management does not create a life-threatening risk or impact on organ systems. Even when they
Age and treatment outcomes of muscle-invasive bladder cancer
When muscle invasive UCB is diagnosed in the elderly, considerations of selective treatments become even more complicated. The standard treatment for muscle-invasive bladder cancer is radical cystectomy [113], [114]. Many also believe that a course of neo-adjuvant chemotherapy may be of benefit in certain patients [115], [116], [117], [118], [119], [120], [121]. Each of these treatments creates substantial challenges to the various organ systems in the body both individually and in aggregate,
Age and chemotherapy
Adding to the complexity and risk for older individuals is the perioperative use of systemic chemotherapy Although perioperative chemotherapy improves cancer-specific survival in patients with muscle-invasive UCB [115], [116], [117], [118], [119], [120], [121], it can also have a general deleterious effect on various organ systems with potential side effects that delay surgery and from which an older patient may not fully recover. The various systemic agents used may compromise the immune
Conclusions
Data on aging and increased life expectancy underscore the need for greater attention to the development of cancer in the elderly. The influence and expansion of interest in the concomitant age-associated illness burden of older persons diagnosed with UCB is essential. Urologists and medical oncologists must deal with the concurrent health problems of aged individuals in medical practice, as cancer occurs frequently in the presence of one or more other chronic diseases or health problems. These
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Partially supported by The Sidney Kimmel Center for Prostate and Urologic Cancers, and a T32 grant from the National Institute of Health (T32CA082088).
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S.F.S. is partially sponsored by the National Institute of Health training grant (T32CA082088).