Prediction of treatment-related toxicity and outcome with geriatric assessment in elderly patients with solid malignancies treated with chemotherapy: a systematic review.

INTRODUCTION: The number of older patients with cancer is increasing. Standard clinical evaluation of these patients may not be sufficient to determine individual treatment strategies and therefore Geriatric Assessment (GA) may be of clinical value. In this review, we summarize current literature that is available on GA in elderly patients with solid malignancies who receive chemotherapy. We focus on prediction of treatment toxicity, mortality and the role of GA in the decision-making process. DESIGN: We conducted a systematic search in PubMed. Studied populations needed to fulfill the following criteria: 65 years or older, diagnosis of solid malignancy, treatment with chemotherapy, submission to GA, either designed to study prediction of treatment toxicity or mortality or to evaluate the role of GA in the decision-making process. RESULTS: Our search provided 411 publications. Thirteen met the predefined criteria. These studies revealed: (i) up to 64% of elderly patients suffer from severe toxicity caused by polychemotherapy, (ii) Nutritional status, functionality and comorbidity are often associated with worse outcome, (iii) GA reveals (unknown) geriatric problems in more than 50% of elderly patients with cancer and (iv) 21%-53% of chemotherapy regimens are being modified based on GA. CONCLUSIONS: In geriatric oncology, an accurate predictive test to guide anticancer treatment in order to prevent serious toxicity is needed. The value of GA in predicting toxicity and mortality in older patients with cancer undergoing treatment with chemotherapy has not been proven. It may be valuable in revealing geriatric problems but current evidence for its usefulness to guide treatment decisions in this setting is limited. However, we are convinced that GAs should be carried out to optimize treatment strategies in elderly patients with cancer to improve treatment efficacy and minimize toxicity.

A high response is not essential to prevent selection bias: results from the Leiden 85-plus study.

We tested the hypothesis that an additional effort to increase the response rate would diminish selection bias in a community-based cohort study. In the Leiden 85-plus Study, all subjects of the town of Leiden who had reached their 85th birthday were informed of the study by mail and then asked to participate by telephone. In an additional recruitment stage, those subjects who did not participate directly were visited and personally asked to participate. When these subjects refused, some nonresponse questions were asked. In this way we collected data on the whole source population. Of 691 eligible elderly subjects, 511 subjects (74%) participated directly. Of those who did not participate directly, 88 subjects participated after the additional effort. The response rate increased from 74% to 87%. Compared to the 511 subjects who directly participated, the 88 subjects who entered the study after the additional effort had poorer health and lower survival. The subjects who refused were more healthy and had poorer mood. The direct sample did not differ from the source population with respect to socio-demographics, health, and mortality. In conclusion, we showed that given a moderately high direct response the additional effort was effective in increasing the response rate, but was also selective and was not necessary to prevent selection bias.

Successful aging in the oldest old: Who can be characterized as successfully aged?

BACKGROUND: Successful aging is a worldwide aim, but it is less clear which indicators characterize elderly persons as successfully aged. We explored the meaning of successful aging from 2 perspectives. METHODS: Analysis of data from the first cross-sectional part of the longitudinal Leiden 85-plus Study, conducted in Leiden, the Netherlands. All inhabitants of Leiden aged 85 years were eligible. Data were obtained from 599 participants (response rate, 87%). Successful aging from a public health perspective was defined as a state of being. All participants were classified as successful or not successful based on optimal scores for physical, social, and psychocognitive functioning and on feelings of well-being, using validated quantitative instruments. Qualitative indepth interviews on the perspectives of elderly persons were held with a representative group of 27 participants. RESULTS: Although 45% (267/599) of the participants had optimal scores for well-being, only 13% (79/599) had optimal scores for overall functioning. In total, 10% (58/599) of the participants satisfied all the criteria and could be classified as successfully aged. The qualitative interviews showed that most elderly persons viewed success as a process of adaptation rather than a state of being. They recognized the various domains of successful aging, but valued well-being and social functioning more than physical and psychocognitive functioning. CONCLUSIONS: If successful aging is defined as an optimal state of overall functioning and well-being, only a happy few meet the criteria. However, elderly persons view successful aging as a process of adaptation. Using this perspective, many more persons could be considered to be successfully aged.

Disability in the oldest old: "can do" or "do do"?

OBJECTIVE: To investigate the discrepancies between outcomes for competence (can do) and actual performance (do do) in activities of daily living (ADLs). DESIGN: Baseline measurements of a population-based follow-up study. SETTING: Leiden 85-Plus Study, the Netherlands. PARTICIPANTS: Five hundred and ninety-nine persons, age 85. The response rate was 86%. MEASUREMENTS: Face-to-face interviews. Measurements of competence and actual performance were based on the Groningen Activity Restriction Scale. Help received was assessed for several domains. Prevalence rates for disability were assessed according to the concepts of both competence and actual performance. Analysis was performed separately for basic activities of daily living (BADLs) and instrumental activities of daily living (IADLs). RESULTS: Seventy-seven percent of the oldest old were competent to perform all the BADLs and performed them regularly. Fifteen percent were not competent to perform certain BADLs independently but performed them regularly with help from others. The prevalence of disability defined as inability in one or more BADLs was 22% for women and 10% for men. The prevalence of disability defined as inactivity in one or more BADLs was 16% for women and 17% for men. Only 5% of the oldest old were competent to perform all IADLs and performed them regularly. In spite of being competent, 70% did not perform certain IADLs regularly. The prevalence of disability defined as inability in one or more IADLs was 64% for women and 55% for men. The prevalence of disability defined as inactivity in one or more IADLs was 92% for women and 98% for men. CONCLUSION: The structural discrepancies between the outcomes of competence and actual performance have important consequences when estimating disability in old people. Promoting actual performance in IADLs may reduce disability.

Cardiopulmonary resuscitation preferences in Dutch community-dwelling and hospitalized elderly people: an interaction between gender and quality of life.

OBJECTIVE: To study the effects of information, gender, quality of life, and hospitalization on cardiopulmonary resuscitation (CPR) preferences and on the wish for information and participation in CPR discussions. METHODS: Seventy-five community-dwelling inhabitants of the city of Leiden and 45 consecutive patients in two hospitals in Leiden, The Netherlands, aged 75 years or older, were interviewed about their CPR preferences in their current states of health and in three hypothetical scenarios. Health-related quality of life (QOL) was assessed in separate items. The subjects were asked about their wishes for information and participation in CPR discussions. RESULTS: The chances of surviving CPR were overestimated. After receiving accurate information, 65% of the subjects, more women than men, did not want CPR. Overall QOL did not differ between men and women. Concerning the separate QOL items, men's CPR preferences were more associated with pain, whereas women's were more associated with being impaired in physical functioning and daily and social activities. CPR preferences in the current state of health did not differ significantly between community-dwelling and hospitalized participants. Although only 6% of all participants had ever discussed CPR with their doctors, 70% indicated they wanted routine CPR discussions (either when in good health at home or upon hospital admission), and 61% preferred to make the final decision about CPR themselves. CONCLUSIONS: CPR preferences are affected by different QOL items in men and women. CPR preferences in the current state of health do not differ between hospitalized and community-dwelling elderly people. As the majority of elderly people want CPR discussions, they should be involved in decision making concerning CPR.

Idiopathic senile gait disorders are signs of subclinical disease.

OBJECTIVES: To evaluate survival and causes of death in subjects with idiopathic senile gait disorders. DESIGN: A population-based longitudinal study. SETTING: Survival analysis of the oldest old within the Leiden 85-plus Study. PARTICIPANTS: We distinguished three different groups according to their gait: subjects with a normal gait (n = 25), subjects with senile gait disorders (n = 14), and subjects with gait disorders due to known disease (n = 87). The mean age was 90 years in all groups (range 87 to 97 years). MEASUREMENTS: The risk of all cause mortality and cardiovascular mortality was estimated over 5 years of follow-up in a Cox-proportional hazards model, adjusted for age and sex. RESULTS: Eighty-nine of 126 subjects died during follow-up. Mean survival differed among the three groups (P log-rank = .01). All cause mortality risk was increased in subjects with senile gait disorders compared with subjects with a normal gait (RR = 2.8; 95% CI, 1.1-7.3, P = .03) and was similar to subjects with gait disorders caused by known disease (RR = 1.2; 95% CI: .6-2.5, P = .6). Mortality caused by cardiovascular disease also differed among the three groups (P log-rank = .03). The risk of cardiovascular death in subjects with senile gait disorders was twofold greater than in subjects with a normal gait (RR = 2.1; 95% CI, 0.4-10.3). CONCLUSIONS: Senile gait disorders are related to subclinical, perhaps cardiovascular, disease. Senile gait disorders should not be accepted as an inevitable, benign concomitant of the normal aging process.

Common paraoxonase gene variants, mortality risk and fatal cardiovascular events in elderly subjects.

Recent studies indicate that the enzyme paraoxonase may be an important modulator of cardiovascular disease risk because of its ability to protect LDL from oxidation. We tested for association between two functional variants of the paraoxonase gene (Met-55/Leu and Gln-192/Arg) and both all-cause mortality and fatal cardiovascular disease. This was done within a population-based study among subjects aged 85 years and over in a cross-sectional and a prospective design. In the cross-sectional analysis, the distribution of both paraoxonase genotypes was found to be similar in the subset of 364 elderly subjects who were born in Leiden, The Netherlands, as compared with 250 young subjects whose families originated from the same geographical region. The polymorphisms were in strong linkage disequilibrium (P<0.00001) and the frequency of the haplotype carrying both risk alleles was not lower in the elderly than in the young (0.313 vs. 0.284). The complete cohort of 666 elderly subjects was followed over 10 years. The risk of all-cause and cardiovascular mortality was not increased in elderly subjects with the paraoxonase Leu/Leu (RR, 1.1 [95% CI, 0.9-1.5] and 1.3 [95% CI, 0.8-2.0], respectively) or the Arg/Arg genotype (RR, 0. 9 [95% CI, 0.7-1.2] and 0.7 [95% CI, 0.4-1.3], respectively). In a subset of patients with diabetes, the all-cause mortality risk was elevated in Arg/Arg carriers (RR, 2.1 [95% CI, 0.8-5.8]) but this did not reach statistical significance. Analysis of genotype combinations did not yield significant associations with mortality. The paraoxonase gene variants, previously associated with coronary artery disease, are thus not likely to have a major effect on the risk of fatal cardiovascular disease in the population at large. Adverse effects of the gene variants might be observed in subjects exposed to factors that enhance oxidative stress such as diabetes.

HMG-CoA reductase inhibitors in the prevention of stroke.

Stroke is a heterogeneous disorder, with the definition including both haemorrhagic and ischaemic stroke. Although these subtypes of stroke have different underlying pathophysiological mechanisms, atherosclerosis plays a pivotal role in both. Most risk factors for cardiovascular disease are also risk factors for stroke. Patients with a history of cardiovascular events are at an increased risk of stroke. Although hypercholesterolaemia is the most characteristic risk factor for atherosclerotic diseases, recent data suggest that the correlation between cholesterol levels and either ischaemic or haemorrhagic stroke is weak. However, the interpretation of these results is hampered by the inconsistent use of classifications of the various subtypes of stroke in studies. Pooled data on the effect of HMG-CoA reductase inhibitors show a 30% risk reduction in strokes. These beneficial effects are obtained from studies in middle aged patients with ischaemic heart disease, the interpretation being that the effects of HMG-CoA reductase inhibitors on stroke are mediated via (i) cholesterol-lowering effects on the coronary vasculature or (ii) cholesterol-independent effects of these agents. The results cannot be extrapolated to the elderly, among whom stroke most frequently occurs.

The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk.

The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomized, double-blind, placebo-controlled trial designed to test the hypothesis that treatment with pravastatin will diminish risk of subsequent major vascular events in a cohort of men and women (70 to 82 years old) with preexisting vascular disease or significant risk of developing this condition. Five thousand eight hundred four men and women in addition to receiving advice on diet and smoking, have been randomized equally to treatment with 40 mg pravastatin/day or matching placebo in 3 centers (Cork, Ireland, Glasgow, Scotland, and Leiden, The Netherlands). Following an average 3.5-year intervention period, a primary assessment will be made of the influence of this therapy on major vascular events (a combination of coronary heart disease, death, nonfatal myocardial infarction, and fatal and nonfatal stroke). A number of additional analyses will also be conducted on the individual components of the primary end point, on men, on women, and on subjects with and without previous evidence of vascular disease. Finally, an assessment will be made of the effects of treatment on cognitive function, disability, hospitalization or institutionalization, vascular mortality, and all-cause mortality.

Thermolabile methylenetetrahydrofolate reductase gene and the risk of cognitive impairment in those over 85.

OBJECTIVES: Previous reports have shown raised plasma concentrations of homocysteine in older persons with cognitive impairment. This may be caused by environmental and genetic factors. The relation between cognitive function and a common ala/val mutation in the methylenetetrahydrofolate reductase (MTHFR) gene was studied in those over 85. Homozygous carriers of this mutation are characterised by a lifelong exposure to moderately raised plasma concentrations of homocysteine. METHODS: In the Leiden 85-plus Study, a population based study of persons aged 85 years and over, the score on the mini mental state examination (MMSE) and the presence of dementia dependent on the MTHFR genotypes were compared in 641 participants (456 women, 185 men) at baseline. In addition, the association between the MTHFR genotype and cognitive decline was studied by re-examining cognitive function of 172 participants without dementia at baseline after a median follow up of 4.0 years. RESULTS: At baseline, carriers of the ala/ala genotype had a median MMSE score of 27 points (interquartile range (IQR) 21.5-29), for the ala/val genotype it was 26 points (IQR 20-29), and for the val/val genotype it was 27 points (IQR 20-28.3) (p=0.3). The prevalence of dementia was also not significantly different for the various genotypes (ala/ala 22%, ala/val 28%, val/val 27%; p=0.4). None of the carriers of the val/val genotype without cognitive impairment at baseline developed dementia during the follow up. CONCLUSIONS: Although previous studies have shown that older persons with cognitive impairment have raised plasma concentrations of homocysteine, homozygosity for the ala to val mutation in the MTHFR gene is not a genetic risk factor for cognitive impairment in persons aged 85 years and over.

Mortality risk in men is associated with a common mutation in the methylene-tetrahydrofolate reductase gene (MTHFR).

An elevated level of homocysteine in plasma is associated with the occurrence of cardiovascular disease. A common ala-to-val mutation in the methylenetetrahydrofolate reductase gene (MTHFR) is associated with an elevated level of plasma homocysteine. We studied the possible detrimental effects of the MTHFR mutation on mortality. Within a population-based study in the city of Leiden, the Netherlands, we first compared the MTHFR genotype distribution among 365 elderly subjects aged 85 years and over born in Leiden, and 250 young subjects aged 18 to 40 years whose families originated from the same geographical region. Second, the complete cohort of 666 subjects aged 85 years and over was followed over a period of 10 years for all-cause and cause-specific mortality and stratified according to MTHFR genotype. The frequency of the MTHFR mutation was significantly lower in the elderly than in the young (0.30 and 0.36, respectively; P = 0.03). The difference in genotype distribution was only present in men. The estimated mortality risk up to 85 years in men carrying the vallval genotype was 3.7 (95% confidence interval (CI), 1.3-10.9). Over the age of 85, mortality in men with the vallval genotype was increased 2.0-fold (95% CI, 1.1-3.9) and appeared to be attributable to cancer rather than cardiovascular causes of death. Among women aged 85 years and over, no deleterious effect of the MTHFR mutation was observed. In conclusion, the MTHFR mutation is associated with increased mortality in men in middle and old age, but not in women.

[The tooth of time, aging and health]. / De tand des tijds, veroudering en gezondheid.

Older patients are becoming significantly more important in the health care service. Important topics in geriatric medicine are discussed such as characteristics of geriatric patients, the concept of 'normal' and 'successful' ageing, age discrimination and the multidisciplinary geriatric team. These concepts may also be useful in geriatric dentistry.

Total cholesterol and risk of mortality in the oldest old.

BACKGROUND: The impact of total serum cholesterol as a risk factor for cardiovascular disease decreases with age, which casts doubt on the necessity for cholesterol-lowering therapy in the elderly. We assessed the influence of total cholesterol concentrations on specific and all-cause mortality in people aged 85 years and over. METHODS: In 724 participants (median age 89 years), total cholesterol concentrations were measured and mortality risks calculated over 10 years of follow-up. Three categories of total cholesterol concentrations were defined: < 5.0 mmol/L, 5.0-6.4 mmol/L, and > or = 6.5 mmol/L. In a subgroup of 137 participants, total cholesterol was measured again after 5 years of follow-up. Mortality risks for the three categories of total cholesterol concentrations were estimated with a Cox proportional-hazards model, adjusted for age, sex, and cardiovascular risk factors. The primary causes of death were coded according to the International Classification of Diseases (ICD-9). FINDINGS: During 10 years of follow-up from Dec 1, 1986, to Oct 1, 1996, a total of 642 participants died. Each 1 mmol/L increase in total cholesterol corresponded to a 15% decrease in mortality (risk ratio 0.85 [95% CI 0.79-0.91]). This risk estimate was similar in the subgroup of participants who had stable cholesterol concentrations over a 5-year period. The main cause of death was cardiovascular disease with a similar mortality risk in the three total cholesterol categories. Mortality from cancer and infection was significantly lower among the participants in the highest total cholesterol category than in the other categories, which largely explained the lower all-cause mortality in this category. INTERPRETATION: In people older than 85 years, high total cholesterol concentrations are associated with longevity owing to lower mortality from cancer and infection. The effects of cholesterol-lowering therapy have yet to be assessed.

Stroke, statins, and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors.

BACKGROUND AND PURPOSE: To estimate the effect of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors ("statins") on stroke ris, we combined the data of the randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors published so far. METHODS: The studies were identified using the Medline CD+ and Current Contents databases from January 1980 through May 1996, inclusive. All studies were evaluated on the use of a placebo control, monotherapy, and double blindness. When the type of stroke or the occurrence of clinical events or adverse effects were incompletely or not reported, the investigators were contacted personally. For each trial, the number of strokes in the treatment arm was compared with the number of strokes expected on all observations under the assumption that drug treatment had no effect. RESULTS: A total of 462 strokes among 20438 participants in 13 trials could be analyzed. A total of 181 strokes were observed in patients randomized to treatment with an HMG-CoA reductase inhibitor and 261 strokes in patients randomized to placebo. A lower than expected number of strokes was observed in the treatment groups of all but one trial (P = .001). Treatment with an HMG-CoA reductase inhibitor led to an overall risk reduction of 31% (odds ratio, 0.69; 95% confidence interval, 0.57 to 0.83). CONCLUSIONS: The combined data suggest that treatment with HMG-CoA reductase inhibitors prevents stroke in middle-aged persons. Because stroke is especially common in older age, these data reinforce the need for clinical trials to evaluate the effect of HMG-CoA reductase inhibitors in preventing stroke in the elderly.

[Gait impairment in the oldest old]. / Loopbeperkingen bij de alleroudsten.

To evaluate senile gait patterns in octogenarians and nonagenarians, we provided a standardized questionnaire on gait disabilities to 153 elderly subjects over 88 years of age. Subjects represented a relatively healthy subgroup of non-institutionalized residents who participated in a gerontological survey of all inhabitants of the city of Leiden who were 85 years or older. Of the 142 subjects who responded to this questionnaire, 87 persons (61%) claimed distinct diseases as a cause of gait impairment. Of the remaining 55 persons, 42 received a standardized gait assessment. Gait was classified as completely normal in 25 persons (18% of all responders), whereas in three other persons gait could not reliably be classified as either normal or abnormal. A wide spectrum of clear gait abnormalities-mainly with ataxic features-was encountered in the remaining 14 persons (10%). It is concluded that some elderly subjects have a mainly ataxic gait disturbance which seems unrelated to the presence of distinct diseases. Although additional investigations might still reveal underlying pathology in these subjects, their gait impairment may represent the "idiopathic senile gait disorder'. In addition, a relatively high number of very old community residents have a completely normal gait.

Dehydroepiandrosterone sulphate (DHEAS) in the oldest old, aged 85 and over.

Dehydroepiandrosterone (DHEA) and its sulphonated metabolite DHEAS are the major secretory products of the human adrenal gland. Despite the abundancy of these steroids in the circulation the precise function is uncertain. It has been postulated that they may be involved in the maturing and aging processes in man. An intriguing inverse relation has been described between DHEAS and cardiovascular mortality in men. In women from the same population this was not the case and in fact mortality due to cardiovascular disease was highest in women with the highest levels of DHEAS. Another interesting association is reported between DHEA and DHEAS and the enhancement of memory retention in mice. Reduced plasma concentration of DHEAS have been described in patients with Alzheimer's disease compared with age-matched controls. In the framework of a gerontologic study concerning all 1259 inhabitants aged 85 years and over of the Dutch community of Leiden (population +/- 105,000), DHEAS levels were determined in 138 subjects of this cohort. Of these, 53 were healthy subjects, selected from the population according to the health criteria of the SENIEUR protocol, which is based on clinical, pharmacological and laboratory data. This enabled us to assess reference values for this age group. Additionally DHEAS levels were measured in 64 young controls, 20-40 years of age, who also fulfilled these criteria. Reference values for the oldest old, derived from the healthy group, are 1.7 +/- 1.4 mumol/l for women and 2.2 +/- 1.1 mumol/l for men. DHEAS levels decreased fourfold between the young adults and those aged 85 and over. In men this decrease continued after the age of 85. DHEAS values tended to be higher in men than in women, both in the elderly, in all subgroups of elderly subjects, and in the young control group, but this sex-difference did not reach statistical significance. No difference was found between the DHEAS levels in subgroups according to the health status, the survival rate or the diagnosis of probable Alzheimer's disease. Many uncertainties concerning the role of DHEAS in the neuro-immuno-endocrinological network have yet to be unravelled and the question remains whether the age-related decrease of DHEAS is related to organ-specific failure on the level of the adrenals or the gonads, or whether it is a result of changes in feedback or regulatory mechanisms. DHEAS is one of the few compounds that shows a gradual decrease with advancing age, reaching an asymptotic low at the age of the maximum recorded life span.(ABSTRACT TRUNCATED AT 400 WORDS)