Medical considerations for treatments for invasive bladder cancer in the elderly

Deterioration in physiologic function, prolonged exposure to deleterious and damaging substances, and the consequent co-morbidities associated with ageing may affect considerations of various treatment approaches for invasive bladder cancer in the elderly. Therapeutic efficacy, side-effects, potential complications, and effects on overall quality of life are all important factors in this context. In addition, various individual host factors (life expectancy, co-morbid conditions, physiologic reserve, and psychologic and environmental support) can also affect considerations in therapy.

Treatments for invasive cancer of the urinary bladder include cystectomy, extensive transurethral resection, external radiation therapy, systemic chemotherapy, and combinations of all of the above. Importantly, the need for urinary diversion with cystectomy also has implications for additional risks and side-effects of treatment that need to be considered in the context of an individual's physiologic and co-morbid status.

In considering major surgery such as cystectomy, pre-operative management of factors associated with the increased risk of specific complications may minimize such risks. At the outset the extent and severity of co-morbid conditions need to be evaluated. In addition, current and anticipated pharmacologic therapy (including anaesthetic management) need to be assessed.

The major risks associated with cystectomy are cardiac, respiratory, thromboembolic, and central neurologic (delirium). Cardiac risk is increased in patients with hypertension, and such patients may be especially vulnerable because of the fluctuations in blood pressure that may occur during surgery. The elderly are particularly susceptible in this regard because of their sensitivity to various anaesthetic agents, their use of various medications, their vulnerability to vascular changes and changes in intravascular volume, and their unpredictable responsiveness to various pain stimuli.15 As a consequence the elderly may be particularly sensitive to perioperative myocardial infarction. If this occurs, a mortality rate of50-80% has been reported.16 Evaluation and correction of coronary artery disease have therefore been considered of major importance prior to elective major surgery.

In the elderly, respiratory problems are the cause of post-operative morbidity in approximately 40% of patients.17 Therefore, cessation of smoking, use of prophylactic antibiotics, application of physiotherapy, and use of incentive spirometry may all contribute to a decrease in morbidity. The incidence of deep vein thrombosis and embolus also increases in the elderly due to their decreased leg musculature, hypercoagulability, and their accumulation of increased systemic disease risk factors.18 Of patients undergoing general surgery, 20-30% develop deep vein thrombosis.19 Significant pulmonary emboli have been reported to occur in 1-5% of all patients undergoing major surgery, a risk that is increased to >20% in the elderly.20 The mortality at one year after pulmonary embolus approaches 40%.21

The 30-50% decrease in numbers of glomeruli that can be seen by the seventh decade may lead to compromised renal function and diminished renal reserve that can affect the outcome of major surgery. The loss of functioning nephrons with age increases the solute load per nephron, adversely affects the nephron's concentrating capacity and can thereby produce volume depletion, which can contribute to failure in other sytems.22 Acute renal failure as a consequence of surgery and anaesthesia has been found to have a 40-80% mortality rate.23

Deterioration of endocrine function in the elderly is also important.24 Diabetes mellitus predisposes to increased morbidity from cardiovascular and infectious complications. Maintenance of good control in diabetics is critical in preparing them for major surgery and anaesthesia. Hypothyroidism has a prevalence of approximately 10% in the elderly who are hospitalized. The consequence of this in the metabolism of various drugs and responsiveness to surgery needs to be taken into account in planning for a safe perioperative course.

Although the nutritional status of a person is thought to be important in considering major surgery, the role of pre-operative nutritional assessment, and even pre-operative nutritional therapy, remains unclear.25 However, positive anabolic balance in the post-operative period, or at least avoidance of prolonged catabolic balance, is thought to be important in maximizing successful recovery following major surgery.

The prevalance of dementia has been reported to be as high as 25% in persons over the age of 80 years, while delirium has been suggested to be as high as 45%.26 Each of these is of major importance when considering post-operative assessment and management of patients who have undergone major surgery. This may be of particular relevance in bladder cancer when urinary diversion is required and management is considered in the context of the overall capabilities of many elderly patients.

Various classifications in the assessment of patients for major surgery have been developed. These include classification of physical status for anaesthesia, cardiac scores, based on an index of cardiac risk in patients undergoing non-cardiac surgery, and classification of probabilities for post-operative cardiac complications.27 Each of these can be used to advantage in identifying patients who may present particular risks for major surgery. Such patients will then benefit from pre-operative rehabilitation to minimize certain risks, intra-operative and post-operative monitoring and treatment measures to intervene either in preventing risks or recognizing their appearance sufficiently early to permit reduction in the morbidity they may cause, and post-operative recovery measures to facilitate rapid return to health and normal function, and to maximize quality of life and reserve systemic function, particularly if adjunctive treatments become necessary.

The importance of these considerations is based upon the assumption that cystectomy offers the best opportunity for curing muscle-infiltrative transitional cell cancer of the bladder. This impression is supported by observations of an increased likelihood of regional and distant disease recurrence in those patients who undergo alternative treatments and whose longevity and disease-free survival may be compromised accordingly. Even though cystectomy has not been predictably successful, largely because of the occult metastases that a substantial proportion of such patients have, in those individuals fortunate enough to have disease confined to the bladder when initial diagnosis of muscle-invasive cancer is made, the outcome in terms of longevity and the absence of regional morbidities appears to be served best by this approach, in association with an appropriate form of urinary diversion.

These considerations are of particular importance in the elderly because of their compromised physiology and organ functional reserve, their accumulation ofrisk factors and co-morbid conditions that may accentuate potential complications following surgery (both from the cystectomy itself, the form of urinary diversion selected, and the type and duration of general anaesthetic used for the procedure), their possibly limited life expectancy, their overall health limitations from the presence of cancer itself and other treatments that may already have affected other systems in their bodies, and considerations involving their expected degree of recovery and ability to tolerate morbidities of varying severity. Consideration of these factors makes it clear that patients need to be selected carefully for particular treatments. However, even with a selected group of patients, success rates and outcomes can be compromised, morbidities and complications can occur, and the predictability of each may be inadequate.

The literature concerning results of cystectomy in the elderly generally suggests that the surgery may be well tolerated and successful. However, the procedure is not without risk. Moreover, it generally involves highly selected patients and the good outcomes they experience may reflect the biology of their disease in the context of their own body's biological and functional reserve.

In analyzing one report of 404 patients over a median age of 70 years (selected from 1,176 total patients who underwent cystectomy), as an example, mortality rate was only 2.8% (11/404), but the complication rate was 32% (129/404).28 These included persistent urinary leak in 20, intestinal leak in six, bowel obstruction in 13, renal failure in 11, cardiovascular complications in 19, and pulmonary emboli in seven. Given the potentially compromised reserve of these patients (see above), any or all of these complications could have contributed to mortality. It is a testament to the successful perioperative management that the mortality rate was kept as low as it was. On the other hand, this was a highly selected group of otherwise presumably healthy patients and their median age of over 70 (implying that many were younger than 70) may not necessarily have made them physiologically elderly.

In this study, non-diversion-related complications occurred in 24% (85/352) of patients 70-79 years old, in 29% (15/52) of patients over the age of 80, and 17% (129/762) of those <70 years. The somewhat higher rate of complications observed in the older patients could conceivably be interpreted as age-related, as the initial selection of patients may have been far more rigorous in this age group than in those <70. Certainly their rate of complications is not something that can be easily dismissed, especially in view of the possible long-term effects that these complications could have (see below).

Although overall five-year survival of patients >70 years was less than that of patients <70 years, their disease-free survival was comparable. This appears to be a manifestation of biologic selection. Thus, patients chosen for cystectomy in the elderly age group comprised 32% with organ-confined disease, 41% with extravesical disease, and 27% with positive lymph nodes.28 The latter two groups of patients had disease sufficiently extensive that it undoubtedly would have predisposed them to failure, as indicated by the disease-free five-year survival of only 35%. However, these results still compare favourably with those of radiation therapy, in which five-year survival has ranged between 15% and 20%, pelvic recurrence has ranged between 40% and 70%, and the complication rate has been significant (see below). In those patients who had organ-confined disease, therapeutic efficacy was far better.28 Although quality of life measures were not included, this series suggested the value ofcystectomy in such patients, the importance ofcareful selection, and the unpredicability of risk notwithstanding preventive perioperative measures.

Similar observations have been made in other cystectomy series. Wood et al. demonstrated a 5.3% (2/38) mortality in patients >70 years old, and a 34% morbidity (14/38).29 The occurrence of myocardial infarction and renal failure was higher in the elderly population. Similarly, in a series of patients >80 years old (comprising 44 of 1,186 total cystectomies) from Memorial Hospital, a 4.5% (2/44) operative mortality, a 51% (23/44) morbidity, a 66% (29/44) rehopitalization rate for complications, and a 50% (22/44) disease-specific mortality (with a median survival of only 25 months) were reported.30 The mean Karnovsky score of all patients in this series was 72 (range 50-90). Of these, 34/44 had co-morbid conditions, which included 55% with cardiac problems, 20% with hypertension, 18% with chronic obstructive pulmonary disease, and 13% with vascular disease. The 65 patients with advanced transitional cell cancer who did not undergo cystectomy succumbed rapidly to their disease. However, this may have reflected the severity of their co-morbid conditions that excluded these patients from surgery, or the degree of disease that precluded them from being candidates for 'curative' surgical treatment (15 patients had hydronephrosis and 14 had a palpable mass, both ominous risk factors suggesting that at least a third of those who underwent surgery had more advanced disease and were destined to die of their disease).

These observations prompted the suggestion that cystectomy was justified largely when life expectancy was greater than two years, since most patients with untreated invasive transitional cell cancer presumably would die within a lesser time.30 However, since conservative or alternative strategies would often result in progressive, uncontrolled cancer associated with various local symptoms and the need for repeated bladder instrumentation and possibly frequent hospitalization, it was felt that cystectomy could improve the quality of life by eliminating these symptoms and problems. Measures of quality of life were not reviewed, and risks and complications were substantial despite a high degree of selection of patients as candidates for surgery.

Each of these studies implied benefits in the rigorous selection of patients on the basis of co-morbid conditions and performance status. Each suggested the value of pre-operative assessment and intensive treatment to prevent or minimize the effects of potential medical problems. However, results in these series indicated that the occurrence of even one complication could lead to other complications and could increase mortality. On the other hand, each study suggested that death caused by undertreated cancer was more likely than death related to intercurrent medical diseases. The consensus, therefore, appeared to favour the position that avoidance of surgery in the elderly on the basis of age alone was unjustified. It was further felt that the elderly patient who is thought to be suitable for surgery but is not offered this possibility is not only deprived of the right to definitive curative therapy (if the biology of the disease is such that this is possible), but is also exposed to higher morbidity, mortality and a worse quality of life with other treatments.

Nonetheless, there remains an understandable tendency to assume that an increased risk of complications is likely to characterize surgery in the elderly. The consequence of such thinking is the inclination to advocate definitive radiation therapy in such patients. The standard technique has involved use of a linear accelerator applied through a number of fields with delivery of a total split fractionated dose that ranges between 50 and 70 Gy.31 The frailty of many of these elderly patients, however, and their poor condition, together with radiation toxicity to the bladder and the bowel have often limited the intensity and dose of treatment. It has been suggested that this has interfered with the potential efficacy that might otherwise hve been achieved.

In one series, for example, Philips reported on 76 patients (mean age 78.4 years), only 53 of whom (70%) completed the full course of treatment.32 Of these, 19 (36%) had an apparent complete response (but with a median survival of only 14 months). The median survival of the entire cohort was only 13 months. Significant toxicity was seen in 10/53 (18%). Similar findings were made by Sengelov et al., who reported on 71/94 (80%) patients (median age 78 years) who completed their course of treatment and experienced a median survial of only 18.8 months.33 Toxicity resulted in hospitalization of 49 patients. Recurrent disease was experienced by 53% of the patients completing radiation (median time to recurrence 7.3 months). Only 7% of the entire group survived for five years, and only 29% survived for two years. Good performance status and stage of disease were the major determinants of survival.

In a series of 120 patients reported by Bell et al., 67 (59%) experienced local recurrence (30% with invasive disease) at a median time of 7.4 months.34 The five-year and median survival were 50%, but the series included 18 patients (15%) with stage T1 disease. Of the 27% (33/120) who underwent salvage cystectomy, the median disease-free survival was only 12.5 months.

In view of the limited access in achieving durable survival in these series, some have suggested a possible palliative role for radiation in treating transitional cell cancer of the bladder in the elderly. McClarin et al. treated 65 patients (median age 78 years) who were unable to tolerate a full course of radiation because of poor performance status or co-morbid illnesses with 30-36 Gy.35 All had muscle-invasive disease and 85% had severe symptoms. Palliation was 'successful' in 28/55 (51%) patients, but for only seven months' duration. Transient worsening of symptoms (29% urinary and 25% bowel) was seen in 28 patients. The medial survival was only nine months, with 52/55 dying of disease.

Overall, radiation therapy has not been well tolerated, has resulted in significant toxicity in at least 50% of patients, has demonstrated limited durability of response, and has had minimal salutary effect on disease-free survival. The most important factors associated with survival have appeared to be primary stage and performance index, which is similar to results with exenterative surgery. However, radiation therapy has additionally been compromised in the elderly by these patients' decreased tolerance to this treatment, their slow recovery, and their limited life expectancy.

Holmang et al. summarized their studies of radiation therapy in the elderly with the treatment of 74 patients between 70 and 75 years old who were considered unfit for surgery.36 Included in this series were 17 patients with stage T0-1 disease (median survival of 32 months), 40 patients with stage T2 disease (median survival of 16 months), and 17 patients with stage T4 disease with positive nodes (medial survival of nine months). Of the 'superficial' tumours, 9/11 who became tumour free recurred, and only 4/17 (24%) were alive at five years. Among those with muscle-invasive disease who were tumour free after radiation, 9/19 (48%) recurred and only 6/40 (15%) were alive at five years. Ninety percent of stage T4 tumour patients (5/7) recurred and none were alive at five years. On the basis of these disappointing results, Holmang et al. expressed their concern that 50% of treated bladder cancer patients appeared to have no response to radiation therapy and would have a poor prognosis if their bladder was retained. Thus, of those who responded initially, 25-50% recurred. They also suggested, however, that such results could probably have been biased, at least in part, because of the selection of the 'best' patients for cystectomy, the selection of patients with best performance status for 'curative' radiation, and the remaining frail and elderly patients to receive only palliative radiation. Thus, they concluded both from their own studies and from their review of other reports that the results of radiation were worse in the elderly, that survival in the elderly was not improved with salvage cystectomy, and that the elderly experienced a high rate of treatment morbidity and mortality.

Furthermore, in association with a very low rate of local 'cure' with radiation and a high rate of local recurrence, there was also a high rate of serious complications.36 Therefore, not only was there a question as to whether radiation added any benefit to transurethral resection in the elderly, but whether radiation that was only palliative actually provided any benefit or was only harmful. Side-effects were often seen even with palliative radiation with minimal therapeutic efficacy. There appeared to be no improvement in local symptoms, and 23% of patients needed rehospitalization among the 47% who experienced acute side-effects.

To compound these problems, guidelines that have been used to evaluate the results of radiation have been criticized because of the means by which outcomes are assessed. Shipley et al. have suggested that the major endpoint in characterizing efficacy was cystoscopic 'response' at six months, 'which has been shown to be a good predictor of outcomes'.37 Phillips et al. suggested more recently that 'cystoscopic response is more appropriate than survival in the elderly cohort'.38 These criteria in assessing efficacy are difficult to accept, and one wonders whether these statements are acceptable in the context of actual experience with efficacy and complications.

Much has been made ofthe possible efficacy ofchemotherapy in treating advanced transitional cell cancer of the bladder. Although various agents have been found individually and in combination to have measurable effects, they have ultimately been found to be ineffective in enhancing survival.39 Protocols that have tested the possibility of combining extensive transurethral resection with radiation and systemic chemotherapy, in an effort to eradicate tumour or possibly even palliate patients with advanced bladder cancer, have not only been unsuccessful in terms of their efficacy in survival and palliation, but their morbidity and mortality have been substantial.40,41

Although several studies of extensive transurethral resection and chemotherapy in selected elderly cases have reported 50% complete and partial responses, the durability of these responses has only been for 812 months on average, with an actuarial median survival of only 10-14 months.42,43 Dose modification has often been necessary to accommodate the reduced physiological capabilities of the various organ sytems in the elderly, particularly to minimize cardiotoxicity (from adriamycin) and nephrotoxicity (from cisplatin). In one oft-quoted study, Kaufman et al. reported complete responses in 11/20 (55%) patients with muscle-invasive disease.44 In those who were initially staged as having only superficial muscle invasion, complete response was more likely and five-year survival was 49%. In contrast, all patients with incomplete response died within three years. Moreover, overall actuarial five-year cause-specific survival was 43%. Toxicities were often significant and included leukopenia in 10%, gastrointestinal symptoms in 15%, and cystitis in 10%.

Because of the toxicity of chemotherapy, some have suggested that extensive transurethral resection alone may be appropriate in selected elderly patients. The primary consideration mandatory for success in this setting is the documentation of disease limited to the superficial muscularis propria. Those patients who are found to have no residual cancer after an aggressive repeat transurethral resection have been found to have a five-year survival of 15-45%, figures comparable to those achieved with more extensive disease, and other treatments, either alone or in combination.45,46 However, such figures are at odds with those suggesting that superficial muscle invasion may have a much higher rate of response and survival by various treatment modalities.47 Moreover, the need for salvage cystectomy to consolidate survival in 20-30% of these patients suggests further that many of these patients may actually have more extensive disease and points to the difficulty of assessing the extent of a bladder cancer with sufficient accuracy to permit appropriate treatment decisions.

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