aging interface

J O U RN A L OF GE RI A TR IC O NC O L O G Y 2 ( 2 01 1 ) 1 7 7 –1 86

available at www.sciencedirect.com

Review Article

Nutritional aspects of the cancer/aging interface Federico Bozzetti Faculty of Medicine, University of Milan, Italy

AR TIC LE I N FO

ABS TR ACT

Article history:

The progressive aging of populations coupled with the increasing prevalence of cancer in

Received 19 January 2011

elderly people, due to their long exposure to potential oncogenic factors, represents a

Received in revised form 11

formidable challenge for the health system. Moreover, whereas in many adult cancer

March 2011

patients, malignancy represents the primary basic target to be treated, in the elderly

Accepted 24 March 2011

patients a concurrent status of sarcopenia multiplies the risk of aggressive therapies and

Available online 27 April 2011

forces the clinician to maintain a holistic view of his patient. A common problem for the elderly cancer patient is the progressive malnutrition which is

Keywords:

due to coexistence and/or potentiation of the metabolic alterations related to sarcopenia

Elderly cancer patients

with underlying cancer cachexia. Both processes lead to loss of body weight, lean body

Cancer cachexia

mass, and muscle function, as well as a progressive deterioration of function of many organ/

Sarcopenia

systems, a poor quality of life and finally to a poor adaptation to any stress event.

Nutritional support of the elderly

Although neither sarcopenia nor cancer cachexia may be reduced to a condition of simple

patient

starvation, an adequate nutritional intake is the conditio sine qua non which can make possible any attempt of aggressive oncologic therapies which are validated in adult subjects. This paper, after a short review of topics including the interaction between sarcopenia and cancer cachexia, the nutritional status as a component of geriatric assessment tools, the prevalence of malnutrition and the negative prognostic role of malnutrition, focuses on the theoretical and practical aspects of the nutritional support of the elderly cancer patient. © 2011 Published by Elsevier Ltd.

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interaction Between Sarcopenia (Aging, Poor Diet, and Inactivity) and Cachexia Nutritional Status as a Component of Geriatric Assessment Tools . . . . . . . Prevalence of Malnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Malnutrition as a Negative Prognostic Determinant . . . . . . . . . . . . . . . Nutritional Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Energy and Substrates Metabolism . . . . . . . . . . . . . . . . . . . . . 6.3. Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

E-mail address: [email protected]. 1879-4068/$ – see front matter © 2011 Published by Elsevier Ltd. doi:10.1016/j.jgo.2011.03.003

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

. . . . . . . . .

178 178 179 179 179 180 180 180 180

178

J O U RN A L O F GE RI A TR IC O NC O LOG Y 2 ( 2 01 1 ) 1 7 7 –18 6

7.

Towards an Integrated Approach . . . . . 7.1. Enteral Nutrition . . . . . . . . . . 7.1.1. Oral Supplements . . . . . . 7.1.2. Tube Feeding. . . . . . . . . 7.2. Parenteral Nutrition . . . . . . . . . 7.3. Future Perspectives and Conclusion Conflict of Interest Statement . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . .

1.

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

Introduction

We are currently crossing a demographic revolution as a consequence of the aging of populations worldwide, particularly in Western countries where people older than 65 years already compose 15% to 18% of the population.1 The number of Americans2 and people living in Western Europe over the age of 65 is expected to double by the year 2030, and they will represent 20% and 36% in UK and China, respectively. A projection of the Ministry of Health of Italy reports that people over the age of 65 are 20% of the overall population (but they account for 40% of the hospitalized population) and are expected to be 37% by the year 2050. People 85 years of age and older are the most rapidly growing segment of the population3 and consequently cancer incidence is increasing in older people as a result of a longer life span that promotes both a prolonged exposure to carcinogens and an accumulation of genetic alterations. Malignancy represents a major cause of mortality in this population, and cancer-specific mortality increases as a function of age, despite recent progress observed in oncologic therapies in the general population.4 Data from Surveillance, Epidemiology and End Results in the United States suggest that the median age at diagnosis of cancer is 70 years5: the median age of patients with acute myeloid leukemia is 65 to 70 years,6 the mean/median age for esophageal adenocarcinoma in England was 68 and 70 years in males and 75 and 78 years in females, respectively,7 more than 50% of advanced NSCLCs are diagnosed in patients older than age 65 years,8,9 and one half of lymphoma cases occur in patients older than 65.10 In conclusion, more than half of new cancers occur in the elderly11 and more than 70% of cancer deaths occur in people over the age of 65 years.12 Advanced age is not only associated with a growing incidence of tumors, but also with an increase in illnesses and health problems including those which can alter the nutritional status.13 Therefore, therapeutic approaches in older persons with cancer need to be based upon a comprehensive understanding of the heterogeneity of the health and functional status of older persons. Malnutrition is one of the more important issues for elderly cancer patients not only for its frequency and its impact on the outcome but also because it is a condition amenable to a proper treatment in combination with the primary care of the cancer. This paper focuses on the interrelationship among cancer, nutritional status and aging.

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

181 181 181 182 182 182 182 182

2. Interaction Between Sarcopenia (Aging, Poor Diet, and Inactivity) and Cachexia From the age of 50 years onwards, aging is associated with a degenerative loss of skeletal muscle which is defined as sarcopenia. Sarcopenia is defined by the combined presence of the two following criteria: I. A low muscle mass, i.e. a percentage of muscle mass ≥ 2 standard deviations below the mean measured in young adults of the same sex and ethnic background. Subjects aged 18–39 years in the 3rd National Health and Nutritional Examination Survey (NHANES) population 14 might be used as a reference. II. Low gait speed, e.g. a walking speed below 0.8 m/s in the 4 meter walking test.15 The underlying mechanisms are not well understood and many factors including reduction of circulating anabolic hormones, inadequate diet and inactivity undoubtedly play a role. The onset of sarcopenia is insidious, but its progression may be dramatically accelerated by physical inactivity and poor nutrition. In fact in recent studies examining changes in protein synthesis and muscle mass in healthy adults, it appeared that after 10 days of inactivity, older healthy subjects experienced an approximately three-fold greater loss of lean leg muscle mass (10% total lean leg mass) than a cohort of younger individuals confined to bed for 28 days.16,17 Besides a protein-deficient diet, which is a common finding in elderly subjects, it also appears that there is a decreased sensitivity and responsiveness of muscle protein synthesis to essential amino acids, probably associated with decrements in the expression and activation of components of anabolic signaling pathways [mammalian target of rapamycin, mTOR; p70 S6 kinase, or p70(S6k); eukaryotic initiation factor (eIF4BP-1 and eIF2B)].18 Furthermore there is a marked increase in the transcription of NF-κB. The consequence is that although the post-absorptive rate of protein muscle synthesis is similar between young and elderly people, the skeletal muscle of the elderly does not respond appropriately to the essential amino acid load that is associated with the expected 50% marked increase in muscle protein synthesis.19 The fall in the muscle protein synthesis and a blunted essential amino acid-induced stimulation of protein synthesis in inactive elderly has been reported also by Biolo et al.20

J O U RN A L OF GE RI A TR IC O NC O L O G Y 2 ( 2 01 1 ) 1 7 7 –1 86

If we consider that a high proportion of cancer patients are elderly, it appears that the derangement in the nutritional status is the consequence of both the age-related sarcopenia and the presence of the cancer-related cachexia.

3. Nutritional Status as a Component of Geriatric Assessment Tools The relevance of nutritional status in the care of the elderly cancer and non-cancer patients is demonstrated by the incorporation of nutritional parameters in geriatric assessment tools which have a well recognized prognostic value. Besides the Mini Nutritional Assessment (MNA), whose prognostic value is widely validated in the general elderly population, unintentional weight loss of 10 lbs or 10% of usual body weight or presumptive muscle wasting, body mass index less than 18.5 kg/m2, and a low serum albumin level ( ≤ 3.7 g/dL) are included in the minigeriatric assessment21 and are recognized criteria for defining frailty.22–25 An interesting analysis was performed by Stauder et al.26 who applied the same assessment instruments simultaneously in one and the same elderly cancer patient to determine which of the scores used in the assessment cover overlapping aspects and which of them address different domains. They applied the following geriatric assessment tools: WHO Performance Status,27 the Karnofsky Index,28 the functional activities were assessed by means of the scores for Activities of Daily Living (Barthel Index),29 Instrumental Activities of Daily Living30 and the Timed Up and Go Test. Screening instruments used were the 7item physical performance test31,32 and the Vulnerable Elderly Survey 13.33 Health-related quality of life was assessed with the Functional Assessment of Cancer Therapy General Scale.34,35 Screening for depression was assessed with the Geriatric Depression Scale.36 Cognitive function was evaluated with the Mini Mental Status Examination.37 Comorbidities were evaluated using the Cumulative Illness Rating Scale for Geriatricians27 as well as the Charlson Comorbidity Index.38 Social support was evaluated with the F-SozU (questionnaire for the assessment of social support). Using factor analysis, nutritional status resulted in one of the six domains that were identified as independent dimensions covered by the Geriatric Assessment.

4.

Prevalence of Malnutrition

There is wide literature reporting the association between presence of a malignancy and a state of malnutrition.39 Although a majority of these surveys have been performed in a population of adult cancer patients, it has to be pointed out that elderly patients accounted for a high proportion of these series. Few studies have specifically focused on elderly cancer patients: according to Pailloud et al.40 the percentage of patients with more than 10% of weight loss was 71% in the elderly patients and the percentage of those with BMI < 20 was 44%. In addition, during their stay in the hospital, triceps skinfold and fat mass further decreased in older patients.

179

Lecleire et al.41 reported a study including 120 patients with esophageal cancer (median age 68.8 ± 9.9 years). The introduction of a therapeutic prosthesis induced a decrease in BMI, serum albumin level and ECOG, though dysphagia was improved in 89.1% of patients. Blanc-Bisson et al.42 reported that nutritional status could be impaired in 66% of elderly patients with cancer according to MNA questionnaire scores (score < 24) and low serum albumin levels (< 35 g/L). The prevalence of malnutrition is related to the composition of the case: in studies mainly represented by patients with breast cancer the nutritional status was reported to be poor (BMI< 22 kg/m2) 43 in only 14% of the patients, with 7.7% having lost more than 10% of their usual weight (BMI < 18.5 kg/m2).44 In an ongoing study on the nutritional status of cancer outpatients45 we recently found that in 689 ≥ 65-year old subjects the mean weight loss was 9.5% (median value 8.2%) and percentage of patients with a weight loss ≥10% of their usual body weight was 42.5%. Moreover, the percentage of patients with a Nutritional Risk score ≥3 was 61.2%. This screening system, endorsed by ESPEN, the European Society for Clinical Nutrition and Metabolism, was validated against over 100 randomized clinical trials comparing nutritional support versus spontaneous intake 46,47 and proved highly effective in prospective clinical investigations since patients identified “at nutritional risk” had better outcomes if supported nutritionally. If the patients at the initial screening have a BMI < 20.5, have lost weight in the last 3 months, have a reduced dietary intake in the last week, or are severely ill, then they are moved to the final screening where a quantification of the previous parameters is completed and is summed with the severity of the disease. The final scoring ranges from 0 to 7, being 0 = no risk, 1–2 = low risk, 3–4 = medium risk and >5=high risk. For age ≥70 years, 1 additional score is added. A score ≥3 is considered worth requiring a further deeper nutritional assessment for a potential nutritional intervention.

5. Malnutrition as a Negative Prognostic Determinant Recent research in cancer patients has shown that malnutrition, age and gender are independent determinants for hand grip, knee extension strength, peak expiratory flow, and functional status.48 Again, the negative impact of malnutrition on the outcome of cancer patients is largely reported in literature. More specifically Lecleire et al.41 reported that low serum albumin levels, BMI < 18 kg/m2 and ECOG > 2 at prosthesis insertion were independent predictive factors of mortality at 30 days for elderly patients with esophageal cancer. Quite recently, Kastritis et al.49 found that weight loss was a significant predictor of outcome in multivariate analysis of patients receiving platinum-based chemotherapy for cervical cancer. Although tolerant, toxicity and efficacy of different chemotherapeutic regimens are comparable in adult and elderly patients despite the presence of comorbidity,50–53 only a limited proportion of elderly patients is routinely treated54–58 with few exceptions.59 Moreover, elderly patients tend to be

180

J O U RN A L O F GE RI A TR IC O NC O LOG Y 2 ( 2 01 1 ) 1 7 7 –18 6

under-represented in clinical trials,60 since physicians usually avoid to enroll aged patients in prospective investigations.61 The reasons for therapeutic abstention are most frequently unclear.55 An interesting study by Marenco et al.62 showed that the probability of recommending an active treatment, adjusted for all the variables analyzed, was negatively associated with increasing age, living alone, an ADL score >0 and a low BMI. Except for low BMI, all other variables (age, education, living condition, and multi-dimension geriatric assessment scores) did not appear to influence survival when the oncological variables were accounted for. Similar results were reported by Girre et al.44

corresponding to 1 ml/kcal energy consumed and the third to 100 ml/kg for the first 10 kg, 50 ml for the next 10 kg and 15 ml for the remaining kilograms. An interesting investigation was performed by Persson and Elmstahl77 and showed that in a population of institutionalized elderly residents the intake of fluid was adequate with a regimen of 30 ml/kg body weight, but it resulted to be low for underweight residents. On the contrary, the second formula results were more than adequate, and the third standard was found inadequate. According to the ESPEN Guidelines 78 the total volume of fluid and sodium should not exceed 30 ml and 1 mmol/kg/day, respectively, according to the experts' opinion.

6.2.

6.

Nutritional Requirements

There is no specific clinical or metabolic experience for nutritional support in elderly cancer patients, hence our knowledge relies on the research on enteral and parenteral nutrition in normal elderly people and in patients with cancer. It is noteworthy, however, that the majority of patients with cancer are elderly.

6.1.

Water

If we consider elderly cancer patients, a restriction in water administration is advised for several reasons. Advanced cancer is often associated with the expansion of the extracellular fluid volume and an overzealous administration of water, glucose and sodium can sharply result in a fluid overload with edema not only in peripheral tissues but also in the central organs. Gamble63 first demonstrated that glucose reduces renal sodium excretion and, for the same reasons, the loss of extracellular fluid and Bloom64 suggested that this effect was mediated by insulin, a potent antinatriuretic and antidiuretic hormone65 released through an increased sympathetic activity. The effects of a glucose-based parenteral nutrition on positive water and sodium balance have been described by Rudman et al.66 and subsequently described in oncologic patients by Fan et al.,67 Bozzetti et al.68 and Gray and Meguid.69 Moreover cancer patients may have an excessive production of antidiuretic hormone due to the tumor,70 to the presence of nausea which frequently occurs in advanced stages of disease, or to the administration of morphine. Wasting is associated with loss of intracellular water and solutes which through the activation of the hypothalamic osmoreceptor cells, stimulate the ADH release at levels which maintain serum osmolality and sodium concentration at subnormal values.71 As a consequence, the clearance of free water is decreased. In addition, the urea load presented to the kidney is reduced due to the protein depletion secondary to the undernutrition. The synthesis of endogenous water is maintained by the oxidation of energetic substrates (carbohydrates and fats)72 and the insensible water loss drops because of the reduced physical activity.73 As already reported74 three standards of fluid intake are proposed for the elderly.75 One, corresponding to a fluid intake of 30 ml/kg body weight76 for subjects >65 years, the second

Energy and Substrates Metabolism

There is a paucity of data regarding the energy requirements of elderly cancer patients. Lindmark et al.79 reported that the resting energy expenditure (REE) of weight-losing cancer patients was higher than predicted and was quantified by Hansell et al.80 as 24.6 kcal/kg/day. In weight-stable patients REE was 22.7 kcal/kg/day, a value significantly lower than in weight-losing cancer patients but higher than weight-stable controls. Gibney et al81 measured total energy expenditure (TEE) in eight elderly free-living patients with small-cell lung cancer for one or two days and reported a 6% elevation in basal energy expenditure and a TEE/REE of only 1.36. They concluded that the energy requirements of these cancer patients were not increased because their mild basal hypermetabolism was overbalanced by decreased physical activity. A more recent study by Bencini et al.82 reported that in hospitalized elderly advanced cancer patients total energy expenditure was 28±3 kcal/kg/day. Hansell et al.80 reported that elderly patients with cancer had significantly higher fat oxidation rates and significantly lower carbohydrate oxidation rates when compared with controls. Weight-losing cancer patients had significantly higher (p< 0.02) fat oxidation rates when compared with weight-stable cancer patients, weight-stable controls, and weight-losing controls. Aberg et al.83 showed that elderly healthy men have a similar capacity as young healthy men to clear and oxidize a high triacylglycerol load administered as a hypertriglyceridemic clamp and more recently Al-Jaouni et al.84 reported that in the elderly patients with intestinal failure parenteral nutrition was associated with significantly higher lipid oxidation and lower glucose oxidation than in younger patients. Gambardella et al.85 showed that autonomic nervous system dysfunction occurs and is responsible for elevated REE in elderly cancer patients, and intralipid infusion combined with propanol administration was able to rectify the calorie intake without a strong increase in energy expenditure. These data suggest parenteral nutrition formulas and flow rates should therefore be adapted in the elderly.

6.3.

Protein

Most of the available evidence refers to elderly healthy subjects or sarcopenic patients. Because of age-dependent metabolic alterations, in general older persons may synthetize less muscle protein than younger subjects from the same amount of dietary protein. However,

J O U RN A L OF GE RI A TR IC O NC O L O G Y 2 ( 2 01 1 ) 1 7 7 –1 86

even if aging is associated with an inability to respond to low doses of protein (20 g) or essential amino acids (<8 g), higher doses (protein > 25 g; essential amino acids 10–15 g) are capable of stimulating muscle protein synthesis in older adults to a similar extent as in the young.86–90 Symons et al.91 reported that a moderate (113 g) serving of an intact protein (i.e. lean beef) contains sufficient essential amino acids (30 g total: ~12 g essential amino acids) to increase mixed-muscle protein synthesis by 50% in both young and elderly men and women. Volpi et al.92 were among the first to show that the intravenous administration of amino acids stimulates net muscle protein synthesis in the elderly. Essential amino acids appear to be the primary stimulus of protein synthesis and act synergistically with exercise to increase fractional protein synthesis.93 Leucine seems to be the most active of the amino acids94 and the anabolic effect of leucine-enriched essential amino acids acts not only as building blocks for protein synthesis but is also involved in the muscle stimulation of the mammalian target of rapamycin (mTor) pathway, a serine/threonine protein kinase that drives protein synthesis. Therefore many authors argue that the recommended daily allowance for protein (1.0 g/kg/day), although sufficient to maintain muscle mass95 in healthy individuals, fails to prevent muscle loss with aging.89,90,96,97 On the contrary, levels of protein intake as high as 1.6 g of protein/kg/day have been demonstrated to increase exercise-induced muscle hypertrophy.98 Hence the recommendation by the International Cachexia Society for older persons is to ingest between 1.0 and 1.5 g of protein/kg/day. In addition, since a threefold increase in protein and energy content (90 g total: ~36 g essential amino acids) was not able to achieve a further increase in protein synthesis in the young and elderly,91 it is recommended that the amount of protein ingested should be spread equally throughout the day, i.e. equivalent amounts at breakfast, lunch, and dinner.99 If additional protein supplementation is given it should be administered between meals. From the clinical point of view it is important to consider that a protein source of high biologic value, namely those from animal sources, provides the highest concentration of branched chain amino acids such as leucine, capable of stimulating muscle protein synthesis90,100 and of preventing muscle protein loss which occurs in humans during bed rest.101 Milk proteins, whey and casein are high-quality proteins but produce a different response in young and in older people: whey is digested faster than casein and produces a relatively better response on protein balance in older people.102,103 In a long-term study of elderly sarcopenic persons104 the provision of 8 g of essential amino acids per day over 18 months increased muscle mass, reduced tumor necrosis factor-α, and improved insulin sensitivity. The optimal nitrogen supply for cancer patients cannot be determined at present but recommendations (expert opinion) for malnourished cancer patients range between a minimum protein supply of 1 g/kg/day 104 and a target supply of 1.2–2 g/kg/day.105–107

7.

Towards an Integrated Approach

Since cancer cachexia, as well as sarcopenia, cannot be equaled to simple undernutrition, and results with an appropriate nutritional intervention in adults/elderly cancer

181

patients may only partially prevent a further nutritional deterioration but do not restore the nutritional status, recent research is focusing on a combined approach, namely the association of nutritional support with exercise and or anabolic/anticatabolic agents. Unfortunately most of the available results are from shortterm experimental investigations in healthy elderly volunteers or in patients with sarcopenia. Exercise is known to increase muscle mass in elderly subjects,108 however this approach can be fully adopted only in patients who are not severely ill. Providing amino acids immediately before or after exercise can increase muscle protein synthesis by approximately 2.5 times greater than the effect from exercise alone.109,110 In the elderly, consumption of protein should be done immediately after exercise to realize some benefit.109–111 Fiatarone et al.112 have shown that nutrient supplements without concomitant exercise do not reduce physical frailty and consumption of whey protein supplements are able to increase the muscle strengthening effects of resistance exercise.113,114 Bermon et al.115 have demonstrated that a 3-week aerobic training program associated with enteral nutrition better improves the global nutritional deficiency index, serum albumin and prealbumin. Resistance exercise training results in increased muscle strength and size, increased muscle protein accumulation and, consequently, reduced urinary nitrogen loss and overall increased nitrogen retention.116 Some authors have shown that growth hormone and testosterone are able to increase muscle mass and in some cases strength in older persons117–122 but clinicians should be cautious with such treatments because of the adverse effects and because the benefit tends to disappear when these agents are withhold. Some authorities also advise on the administration of 50000 UI of vitamin D upon hospital admission.

7.1.

Enteral Nutrition

7.1.1.

Oral Supplements

Oral treatment is the preferred approach when swallowing is possible and the gut is working. Research did not always support the role of dietary counseling in treatment of weight loss. A systematic review by Baldwin et al.123 showed lack of evidence in support of the use of dietary advice to manage malnutrition but a larger benefit from oral nutritional supplements. However more recent data 124–126 showed that there was less loss of weight and lean body mass, and less deterioration in nutritional status, quality of life, and physical functioning in cancer patients undergoing oncologic therapy who received nutritional counseling compared with those who do not. A recent Cochrane analysis127 on the effects of oral supplements evaluated a total of 10,187 randomized participants from the 62 trials. The authors suggested that supplementation appears to produce a small but consistent weight gain. There was no evidence of a beneficial effect on mortality overall, but there may be a beneficial effect on mortality in some groups of patients. The results of mortality were statistically significant when participants were undernourished, at least

182

J O U RN A L O F GE RI A TR IC O NC O LOG Y 2 ( 2 01 1 ) 1 7 7 –18 6

400 kcal were offered per day in the supplement, patients were ≥75 years old, and when supplementation was continued for longer than 35 days. Supplementation may also reduce the number of complications. The reported acceptance of supplements was variable between trials and some adverse effects such as nausea or diarrhea were reported. The administration of oral supplements represents a particular challenge to relatives, nurses and physicians because the compliance with oral supplements by elderly patients is only about 52% and even less in elderly cancer patients and in those receiving an oncologic treatment. Factors affecting compliance were: failure of delivery to patients, lack of staff supervision, excessive volume prescribed, nausea, palatability and taste, and cancer anorexia. Potter et al.128 described close to 100% compliance when supplements were administered under nursing supervision on drug rounds.

7.1.2.

Tube Feeding

The effectiveness of tube feeding on nutritional status may be compromised by poor compliance with the tubes and by side effects. Many tube fed patients are bedridden and consequent immobility further enhances muscle wasting and prevents gain in lean body mass. Weighing the patient may also be problematic.

7.2.

Parenteral Nutrition

ESPEN Guidelines129 support the tenet that age per se is not a reason for excluding patients from parenteral nutrition (PN). In a British survey on PN in Northern England the median age of PN patients was 67 years.130 Elderly patients represent 22% of the cancer patients receiving home parenteral nutrition (HPN) according to the North America HPN registry131 even if survival, rehabilitation and capacity to resume oral food intake were clearly age-dependent. Older age was associated with a higher risk of central catheter vascular erosion132 but not of bloodstream infections.133 As we noticed for enteral nutrition the effects of PN on the nutritional status are weaker for elderly patients compared to younger patients. A study in 325 surgical patients on PN has reported that with a similar nutritional intake, depleted body cell mass was restored more slowly in older patients134 but Volpi et al.92 recently showed that muscle is able to respond to a load of intravenous amino acids with increased protein synthesis and that oral and intravenously administered amino acids produce similar effects on muscle protein synthesis in the elderly.135

7.3.

Clinicians are aware that an optimal nutritional support is unable to reverse a status of both sarcopenia and cachexia, that it can only prevent a further acute nutritional deterioration and that this condition should be faced with a combined approach: nutritional, pharmacologic and perhaps rehabilitative. Unfortunately current research in this field does not discriminate young, adult and elderly patients and actually investigations on new anabolic/anticatabolic agents (namely nonsteroidal anti-inflammatory drugs, n−3 fatty acids, anabolic steroids) have not come up to the clinicians' expectations because of the limited benefits, potential adverse effects with long-term administration and poor compliance of such products. This does not imply that an optimal nutritional regimen can be neglected in these patients even though we know it relies more on physiologic than pathophysiologic basis. Moreover we cannot expect any success from any new pharmacologic or a rehabilitative approach if these measures are applied on subjects who are not adequately fed. Thus we can actually summarize the best approach for the malnourished elderly patient in the following steps: - Early intervention, when the clinical picture shows an impending deterioration of the nutritional status or when the natural history of the disease suggests an evolution toward a progressive wasting. In such conditions it is easier to ameliorate the protein-energy intake with non-invasive measures (dietary counseling, anti-anorectic agents, oral supplementation). Such an early intervention requires that oncologists should be alerted to screen the nutritional status not only in hospitalized patients but also in outpatients when an unexpectedly high rate of malnutrition can be detected.45,136 - The nutritional regimen must be optimized especially in the case of total artificial (enteral, parenteral, or mixed) nutrition, through the use of water/sodium restricted and lipid- and protein-enriched admixtures, as reported in the previous sections. The oral/enteral route should be privileged but intravenous supplementation is quite practical especially if patients already harbor a central venous catheter, oral alimentation cannot be further forced and if tube feeding is refused. - Finally, the prudent use of anabolic/anticatabolic agents should be considered by following the same recommendations reported for adult cancer patients.78,137 The efficacy of these agents is controversial and we cannot expect any benefit if their administration is not associated with an adequate nutritional regimen.

Future Perspectives and Conclusion

Conflict of Interest Statement The treatment of the malnourished elderly patient with cancer is a challenge. In such subjects there is a coexistence of different pathophysiologic alterations, those due to sarcopenia and those due to cancer cachexia, and a poor nutrient intake frequently represents a common link between them. Certainly a better interexchange of information among oncologists, geriatricians, nutritionists as well as with specialists of sport medicine would help to set up an integrated strategy to adopt in these patients.

The author has no conflict of interest. The author states that there was no funding source. REFERENCES

1. Yancik R. Population aging and cancer: a cross-national concern. Cancer J 2005;11:437–441.

J O U RN A L OF GE RI A TR IC O NC O L O G Y 2 ( 2 01 1 ) 1 7 7 –1 86

2. US Census Bureau: US interim projections by age, sex, race, and Hispanic origin; 2004. http://www.census.gov/ipc/www/ usinterimproj/natprojtab02a.pdf 3. Schneider EL, Guralnik JM. The aging of America: impact on health care costs. JAMA 1990;263:2335–2340. 4. National Cancer Institute: Surveillance, Epidemiology, and End Results (SEER) 17 Registry (2000–2003): Age-Adjusted Incidence Rates. Bethesda, MD, National Cancer Institute www.seer.cancer.gov/csr. 5. Havlik RJ, Yancik R, Long S, et al. The National Cancer Institute on Aging and the National Cancer Institute SEER collaborative study on comorbidity and early diagnosis of cancer in the elderly. Cancer 1994;74(suppl 7):2101–2106. 6. Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older patients. J Clin Oncol 2007;25:1908–1915. 7. Cooper SC, Day R, Brooks C, Livings C, Thomson CS, Trudgill NJ. The influence of deprivation and ethnicity on the incidence of esophageal cancer in England. Cancer Causes Control Oct 2009;20(8):1459–1467 Epub 2009 Jun 17. 8. Ries LAG, Eisner MP, Kosary CL, et al: SEER Cancer Statistics Review 1975–2000. http://seer.cancer.gov/csr/1975-2000 9. Gridelli C, Perrone F, Monfardini S. Lung cancer in the elderly. Eur J Cancer 1997;33:2313–2314. 10. Thieblemont C, Coiffier B. Lymphoma in older patients. J Clin Oncol 2007;25:1916–1923, doi:10.1200/JCO.2006.10.5957. 11. Balducci L. Epidemiology of cancer and aging. J Oncol Manage 2005;14:47–54. 12. Yancik R, Ries LAG. Cancer in older persons: an international issue in an ageing world. Semin Oncol 2004;31:128–136. 13. Extermann M. Measuring comorbidity in older cancer patients. Eur J Cancer 2000;36:453–471. 14. Janssen I, Heymsfield SB, Ross R. Low relative skeletal mucle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc 2002;50:889–896. 15. Guralnik JM, Ferrucci L, Pieper CF, Leveille SG, Markides SK, Ostir GV, et al. Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. J Gerontol Biol Sci Med Sci 2000;55:221–231. 16. Kortebein P, Ferrando A, Lombeida J, Wolfe R, Evans WJ. Effect of 10 days of bed rest on skeletal muscle in healthy older adults. JAMA 2007 Apr 25;297(16):1772–1774. 17. Paddon-Jones D, Sheffield-Moore M, Urban RJ, Sanford AP, Aarsland A, Wolfe RR, et al. Essential amino acid and carbohydrate supplementation ameliorates muscle protein loss in humans during 28 days bedrest. J Clin Endocrinol Metab 2004 Sep;89(9):4351–4358. 18. Cuthbertson D, Smith K, Babraj J, Leese G, Waddell T, et al. Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB J Mar 2005;19(3):422–424 Epub 2004 Dec 13. 19. Rennie MJ, Edwards RH, Halliday D, Matthews DE, Wolman SL, Millward DJ. Muscle protein synthesis measured by stable isotope techniques in man: the effects of feeding and fasting. Clin Sci (Lond) 1982 Dec;63(6):519–523. 20. Biolo G, Ciocchi B, Lebenstedt M, Barazzoni R, Zanetti M, Platen P, et al. Short-term bed rest impairs amino acid-induced protein anabolism in humans. J Physiol Jul 15 2004;558(Pt 2):381–388 Epub 2004 May 6. 21. Aparicio T, Girard L, Bouarioua N, Patry C, Legrain S, Soulé JC. A mini geriatric assessment helps treatment decision in elderly patients with digestive cancer. A pilot study. Crit Rev Oncol Hematol Jan 2011;77(1):63–69 Epub 2010 Jan 29. 22. Corti M-C, Guralnik JM, Salive ME, Sorkin JD. Serum albumin level and physical disability as predictors of mortality in older persons. JAMA 1994;272:1036–1042. 23. Fried LP, Kronmal RA, Newman AB, et al. Risk factors for 5-year mortality in older adults. JAMA 1998;279:585–599.

183

24. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med 2001;56: M134–M135. 25. Gill T, Gahbauer EA, Allore HG, et al. Transitions between frailty states among community-living older persons. Arch Intern Med 2006;166:418–423. 26. Stauder R, Moser K, Holzner B, Sperner-Unterweger B. Kemmler G Six independent domains are defined by geriatric assessment in elderly cancer patients. Crit Rev Oncol Hematol 2010;74:97–105. 27. Miller Mark D, Towers A. A manual of guidelines for scoring the cumulative illness rating scale for geriatrics (CIRS)-G; May 1991. 28. Karnofsky DA, Abelmann WH, Craver LF, Burchenal A. The use of nitrogen mustards in the palliative treatment of carcinoma. Cancer 1984;1:634–656. 29. Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. Maryland State Med J 1965;21:61–65. 30. Lawton MP, Brody EM. Instrumental activities of daily living scale (IADL). Gerontologist 1969;9:179–186. 31. Reuben DB, Albert LS. An objective measure of physical function of elderly outpatients. JAGS 1990;38:1105–1112. 32. Sherman SE, Reuben D. Measures of functional status in community dwelling elders. J Gen Intern Med 1998;13:817–823. 33. Saliba D, Elliott M, Rubenstein LZ, et al. The vulnerable elders survey: a tool for identifying vulnerable older people in the community. JAGS 2001;49:1691–1699. 34. Cella David F, Tulsky DS, Gray G, et al. The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol 1993;11(3): 570–579. 35. Overcash J, Extermann M, Parr J, Perry J, Balducci L. Validity and reliability of the FACT-G Scale for use in the older person with cancer. J Clin Oncol 2001;24(6):591–596. 36. Yesavage Jerome A, Brink TL. Development and validation of a Geriatric Depression Screening Scale: a preliminary report. J Psychiat Res 1983;17(1):37–49. 37. Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method for grading the state of patients for the clinician. J Psychiat Res 1975;12:189–198. 38. Charlson Mary E, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic co morbidity in longitudinal studies: developing and validation. J Chron Dis 1987;40(5): 373–383. 39. Bozzetti F, Migliavacca S, Scotti A, Bonalumi MG, Scarpa D, Baticci F, et al. Impact of cancer, type, site, stage and treatment on the nutritional status of patients. Ann Surg 1982 Aug;196(2):170–179. 40. Paillaud E, Caillet P, Campillo B, et al. Increased risk of alteration of nutritional status in hospitalized elderly patients with advanced cancer. J Nutr Health Aging 2006;10:91–95. 41. Lecleire S, Di Fiore F, Antonietti M, et al. Undernutrition is predictive of early mortality after palliative self-expanding metal stent insertion in patients with inoperable or recurrent esophageal cancer. Gastrointest Endosc 2006;64:479–484. 42. Blanc-Bisson C, Fonck M, Rainfray M, Soubeyran P, Bourdel-Marchasson I. Undernutrition in elderly patients with cancer: target for diagnosis and intervention. Crit Rev Oncol Hematol 2008;67:243–254. 43. Hurria A, Gupta S, Zauderer M, Zuckerman EL, Cohen HJ, Muss H, et al. Kornblith ABC developing a cancer-specific geriatric assessment: a feasibility study. Cancer 2005 Nov 1;104(9):1998–2005. 44. Girre V, Falcou MC, Gisselbrecht M, Gridel G, Mosseri V, Bouleuc C, et al. Does a geriatric oncology consultation modify the cancer treatment plan for elderly patients? J Gerontol A Biol Sci Med Sci 2008 Jul;63(7):724–730. 45. Mariani L, Lo Vullo S, Bozzetti F on behalf of the SCRINIO Working Group. Weight loss in cancer patients: a plea for a better awareness of the issue. 2011 Jan 6 PMID:21210155.

184

J O U RN A L O F GE RI A TR IC O NC O LOG Y 2 ( 2 01 1 ) 1 7 7 –18 6

46. Kondrup J, Rasmussen HH, Hamberg O, Stanga Z. Ad hoc ESPEN Working Group Nutrition risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials. Clin Nutr 2003;22:321–326. 47. Kondrup J, Allison SP, Elia M, et al. ESPEN guidelines for nutrition screening 2002. Clin Nutr 2003;22:415–421, doi: 10.1016/S0261-5614(03)00098-. 48. Norman K, Stobäus N, Smoline C, Zocher D, Scheufele R, Valentini L, et al. Determinants of hand grip strength, knee extension strength and functional status in cancer patients. Clin Nutr 2010;29:586–591. 49. Kastritis E, Bamias A, Bozas G, Koutsoukou V, Voulgaris Z, Vlahos G, et al. The impact of age in the outcome of patients with advanced or recurrent cervical cancer after platinum-based chemotherapy. Gynecol Oncol Feb 2007;104(2): 372–376 Epub 2006 Oct 9. 50. Pasetto LM, Rossi E, Jirillo A, Monfardini S. Colorectal cancer adjuvant treatment in elderly patients. Crit Rev Oncol Hematol 2005;55:201–206. 51. Colorectal Cancer Collaborative Group Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. BMJ 2000;321:531–535. 52. Gridelli C, Aapro M, Ardizzoni A, et al. Treatment of advanced non small- cell lung cancer in the elderly: results of an international expert panel. J Clin Oncol 2005;23:3125–3137. 53. Goldberg RM, Tabah-Fisch I, Bleiberg H, et al. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/ leucovorin administered bimonthly in elderly patients with colorectal cancer. J Clin Oncol 2006;24:4085–4091. 54. Bouvier AM, Launoy G, Lepage C, Faivre J. Trends in the management and survival of digestive tract cancers among patients aged over 80 years. Aliment Pharmacol Ther 2005;22: 233–241. 55. Aparicio T, Navazesh A, Boutron I, Bouarioua N, Chosidow D, Miond M, et al. Half of elderly patients routinely treated for colorectal cancer receive a sub-standard treatment. Crit Rev Oncol Hematol 2009;71:249–257. 56. Schrag D, Cramer LD, Bach PB, Begg CB. Age and adjuvant chemotherapy use after surgery for stage III colon cancer. J Natl Cancer Inst 2001;93:850–857. 57. Neugut AI, Fleischauer AT, Sundararajan V, et al. Use of adjuvant chemotherapy and radiation therapy for rectal cancer among the elderly: a population-based study. J Clin Oncol 2002;20:2643–2650. 58. Faivre-Finn C, Bouvier AM, Mitry E, Rassiat E, Clinard F, Faivre J. Chemotherapy for colon cancer in a well-defined French population: is it under- or over-prescribed? Aliment Pharmacol Ther 2002;16:353–359. 59. Kurtz JE, Heitz D, Enderlin P, Imbert F, Nehme H, Bergerat JP, et al. Geriatric oncology, general practitioners and specialists: current opinions and unmet needs. Crit Rev Oncol Hematol Jul 2010;75(1):47–57 Epub 2009 Apr 5. 60. Hutchins LF, Unger JM, Crowley JJ, Coltman Jr CA, Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341:2061–2067. 61. Monfardini S, Sorio R, Boes GH, Kaye S, Serraino D. Entry and evaluation of elderly patients in European organization for research and treatment of cancer (EORTC) new-drug-development studies. Cancer 1995;76:333–338. 62. Marenco D, Marinello B, Berruti A, Gaspari F, Stasi B, Rosato RC, et al. Multidimensional geriatric assessment in treatment decision in elderly cancer patients: 6-year experience in an outpatient geriatric oncology service. Crit Rev Oncol Hematol 2008;68:157–164. 63. Gamble JL. The Harvey Lectures, Series XLIII, 1946–1947: physiological information gained from studies on the life raft ration. Nutr Rev 1989 Jul;47(7):199–201. 64. Bloom WL. Inhibition of salt excretion by carbohydrate. Arch Intern Med 1962 Jan;109:26–32.

65. Ferrannini E, De Fronzo RA. Renal handling of insulin in man. Contrib Nephrol 1984;43:49–53. 66. Rudman D, Millikan WJ, Richardson TJ, Bixler 2nd TJ, Stackhouse J, McGarrity WC. Elemental balances during intravenous hyperalimentation of underweight adult subjects. J Clin Invest Jan 1975;55(1):94–104. 67. Fan ST, Lau WY, Wong KK, Chan PM. Preoperative parenteral nutrition in esophageal cancer : a prospective randomized clinical trial. Clin Nutr 1988;8:23–27. 68. Bozzetti F, Ammatuna M, Migliavacca S, Facchetti G, Cozzaglio L, Morabito A. Comparison of glucose versus fat solutions in cancer patients: a controlled cross-over study. Clin Nutr 1990;9:325–330. 69. Gray GE, Meguid MM. Can total parenteral nutrition reverse hypoalbuminemia in oncology patients? Nutrition 1990;6: 225–228. 70. Moser AM, Streeten DHP. Disorders of the neurohypophysis. In: Isselhacher KJ, et al, editor. Harrison's principles of internal medicine. 13th ed. New York: McGraw-Hill; 1994. p. 1921–1930. 71. Steiner N, Bruera E. Methods of hydration in palliative care patients. J Pall Care 1998;14:6–13. 72. Kerndt P, Naughton J, Driscoll G, Loxterkamp A. Fasting: the history, pathophysiology and complications. West J Med 1982;137:379–399. 73. Bruera E, Belzile M, Watanabe S, Fainsinger RL. Volume of hydration in terminal cancer patients. Support Care Cancer Mar 1996;4(2):147–150. 74. Bozzetti F. Nutritional issues in the care of the elderly patient. Crit Rev Oncol Hematol 2003;48:113–121. 75. Arnaud MJ. Effect of water on health. In: Caruba R, Galyez-Cloutier R, editors. Proceedings of the second international symposium on water, human and future. Cannes; 2000. p. 357–366. 76. Chidester JC, Spangler AA. Fluid intake in the institutionalized elderly. J Am Diet Assoc 1997;97:23–28. 77. Persson M, Elmstahl S, R K. Validation of dietary record routine in geriatric patients using doubly labelled water. Eur J Clin Nutr 2000;54:789–796. 78. Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M. ESPEN guidelines on parenteral nutrition: non-surgical oncology. Clin Nutr Aug 2009;28(4):445–454 Epub 2009 May 23. 79. Lindmark L, Bennegård K, Edén E, Svaninger G, Ternell M. Lundholm Thermic effect and substrate oxidation in response to intravenous nutrition in cancer patients who lose weight. Ann Surg Dec 1986;204(6):628–636. 80. Hansell DT, Davies JW, Shenkin A, Burns HJ. The oxidation of body fuel stores in cancer patients. Ann Surg Dec 1986;204(6): 637–642. 81. Gibney E, Elia M, Jebbs SA, Murgatroyd P, Jennings G. Total energy expenditure with small-cell lung cancer: results of a validated study using the bicarbonate-urea method. Metabolism 1997;46:1412–1417 1997. 82. Bencini L, Di Leo A, Pozzesser D, Bozzetti F. Total energy expenditure in patients with advanced solid tumours. A preliminary report. Nutr Ther&Met 2008;26:45–46. 83. Aberg W, Thörne A, Olivecrona T, Nordenström J. Fat oxidation and plasma removal capacity of an intravenous fat emulsion in elderly and young men. Nutrition Jul-Aug 2006;22 (7–8):738–743. 84. Al-Jaouni R, Schneider SM, Rampal P, Hébuterne X. Effect of age on substrate oxidation during total parenteral nutrition. Nutrition Jan 2002;18(1):20–25. 85. Gambardella A, Tortoriello R, Pesce L, Tagliamonte MR, Paolisso G, Varricchio M. Intralipid infusion combined with propranolol administration has favorable metabolic effects in elderly malnourished cancer patients. Metabolism Mar 1999;48(3):291–297.

J O U RN A L OF GE RI A TR IC O NC O L O G Y 2 ( 2 01 1 ) 1 7 7 –1 86

86. Paddon-Jones D, Sheffield-Moore M, Urban RJ, et al. Essential aminoacid and carbohydrate supplementation ameliorates muscle protein loss in humans during 28 days bedrest. J Clin Endocrinol Metab 2004;89:4351–4358. 87. Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR. Aging is associated with diminished accretion of muscle proteins after the ingestion of a small bolus of essential amino acids. Am J Clin Nutr Nov 2005;82(5):1065–1073. 88. Katsanos CS, Chinkes DL, Paddon-Jones D, Zhang XJ, Aarsland A, Wolfe RR. Whey protein ingestion in elderly persons results in greater muscle protein accrual than ingestion of its constituent essential amino acid content. Nutr Res Oct 2008;28(10):651–658. 89. Ferrando AA, Paddon-Jones D, Hays NP, et al. EAA supplementation to increase nitrogen intake improves muscle function during bed rest in the elderly. Clin Nutr 2010;29:18–23. 90. Paddon-Jones D, Rasmussen BB. Dietary protein recommendations and the prevention of sarcopenia. Curr Opin Clin Nutr Metab Care 2009;12:86–90. 91. Symons TB, Sheffield-Moore M, Wolfe RR, Paddon-Jones DJ. A moderate serving of high-quality protein maximally stimulates skeletal muscle protein synthesis in young and elderly subjects. J Am Diet Assoc Sep 2009;109(9):1582–1586. 92. Volpi E, Ferrando AA, Yeckel CW, Tipton KD, Wolfe RR. Exogenous amino acids stimulate net muscle protein synthesis in the elderly. J Clin Invest May 1 1998;101(9):2000–2007. 93. Layman DK. Role of leucine in protein metabolism during exercise and recovery. Can J Appl Physiol 2002;27:646–663. 94. Rieu I, Balage M, Sornet C, et al. Leucine supplementation improves muscle protein synthesis in elderly men independently of hyperaminoacidaemia. J Physiol 2006;575: 305–315. 95. Arnal MA, Mosoni L, Boirie Y, et al. Protein pulse feeding improves protein retention in elderly women. Am J Clin Nutr 1999;69:1202–1208. 96. Wolfe RR, Miller SL, Miller KB. Optimal protein intake in the elderly. Clin Nutr 2008;27:675–684. 97. Evans WJ. Protein nutrition, exercise and aging. J Am Coll Nutr 2004;23:601S–609S. 98. Campbell WW. Synergistic use of higher-protein diets or nutritional supplements with resistance training to counter sarcopenia. Nutr Rev 2007;65:416–422. 99. Sloane PD, Ivey J, Helton M, et al. Nutritional issues in long-term care. J Am Med Dir Assoc 2008;9:476–485. 100. Symons TB, Schutzler SE, Cocke TL, Chinkes DL, Wolfe RR, Paddon-Jones D. Aging does not impair the anabolic response to a protein-rich meal. Am J Clin Nutr Aug 2007;86(2): 451–456. 101. Paddon-Jones D, Rasmussen BB. Dietary protein recommendations and the prevention of sarcopenia. Curr Opin Clin Nutr Metab Care Jan 2009;12(1):86–90 Review. 102. Dangin M, Guillet C, Garcia-Rodenas C, Gachon P, Bouteloup-Demange C, Reiffers-Magnani K, et al. The rate of protein digestion affects protein gain differently during aging in humans. J Physiol Jun 1 2003;549(Pt 2):635–644. 103. Dangin M, Boirie Y, Guillet C, Beaufrère B. Influence of the protein digestion rate on protein turnover in young and elderly subjects. J Nutr Oct 2002;132(10):3228S–3233S Review. 104. Solerte SB, Gazzaruso C, Bonacasa R, et al. Nutritional supplements with oral amino acid mixtures increases whole-body lean mass and insulin sensitivity in elderly subjects with sarcopenia. Am J Cardiol 2008;101:69E–77E. 105. Nitenberg G, Raynard B. Nutritional support of the cancer patient: issues and dilemmas. Crit Rev Oncol Hematol 2000;34 (3):137–168. 106. Barrera R. Nutritional support in cancer patients. J Parenteral Enteral Nutrition JPEN 2002;26(5 Suppl):563–571. 107. Baracos VE. Meeting the aminoacid requirements for protein anabolism in cancer cachexia. In: Mantovani G, editor.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

185

Cachexia and wasting. A modern approach. Springer Milan; 2006. p. 631–634. Hasten DL, Pak-Loduca J, Obert KA, Yarasheski KE. Resistance exercise acutely increases MHC and mixed muscle protein synthesis rates in 78–84 and 23–32-year-olds. Am J Physiol Endocrinol Metab 2000;78:E620–E626. Biolo G, Tipton KD, Klein S, Wolfe RR. An abundant supply of amino acids enhances the metabolic effect of exercise on muscle protein. Am J Physiol Jul 1997;273(1 Pt 1): E122–E129. Biolo G, Maggi SP, Williams BD, Tipton KD, Wolfe RR. Increased rates of muscle protein turnover and amino acid transport after resistance exercise in humans. Am J Physiol Mar 1995;268(3 Pt 1):E514–E520. Esmarck B, Andersen JL, Olsen S, Richter EA, Mizuno M, Kjaer M. Timing of postexercise protein intake is important for muscle hypertrophy with resistance training in elderly humans. J Physiol Aug 15 2001;535(Pt 1):301–311. Fiatarone MA, O'Neill EF, Ryan ND, Clements KM, Solares GR, Nelson ME, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 1994;330:1769–1775. Hays NP, Kim H, Wells AM, et al. Effects of whey and fortified collagen hydrolysate protein supplements on nitrogen balance and body composition in older women. J Am Diet Assoc 2009;109:1082–1087. Paddon-Jones D, Sheffield-Moore M, Katsanos CS, et al. Differential stimulation of muscle protein synthesis in elderly humans following isocaloric ingestion of amino acids or whey protein. Exp Gerontol 2006;41:215–219. Bermon S, HeÂbuterne X, Peroux J-L, Marconnet P, Rampal P. Correction of protein-energy malnutrition in older adults: effects of a short-term aerobic training program. Clin Nutr 1997;16:291–298. Larsson J, Unosson M, Ek A-C, Nilsson L, Thorslund S, Bjurulf P. Effects of dietary supplementation on nutritional status and clinical outcome in 501 geriatric patients ± a randomized study. Clin Nutr 1990;9:179–184. Onder G, Della Vedova C, Landi F. Validated treatments and therapeutics prospectives regarding pharmacological products for sarcopenia. J Nutr Health Aging 2009;13:746–756. Hoffman JR, Kraemer WJ, Bhasin S, et al. Position stand on androgen and human growth hormone use. J Strength Cond Res 2009;23:S1–S59. Kaiser FE, Silver AJ, Morley JE. The effect of recombinant human growth hormone on malnourished older individuals. J Am Geriatr Soc 1991;39:235–240. Wittert GA, Chapman IM, Haren MT, et al. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003;58:618–625. Bhasin S, Storer TW. Anabolic applications of androgens for functional limitations associated with aging and chronic illness. Front Horm Res 2009;37:163–182. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2010;95:639–650. Baldwin C, Parsons T, Logan S. Dietary advice for illness-related malnutrition in adults. Cochrane Database Syst Rev 2001;2:CD002008. Isenring EA, Capra S, Bauer JD. Nutrition intervention is beneficial in oncology outpatients receiving radiotherapy to the gastrointestinal or head and neck area. Br J Cancer 2004;91:447–452. Ravasco P, Monteiro-Grillo I, Camilo ME. Does nutrition influence quality of life in cancer patients undergoing radiotherapy? Radiother Oncol 2003;67:213–220.

186

J O U RN A L O F GE RI A TR IC O NC O LOG Y 2 ( 2 01 1 ) 1 7 7 –18 6

126. Isenring E, Capra S, Bauer J, Davies PS. The impact of nutrition support on body composition in cancer outpatients receiving radiotherapy. Acta Diabetol 2003;40(suppl 1):S162–S164. 127. Milne AC, Potter J, Vivanti A, Avenell A. Protein and energy supplementation in elderly people at risk from malnutrition (Review). Cochrane Database Syst Rev Apr 2009;15(2):CD003288. 128. Potter JM, Roberts MA, Reilly JJ, McColl JH. An evaluation of protein energy supplementation in medically ill admissions to a geritric unit. Proc Nutr Soc 1998;57:88A. 129. Sobotka L, Schneider SM, Berner YN, Cederholm T, Krznaric Z, Shenkin A, et al. ESPEN guidelines on parenteral nutrition: geriatrics. Clin Nutr Aug 2009;28(4):461–466 Epub 2009 May 22. 130. Hearnshaw SA, Thompson NP. Use of parenteral nutrition in hospitals in theNorth of England. J Hum Nutr Diet 2007;20:14–23. 131. Howard L, Malone M. Clinical outcome of geriatric patients in the United States receiving home parenteral and enteral nutrition. Am J Clin Nutr Dec 1997;66(6):1364–1370. 132. Bozzetti F, Mariani L, Bertinet DB, Chiavenna G, Crose N, De Cicco M, et al. Central venous catheter complications in

133.

134.

135.

136.

137.

447 patients on home parenteral nutrition: an analysis of over 100.000 catheter days. Clin Nutr 2002;21:475–485. Walshe C, Phelan D, Bourke J, Buggy D. Vascular erosion by central venous catheters used for total parenteral nutrition. Intensive Care Med 2007;33:534–537. Shizgal HM, Martin MF, Gimmon Z. The effect of age on the caloric requirement of malnourished individuals. Am J Clin Nutr 1992;55:783–789. Rasmussen BB, Wolfe RR, Volpi E. Oral and intravenously administered amino acids produce similar effects on muscle protein synthesis in the elderly. J Nutr Health Aging 2002;6(6): 358–362. Bozzetti F, the SCRINIO Working Group. Screening the nutritional status in oncology: a preliminary report on 1,000 outpatients. Support Care Cancer Mar 2009;17(3):279–284 Epub 2008 Jun 26. Arends J, Bodoky G, Bozzetti F, Fearon K, Muscaritoli M, Selga G, et al. ESPEN guidelines on enteral nutrition: non-surgical oncology. Clin Nutr Apr 2006;25(2):245–259 Epub 2006 May 12.