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Is the intravenous supplementation of amino acid to cancer patients adequate? A critical appraisal of literature
Clinical Nutrition 32 (2013) 142e146
Contents lists available at SciVerse ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Opinion paper
Is the intravenous supplementation of amino acid to cancer patients adequate? A critical appraisal of literature Federico Bozzetti a, *, Valentina Bozzetti b a b
Faculty of Medicine, University of Milan, 20100 Milano, Italy Neonatal Intensive Care Unit, San Gerardo Hospital, Monza, Italy
a r t i c l e i n f o
s u m m a r y
Article history: Received 10 April 2012 Accepted 3 October 2012
Background & aims: International guidelines are quite vague regarding the optimal doses of amino acid to administer to cancer patients and standard practice appears not to be supported by specific investigations. The purpose of this study is to determine from the literature whether there are some correlates among amino acid infusions and nutritional-metabolic or clinical outcomes. Methods: Through the help of PubMed (www.ncbi.nlm.nih.gov) and the use of a personal database we analysed papers reporting details of infused amino acid and metabolic-nutritional or clinical effects. Results: Five short-term metabolic studies using isotopes showed that infusion of about 2 g amino acid/ kg/day (including high doses of branched chain amino acid) positively affects protein metabolism of severely malnourished cancer patients. In eight studies in less malnourished patients receiving longer periods of parenteral nutrition, to allow the administration of oncologic therapy or to compensate for a decline in oral alimentation, the intravenous addition of 1.5 g amino acid/kg/day to the oral diet achieved positive results. These findings are concordant with recent metabolic results achieved in cancer patients receiving amino acid orally. Conclusion: We think that a higher quantity of parenteral amino acids than that usually administered might be useful to cancer patients and further studies on this issue are warranted. Ó 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Intravenous amino acid in cancer patients Parenteral amino acid in cancer patients Amino acid requirement of cancer patients Protein requirement of cancer patients
1. Introduction A few years after the introduction of intravenous hyperalimentation in clinical practice by S Dudrick in 1968,1 the first reports of its use in oncologic patients appeared in the literature.2 Today, after more than 40 years, the role of parenteral nutrition (PN) in non-surgical cancer patients is still unsettled and opinions on its indication and efficacy are conflicting. Whilst much effort has been devoted to a better understanding of the pathophysiology underlying the progressive weight loss and of the alterations of the energy expenditure of patients with advanced cancer, less attention has been paid to the adequacy of nitrogen to be administered. The most recent guidelines of ASPEN3 do not mention the amino acid (AA) requirement of cancer patients and those of ESPEN4 spend just a few words suggesting that “recommendations range between a minimum protein supply of 1 g/kgBW/day4 and a target supply of 1.2e2 g/kgBW/day5e7”. The purpose of this paper is to investigate, on the basis of the pertinent literature, whether the metabolic or the clinical outcome
* Corresponding author. Tel.: þ39 3297655385; fax: þ39 (0) 226310267. E-mail address: [email protected] (F. Bozzetti).
of cancer patients receiving AA through PN may be related to the quantity or the quality of AA infused. This knowledge could be useful to understand whether the administration of a larger quantity or a different composition of the solutions of AA might potentially translate into a benefit for the patient.
2. Patients and methods We scrutinized the English literature (1970e2011) for published studies concerning parenteral nutrition in non-surgical cancer patients and focussing on nutritional/metabolic or clinical outcomes using PubMed (www.ncbi.nlm.nih.gov). We entered the key words “intravenous infusion of amino acid in cancer patients”, “parenteral infusion of amino acid in cancer patients”, “intravenous administration of amino acid in cancer patients”, “parenteral administration of amino acid in cancer patients”. We only considered full papers which reported information regarding quantity and type of the infused AA and the metabolic/ nutritional or clinical outcome. Furthermore other studies were retrieved from citations of the references of the selected papers as well as a few publications being identified from our personal database. In the few studies where patients received a mixed
0261-5614/$ e see front matter Ó 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. http://dx.doi.org/10.1016/j.clnu.2012.10.017
F. Bozzetti, V. Bozzetti / Clinical Nutrition 32 (2013) 142e146
parenteral and enteral nutrition, the appropriate corrections were made to calculate the overall intake of AA. From an overall number of 498 retrieved papers we finally focused on 18 prospective studies. Our analysis developed in two stages: first we examined whether in metabolic outcome studies there was some correlation between quantity and type of the AA infused and the protein turnover, secondly we analysed in the literature whether there was a correlation between quantity of AA of the PN admixture and the clinical outcome.
143
Table 2 Effects of AA (g/kg/day) on whole body (WBP) and muscular protein (MP) kinetics. AA, g
EAA, g
Author
WBP Synthesis [
2.0
nr-0.5
Y/¼
1.25e1.7
0.34e0.8
-
Shaw et al. 1991 Hyltander et al. 1991 Hyltander et al. 1991 Burt et al. 1984 Bozzetti et al. 2000
nr-0.5e0.8e1.2
-
Shaw et al. 1991 Hyltander et al. 1991 Bozzetti et al. 2000 Jeevanandam et al. 1988
nr-0.8 1.2 0.3e0.5
-Shaw et al. 1991 - Bozzetti et al. 2000 - Jeevanandam et al. 1988, - Hyltander et al. 1991
0.7e0.8
- Bozzetti et al. 2000
Catabolism Y/¼ 1.25e1.7
3. Results Muscle Synthesis [
3.1. Short-term metabolic studies There are a variety of research techniques available to study protein and AA metabolism in man. We focused on whole-body amino acid kinetic studies using stable or unstable isotopes because they can provide significant quantitative information about whole body rates of protein turnover, synthesis, and degradation. In addition, these analyses allow us to understand whether the AA infusion potentially impacts on processes of synthesis or degradation or both. Investigators have also applied isotopic techniques to the evaluation of regional AA kinetics. These methods involve either direct tissue assessment of incorporation of tracer into protein using tissue biopsy or an indirect assessment using more advanced regional kinetic models to evaluate AA incorporation into and release from tissue. A number of papers have examined specific protein kinetic responses to nutritional support8e14 but we consider only those providing the essential details to look for a correlation between quantity and quality of infused AA and the metabolic outcome. Table 1 reports the main characteristics of the series of these studies: often the stage of the tumour was not specifically described but from the reported details most patients appeared to be in stage III or IV. No patient was receiving any kind of oncologic therapy during the period of the study. Table 2 reports the essential data concerning the impact of a different load of AA on protein synthesis and degradation, both in the whole body and in the muscular compartment. From these data it would appear that whole body protein synthesis (WBPS) was increased after the infusion of 2 g AA/kg/day (essential AA ¼ 0.5 g/kg/day) while whole body protein catabolism (WBPC) remained unchanged or decreased with 1.25e1.7 g AA/kg/ day (essential AA ¼ 0.5e1.2 g/kg/day). Similarly the muscle protein synthesis (MPS) was increased or unchanged with 1.4e2 g AA/kg/ day (essential AA ¼ 0.8e1.2 g/kg/day) and muscle catabolism (MPC) was unchanged with 1.4e1.7 g AA/kg/day (essential AA ¼ 0.7e0.8 g/kg/day). Only two studies15,16 from the same laboratory investigated the protein kinetics after an infusion of branched chain amino acid
Table 1 Characteristics of patients and methods in short-term studies. Author
No. Type of pts tumour
Bozzetti et al. 2000 Burt et al. 1984 Hyltander et al. 1991 Jeevanandam et al. 1988 Shaw et al. 1991
3
a
mean value.
WLa
npkcal/ kg/d
Methodology
Gastroenteric
22%
36
L-[
11 12
2 H5] phenylalanine and L-[2H4]tyrosine 15 Oesophagus 16.1% 36 N glycine Miscellaneous 13.6% 26 / 44 L-[U-14C] tyrosine
5
Gastroenteric
18%
29
15
N glycine
43
Miscellaneous 8.4%
24
14
C-leucine
1.4e2.0
¼ 1.25e2.0 Catabolism ¼ 1.4e1.7
nr: not reported. [ means increase; Y means decrease; ¼ means no change.
(BCAA)-enriched PN in gastrointestinal cancer patients who were not receiving any kind of oncologic therapy and presented with a severe weight loss (12.6% and 16% respectively). In these randomized trials Tayek et al.15 and Hunter et al.16 compared a BCAA-enriched (50%) solution (1.2 g total AA/kg/day, 0.6 g BCAA/ kg/day) with an equivalent total AA solution including however only 19% of BCAA (0.2 g BCAA/kg/day). Energy was at 1.3 daily basal energy expenditure. At the end of the infusion period flow rates and volume of infusate were calculated and then the patients were switched to the second formula depending upon the order of randomization. In the first study15 whole body protein turnover was determined by a 10-h continuous infusion of [14C] leucine, whereas in the second study16 both [13C] leucine and [14C] tyrosine were employed as tracers to avoid the potential bias to the different composition of the two parenteral nutrition solutions. The investigators reported that the fractional albumin synthetic rate increased significantly on BCAA-PN from 4.3 2.9 on AA to 8.0 5.1 per cent per day, while the reduction in tyrosine oxidation suggested improved protein synthesis and utilization. These data would seem partially conflicting with the findings by McNurlan et al.17 who reported that the BCAA infused at 0.3 g/kg/day were less effective than conventional intravenous nutrition containing 0.5 g BCAA/kg/day in stimulating protein synthesis in muscle. These last results, however, were obtained in non-malnourished patients. 3.2. Clinical studies These studies include two types of trials: one, aiming to assess a potential nonspecific benefit (lower toxicity, lower morbidity, better compliance and oncologic outcome) of PN in patients receiving aggressive chemotherapy (so called “permissive” PN).18 These patients were not necessarily malnourished or hypophagic and comparisons could be performed in a randomized fashion. In the second type of studies, the authors mainly administered PN to weight-losing and hypophagic patients, consequently randomization was rare and the main end-point of the study was to assess whether PN was able to improve survival together with some parameters of quality of life and of nutritional status (so called “supplemental” PN).18 The first reports investigating the potential efficacy of permissive PN in cancer patients to allow them to receive chemotherapy date back to the early seventies.2,19e23 Unfortunately in these
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papers there is no mention not only of the quantity and type of amino acid infused but also the energy for unit of body weight was not expressed: PN was still “hyperalimentation”! During the following years a series of RCTs were performed, mainly in the United States and data were subsequently summarized in a metaanalysis24 which represented the basis for a position paper of the American Gastroenterological Association.25 On the whole the results were negative (the main reason being that patients receiving PN were not malnourished and possibly they did not need it) and very few of these papers reported the quantities of the infused AA which ranged from 1.026 to 1.327e29 to 1.630,31 g/kg/day. Interestingly, De Cicco et al.32 compared randomly both wellnourished and malnourished cancer patients who receive PN (35 kcal/kg/day, 1.4 g AA/kg/day) or a standard oral diet for a mean period of 13 days during chemotherapy. They found a benefit in prealbumin, retinol-binding protein and nitrogen balance only in the malnourished group receiving PN. Geibig et al.33 studied the effect of 13 days of PN (40 kcal/kg/day) with 1.6 or 2.0 g AA/kg/day in non(severely) malnourished marrow transplants recipients: there was no benefit in clinical outcome but a significantly better nitrogen balance was observed in the patients with higher nitrogen load without a difference in blood urea nitrogen or serum creatinine levels. Finally, Sikora et al.34 showed that patients with esophageal cancer receiving PN support (1e1.5 g AA/kg/day) for 20 days were able to tolerate higher doses of chemoradiation therapy without increased toxicity as compared with a historical group which did not receive PN. More recently two RCTs on long term supplemental home parenteral nutrition (HPN) were published.35,36 In the first Swedish study35 33 non-malnourished patients with testicular carcinoma were randomized to receive HPN (1.5 times their measured caloric need and 1.26 g AA/kg/day) for 2 months during chemotherapy. Total AA intake in HPN group was 1.5 g/kg/day versus 0.7 g/kg/day in the control patients. Despite a significant weight gain in the HPN group there was no improvement in the maximal exercise capacity and in sparing the whole body nitrogen comparing with the control patients. On the contrary the second Swedish study36 involved 309 patients with a mean weight loss 9e10% and with progressive cachexia, who were randomized to HPN or no-HPN when their daily food intake started to decline from 30 to 21e24 kcal/kg. The supplemented group had an estimated total AA intake of 1.4e1.7 g/ kg/day (about 0.8 orally and 0.6e0.9 intravenously) for a median period of 46 days. On an intention-to-treat basis the HPN patients had a significant improvement in energy balance while the astreated analysis demonstrated also a prolonged survival (p < 0.01), improved energy balance (p < 0.001), increased body fat (p < 0.05) and a greater maximum exercise capacity (p < 0.04). In conclusion, it would appear that a long-term intravenous supplementation with 1.5 g AA/kg/day or more in malnourished and hypophagic patients is able to achieve a nutritional and clinical benefit. 4. Discussion In the literature data concerning the relationship between quantity and quality of infused AA and metabolic-nutritional or oncological outcome are scanty and sparse. Our analysis has allowed us to collect two sets of information regarding this issue, those produced by very sophisticated shortterm metabolic studies and those due to clinical trials. The studies on protein kinetics are undoubtedly the most accurate from the metabolic-nutritional point of view because they explore the two components of protein turnover and can also explain which metabolic processes are affected by the
administration of AA. However they are like a snapshot and we have no guarantee that repeating the same measurements after a further period of AA administration would allow us to find the same results. However, some studies have shown that when acute intake of specific nutritional supplements increases muscle protein synthesis, intake of these nutritional supplements for longer periods correlates with improved muscle function.37,38 Hence such approach is preferable to other methods used in the evaluation of the metabolic response of cancer patients to PN. Nitrogen balance is penalized by systematic measurement errors due to underestimation of nitrogen losses (because of incomplete collections of feces and urine and insensible skin losses), while nitrogen intake is commonly overestimated because of unconsumed nutrients especially when they are administered orally.39,40 As a matter of fact data derived from net nitrogen metabolism are only weakly correlated with more direct isotopic studies of protein turnover.41 The use of urinary 3-methylhistidine excretion too, as a research tool, is limited because its tissue specificity has not been defined in man, it does not evaluate protein synthesis, and cannot be used to acutely evaluate factors regulating protein turnover. Clinical studies are obviously also important, but, since in the supplemental PN studies the intravenous AA were added to an unspecified quantity of oral intake of proteins, these results are less accurate than those from studies where the AA intake was exclusively intravenous. However, it should be considered that, thanks to the intravenous extra-supplementation of AA, a higher intake, approaching the ideal protein requirement,6,7 was probably reached in the patients receiving AA by the combined route. Taken together these results seem to suggest that an adequate AA intake could be around 1.8e2 g AA/kg/day because such amount was able to increase WBPS and MPS while maintaining (probably) unchanged the protein catabolism e (Table 2). As regards the composition of the AA solution, data would suggest that BCAA should be given at 0.6 g AA/kg/day and the dosage of EAA should be increased to 1.2 g EAA/kg/day. A recent experimental study (Winter et al, in press in Clinical Nutrition) has confirmed that hyperaminoacidemia due to the intravenous administration of AA is able to activate a normal protein anabolic response in cachectic patients lung cancer patients. A further reason to increase the load of EAA is the observation that the plasma levels of these AA is quite often lower than normal in cancer patients. In fact a recent extensive collective review by Lai et al.42 on 189 patients with cancer of head and neck or of the gastrointestinal tract, that is the patients population which more often requires a nutritional support, showed that the plasma level of all the EAA (except threonine) was always decreased. Finally, these findings are in keeping with the few reports concerning the effect of an oral load of AA. In a short-term metabolic experiment Dillon et al.43 administered 40 g AA (0.67 g/kg) orally in 3 h to six patients with FIGO stage IIIC ovarian cancer having lost more than 10% body weight and reported that despite ongoing therapy and an enhanced inflammatory burden, amino acids were capable of acutely stimulating muscle protein synthesis. Quite recently Deutz et al.44 reported that the oral administration of 40 g of AA (0.48 g/kg) as an oral supplement of a leucine-enriched medical food to advanced non-malnourished cancer patients, significantly increased muscle protein fractional synthesis rate in comparison with the arm randomized to receive 24 g of a conventional medical food. In conclusion, it is well known that the trajectory of the cancer patient towards an overt cachexia evolves through different phases45: initially there is only a mild weight loss, which subsequently worsens and is associated with the presence of systemic symptoms (fatigue, anorexia and early satiety) caused by the same mediators
F. Bozzetti, V. Bozzetti / Clinical Nutrition 32 (2013) 142e146
which are involved in the metabolic derangements including an excessive protein catabolism. When weight loss exceeds 10% of the usual body weight, systemic symptoms are almost invariably present.46 Even if hard data on the optimal protein intake in weight-losing cancer patients are not available in the literature, however the overall findings of the above-mentioned papers would suggest that when patients are severely depleted, as those investigated in shortterm preclinical studies, very high AA intakes (about 2 g/kg/day) according to Shaw et al.14 and Hyltander et al.12 are required to achieve protein replenishment. In less malnourished patients (as those reported in the clinical studies), lower doses, ranging from 1.25 to 1.7 g/kg/day,32,34e36 even if higher than those usually administered, are necessary to compensate for a decline in nutrient intake and to achieve a clinical benefit. This picture parallels the findings in elderly frail patients where increasing protein intake from an average of 0.87 g AA/kg/day to 1.23 g AA/kg/day increased muscle mass47 and increasing dietary protein intake from 0.5 to 1.0, 1.5, and 2.0 g protein/kg/day in elderly malnourished hospitalized patients resulted in progressively greater rates of whole body protein synthesis and improved nitrogen balance.48 Hence, not necessarily the same nutritional regimen applies to both conditions but the worse the nutritional deterioration of the patients, the higher might be the requirement of large amounts of BCAA- and EAA-enriched solutions. It may be that an explanation for the frequent administration of a relatively low quantity of AA in the current standard practice is due both to the poor attention paid to this issue and/or to the unavailability of proper parenteral admixtures: these should have a non-protein calorie to nitrogen ratio 100 to comply with the relatively low resting metabolic expenditure/urinary nitrogen ratio reported in cancer patients during the postabsorbitive status49e52 and an energy density of about 1 kcal/ml to meet the total energy expenditure53e56 and water4 requirements reported in the literature for the advanced oncologic population. This approach might be a reasonable working hypothesis for future specific investigations on this topic both in experimental conditions and in clinical research. Conflict of interest None. References 1. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE. Long-term total parenteral nutrition with growth, development, and positive nitrogen balance. Surgery 1968;64:134e42. 2. Copeland EM, Macfayden Jr BV, Dudrick SJ. Intravenous hyperalimentation in cancer patients. J Surg Res 1974;16:241e7. 3. August DA, Huhmann MB, American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. J Parenter Enteral Nutr 2009 SepeOct;33(5):472e500. 4. Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M. ESPEN guidelines on parenteral nutrition: non-surgical oncology. Clin Nutr 2009 Aug;28(4):445e54 [Epub 2009 May 23]. 5. Nitenberg G, Raynard B. Nutritional support of the cancer patient: issues and dilemmas. Crit Rev Oncol Hematol 2000;34(3):137e68. 6. Barrera R. Nutritional support in cancer patients. J Parenter Enteral Nutr 2002;26(5 Suppl.):563e71. 7. Baracos VE. Meeting the aminoacid requirements for protein anabolism in cancer cachexia. In: Mantovani G, editor. Cachexia and wasting. A modern approach. Milan: Springer; 2006. p. 631e4. 8. Bozzetti F, Gavazzi C, Ferrari P, Dworzak F. Effect of total parenteral nutrition on the protein kinetics of patients with cancer cachexia. Tumori 2000 Sepe Oct;86(5):408e11. 9. Burt ME, Gorschboth CM, Brennan MF. A controlled, prospective randomized trial evaluating the metabolic effects of enteral and parenteral nutrition in the cancer patient. Cancer 1982;49:1092e105.
145
10. Burt ME, Stein TP, Brennan MF. A controlled, randomized trial evaluating the effects of enteral and parenteral nutrition on protein metabolism in cancerbearing man. J Surg Res 1983;34:303e14. 11. Burt ME, Stein TP, Schwade JG, Brennan MF. Whole-body protein metabolism in cancer-bearing patients. Effect of total parenteral nutrition and associated serum insulin response. Cancer 1984;53:1246e52. 12. Hyltander A, Warnold I, Eden E, Lundholm K. Effect on whole-body protein synthesis after institution of intravenous nutrition in cancer. Eur J Cancer 1991;27:16e21. 13. Jeevanandam M, Legaspi A, Lowry SF, Horowitz GD, Brennan MF. Effect of total parenteral nutrition on whole body protein kinetics in cachectic patients with benign or malignant disease. J Parenter Enteral Nutr 1988;12:229e36. 14. Shaw JHF, Humberstone DA, Douglas RG, Korea J. Leucine kinetics in patients with benign disease, non-weight-losing cancer, and cancer cachexia: studies at the whole-body and tissue level and the response to nutritional support. Surgery 1991;109:37e50. 15. Tayek JA, Bistrian BR, Hehir DJ, Martin R, Moldawer LL, Blackburn GL. Improved protein kinetics and albumin synthesis by branched chain amino acid-enriched total parenteral nutrition in cancer cachexia. A prospective randomized crossover trial. Cancer 1986 Jul 1;58(1):147e57. 16. Hunter DC, Weintraub M, Blackburn GL, Bistrian BR. Branched chain amino acids as the protein component of parenteral nutrition in cancer cachexia. Br J Surg 1989 Feb;76(2):149e53. 17. McNurlan MA, Heys SD, Park KG, Broom J, Brown DS, Eremin O, et al. Tumour and host tissue responses to branched-chain amino acid supplementation of patients with cancer. Clin Sci (Lond) 1994 Mar;86(3):339e45. 18. Bozzetti F. Nutritional support in oncologic patients: where we are and where we are going. Clin Nutr 2011 Jul 28;30:714e7. 19. Schwartz GF, Green HL, Bendon ML, Graham 3rd WP, Blakemore WS. Combined parenteral hyperalimentation and chemotherapy in the treatment of disseminated solid tumors. Am J Surg 1971 Feb;121(2):169e73. 20. Lanzotti VJ, Copeland 3rd EM, George SL, Dudrick SJ, Samuels ML. Cancer chemotherapeutic response and intravenous hyperalimentation. Cancer Chemother Rep 1975 MareApr;59(2 Pt 1):437e9. Copeland EM, Macfayden BV Jr., Dudrick SJ. Intravenous hyperalimentation in cancer patients. J Surg Res 1974 Mar;16(3):241e7. 21. Souchon EA, Copeland EM, Watson P, Dudrick SJ. Intravenous hyperalimentation as an adjunct to cancer chemotherapy with 5-fluorouracil. J Surg Res 1975 Apr;18(4):451e4. 22. Copeland 3rd EM, MacFadyen Jr BV, Lanzotti VJ, Dudrick SJ. Intravenous hyperalimentation as an adjunct to cancer chemotherapy. Am J Surg 1975 Feb;129(2):167e73. 23. Copeland 3rd EM, Daly JM, Dudrick SJ. Nutrition as an adjunct to cancer treatment in the adult. Cancer Res 1977 Jul;37:2451e6. 24. Koretz RL, Lipman TO, Klein S. AGA technical review on parenteral nutrition. Gastroenterology 2001;121:970e1001. 25. American Gastroenterological Association medical position statement: parenteral nutrition. Gastroenterology 2001;121:966e9. 26. Clamon GH, Feld R, Evans WK, Weiner RS, Moran EM, Blum RH, et al. Effect of adjuvant central Iv hyperalimentation on the survival and response to treatment of patients with small cell lung cancer: a randomized trial. Cancer Treat Rep 1985;69:167e77. 27. Popp MB, Fisher RI, Wesley R, Aamodt R, Brennan MF. A prospective randomized study of adjuvant parenteral nutrition in the treatment of advanced diffuse lymphoma: influence on survival. Surgery 1981;90:195e203. 28. Popp MB, Fisher RI, Simon RM, Brennan MF. A prospective randomized study of adjuvant parenteral nutrition in the treatment of diffuse lymphoma: effect on drug tolerance. Cancer Treat Rep 1981;65(Suppl. 5):129e35. 29. Samuels ML, Selig DE, Ogden S, Grant C, Brown B. IV hyperalimentation and chemotherapy for stage III testicular cancer: a randomized study. Cancer Treat Rep 1981;65:615e6. 30. Evans WK, Makuch R, Clamon GH, Feld R, Weiner RS, Moran E, et al. Limited impact of total parenteral nutrition on nutritional status during treatment for small cell lung cancer. Cancer Res 1985;45:3347e53. 31. Lawson DH, Nixon DW, Kutner MH, Heymsfield SB, Rudman D, Moffitt S, et al. Enteral versus parenteral nutritional support in cancer patients. Cancer Treat Rep 1981;65(Suppl. 5):101e6. 32. De Cicco M, Panarello G, Fantin D, Veronesi A, Pinto A, Zagonel V, et al. Parenteral nutrition in cancer patients receiving chemotherapy: effects on toxicity and nutritional status. J Parenter Enteral Nutr 1993 NoveDec;17(6): 513e8. 33. Geibig CB, Owens JP, Mirtallo JM, Bowers D, Nahikian-Nelms M, Tutschka P. Parenteral nutrition for marrow transplant recipients: evaluation of an increased nitrogen dose. J Parenter Enteral Nutr 1991 MareApr;15(2):184e8. 34. Sikora SS, Ribeiro U, Kane 3rd JM, Landreneau RJ, Lembersky B, Posner MC. 31. Role of nutrition support during induction chemoradiation therapy in esophageal cancer. J Parenter Enteral Nutr 1998;22:18e21. 35. Hyltander A, Drott C, Unsgaard B, Tölli J, Körner U, Arfvidsson B, et al. The effect on body composition and exercise performance of home parenteral nutrition when given as adjunct to chemotherapy of testicular carcinoma. Eur J Clin Invest 1991 Aug;21(4):413e20. 36. Lundholm K, Daneryd P, Bosaeus I, Korner U, Lindholm E. Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: effects on survival, metabolism and function. Cancer 2004;100:1967e77.
146
F. Bozzetti, V. Bozzetti / Clinical Nutrition 32 (2013) 142e146
37. Ferrando AA, Paddon-Jones D, Hays NP, Kortebein P, Ronsen O, Williams RH, et al. EAA supplementation to increase nitrogen intake improves muscle function during bed rest in the elderly. Clin Nutr 2010;29:18e23. 38. Borsheim E, Bui QU, Tissier S, Kobayashi H, Ferrando AA, Wolfe RR. Effect of amino acid supplementation on muscle mass, strength and physical function in elderly. Clin Nutr 2008;27(2):189e95. PMCID: PMC2430042. 39. Kopple JD. Uses and limitations of the balance technique. J Parenter Enteral Nutr 1987;11:79Se85S. 40. Bier DM. Intrinsically difficult problems: the kinetics of body proteins and amino acids in man. Diabetes Metab Rev 1989;5(11):1e32. 41. Golden M, Waterlow JC, Picou D. The relationship between dietary intake, weight change, nitrogen balance and protein turnover in man. Am J Clin Nutr 1977;30:1345e8. 42. Lai HS, Lee JC, Lee PH, Wang ST, Chen WJ. Plasma free amino acid profile in cancer patients. Semin Cancer Biol 2005 Aug;15(4):267e76. 43. Dillon EL, Volpi E, Wolfe RR, Sinha S, Sanford AP, Arrastia CD, et al. Amino acid metabolism and inflammatory burden in ovarian cancer patients undergoing intense oncological therapy. Clin Nutr 2007 Dec;26(6):736e43. 44. Deutz NE, Safar A, Schutzler S, Memelink R, Ferrando A, Spencer H, et al. Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food. Clin Nutr 2011 Dec;30(6):759e68. 45. Bozzetti F, Mariani L. Defining and classifying cancer cachexia: a proposal by the SCRINIO Working Group. J Parenter Enteral Nutr 2009 JuleAug;33(4):361e7 [Epub 2008 Dec 24]. 46. 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. Support Care Cancer 2012 Feb;20(2):301e9 [Epub 2011 Jan 6]. 47. Chevalier S, Gougeon R, Nayar K, Morais JA. Frailty amplifies the effects of aging on protein metabolism: role of protein intake. Am J Clin Nutr 2003;78:422e9.
48. Bos C, Benamouzig R, Bruhat A, Roux C, Valensi P, Ferriere F, et al. Nutritional status after short-term dietary supplementation in hospitalized malnourished geriatric patients. Clin Nutr 2001;20:225e33. 49. Eden E, Edstrom S, Bennegard K, Schersten T, Lundholm K. Glucose flux in relation to energy expenditure in malnourished patients with and without cancer during periods of fasting and feeding. Cancer Res 1984;44: 1718e24. 50. Lindmark L, Eden E, Ternell M, Bennegard K, Svaninger G, Lundholm K. Thermic effect and substrate oxidation in response to intravenous nutrition in cancer patients who lose weight. Ann Surg 1986;204:628e36. 51. Pirat A, Tucker AM, Taylor KA, Jinnah R, Finch CG, Canada TD, et al. Comparison of measured versus predicted energy requirements in critically ill cancer patients. Respir Care 2009;54:487e94. 52. Richards EW, Long CL, Nelson KM, Tohver OK, Pinkston JA, Navari RM, et al. Protein turnover in advanced lung cancer patients. Metabolism 1993;42: 291e6. 53. Bencini L, Di Leo A, Pozzessere D, Bozzetti F. Total energy expenditure in patients with advanced solid tumours: a preliminary report. Nutr Ther Met 2008;26:45e7. 54. Cereda E, Turrini M, Ciapanna D, Marbello L, Pietrobelli A, Corradi E. Assessing energy expenditure in cancer patients: a pilot validation of a new wearable device. J Parenter Enteral Nutr 2007;31:502e7. 55. Gibney E, Elia M, Jebb SA, Murgatroyd P, Jennings G. Total energy expenditure in patients with small-cell lung cancer: results of a validated study using the bicarbonate-urea method. Metabolism 1997;46(12):1412e7. 56. Moses AW, Slater C, Preston T, Barber MD, Fearon KC. Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids. Br J Cancer 2004;90(5):996e1002.
Contents lists available at SciVerse ScienceDirect
Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu
Opinion paper
Is the intravenous supplementation of amino acid to cancer patients adequate? A critical appraisal of literature Federico Bozzetti a, *, Valentina Bozzetti b a b
Faculty of Medicine, University of Milan, 20100 Milano, Italy Neonatal Intensive Care Unit, San Gerardo Hospital, Monza, Italy
a r t i c l e i n f o
s u m m a r y
Article history: Received 10 April 2012 Accepted 3 October 2012
Background & aims: International guidelines are quite vague regarding the optimal doses of amino acid to administer to cancer patients and standard practice appears not to be supported by specific investigations. The purpose of this study is to determine from the literature whether there are some correlates among amino acid infusions and nutritional-metabolic or clinical outcomes. Methods: Through the help of PubMed (www.ncbi.nlm.nih.gov) and the use of a personal database we analysed papers reporting details of infused amino acid and metabolic-nutritional or clinical effects. Results: Five short-term metabolic studies using isotopes showed that infusion of about 2 g amino acid/ kg/day (including high doses of branched chain amino acid) positively affects protein metabolism of severely malnourished cancer patients. In eight studies in less malnourished patients receiving longer periods of parenteral nutrition, to allow the administration of oncologic therapy or to compensate for a decline in oral alimentation, the intravenous addition of 1.5 g amino acid/kg/day to the oral diet achieved positive results. These findings are concordant with recent metabolic results achieved in cancer patients receiving amino acid orally. Conclusion: We think that a higher quantity of parenteral amino acids than that usually administered might be useful to cancer patients and further studies on this issue are warranted. Ó 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords: Intravenous amino acid in cancer patients Parenteral amino acid in cancer patients Amino acid requirement of cancer patients Protein requirement of cancer patients
1. Introduction A few years after the introduction of intravenous hyperalimentation in clinical practice by S Dudrick in 1968,1 the first reports of its use in oncologic patients appeared in the literature.2 Today, after more than 40 years, the role of parenteral nutrition (PN) in non-surgical cancer patients is still unsettled and opinions on its indication and efficacy are conflicting. Whilst much effort has been devoted to a better understanding of the pathophysiology underlying the progressive weight loss and of the alterations of the energy expenditure of patients with advanced cancer, less attention has been paid to the adequacy of nitrogen to be administered. The most recent guidelines of ASPEN3 do not mention the amino acid (AA) requirement of cancer patients and those of ESPEN4 spend just a few words suggesting that “recommendations range between a minimum protein supply of 1 g/kgBW/day4 and a target supply of 1.2e2 g/kgBW/day5e7”. The purpose of this paper is to investigate, on the basis of the pertinent literature, whether the metabolic or the clinical outcome
* Corresponding author. Tel.: þ39 3297655385; fax: þ39 (0) 226310267. E-mail address: [email protected] (F. Bozzetti).
of cancer patients receiving AA through PN may be related to the quantity or the quality of AA infused. This knowledge could be useful to understand whether the administration of a larger quantity or a different composition of the solutions of AA might potentially translate into a benefit for the patient.
2. Patients and methods We scrutinized the English literature (1970e2011) for published studies concerning parenteral nutrition in non-surgical cancer patients and focussing on nutritional/metabolic or clinical outcomes using PubMed (www.ncbi.nlm.nih.gov). We entered the key words “intravenous infusion of amino acid in cancer patients”, “parenteral infusion of amino acid in cancer patients”, “intravenous administration of amino acid in cancer patients”, “parenteral administration of amino acid in cancer patients”. We only considered full papers which reported information regarding quantity and type of the infused AA and the metabolic/ nutritional or clinical outcome. Furthermore other studies were retrieved from citations of the references of the selected papers as well as a few publications being identified from our personal database. In the few studies where patients received a mixed
0261-5614/$ e see front matter Ó 2012 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. http://dx.doi.org/10.1016/j.clnu.2012.10.017
F. Bozzetti, V. Bozzetti / Clinical Nutrition 32 (2013) 142e146
parenteral and enteral nutrition, the appropriate corrections were made to calculate the overall intake of AA. From an overall number of 498 retrieved papers we finally focused on 18 prospective studies. Our analysis developed in two stages: first we examined whether in metabolic outcome studies there was some correlation between quantity and type of the AA infused and the protein turnover, secondly we analysed in the literature whether there was a correlation between quantity of AA of the PN admixture and the clinical outcome.
143
Table 2 Effects of AA (g/kg/day) on whole body (WBP) and muscular protein (MP) kinetics. AA, g
EAA, g
Author
WBP Synthesis [
2.0
nr-0.5
Y/¼
1.25e1.7
0.34e0.8
-
Shaw et al. 1991 Hyltander et al. 1991 Hyltander et al. 1991 Burt et al. 1984 Bozzetti et al. 2000
nr-0.5e0.8e1.2
-
Shaw et al. 1991 Hyltander et al. 1991 Bozzetti et al. 2000 Jeevanandam et al. 1988
nr-0.8 1.2 0.3e0.5
-Shaw et al. 1991 - Bozzetti et al. 2000 - Jeevanandam et al. 1988, - Hyltander et al. 1991
0.7e0.8
- Bozzetti et al. 2000
Catabolism Y/¼ 1.25e1.7
3. Results Muscle Synthesis [
3.1. Short-term metabolic studies There are a variety of research techniques available to study protein and AA metabolism in man. We focused on whole-body amino acid kinetic studies using stable or unstable isotopes because they can provide significant quantitative information about whole body rates of protein turnover, synthesis, and degradation. In addition, these analyses allow us to understand whether the AA infusion potentially impacts on processes of synthesis or degradation or both. Investigators have also applied isotopic techniques to the evaluation of regional AA kinetics. These methods involve either direct tissue assessment of incorporation of tracer into protein using tissue biopsy or an indirect assessment using more advanced regional kinetic models to evaluate AA incorporation into and release from tissue. A number of papers have examined specific protein kinetic responses to nutritional support8e14 but we consider only those providing the essential details to look for a correlation between quantity and quality of infused AA and the metabolic outcome. Table 1 reports the main characteristics of the series of these studies: often the stage of the tumour was not specifically described but from the reported details most patients appeared to be in stage III or IV. No patient was receiving any kind of oncologic therapy during the period of the study. Table 2 reports the essential data concerning the impact of a different load of AA on protein synthesis and degradation, both in the whole body and in the muscular compartment. From these data it would appear that whole body protein synthesis (WBPS) was increased after the infusion of 2 g AA/kg/day (essential AA ¼ 0.5 g/kg/day) while whole body protein catabolism (WBPC) remained unchanged or decreased with 1.25e1.7 g AA/kg/ day (essential AA ¼ 0.5e1.2 g/kg/day). Similarly the muscle protein synthesis (MPS) was increased or unchanged with 1.4e2 g AA/kg/ day (essential AA ¼ 0.8e1.2 g/kg/day) and muscle catabolism (MPC) was unchanged with 1.4e1.7 g AA/kg/day (essential AA ¼ 0.7e0.8 g/kg/day). Only two studies15,16 from the same laboratory investigated the protein kinetics after an infusion of branched chain amino acid
Table 1 Characteristics of patients and methods in short-term studies. Author
No. Type of pts tumour
Bozzetti et al. 2000 Burt et al. 1984 Hyltander et al. 1991 Jeevanandam et al. 1988 Shaw et al. 1991
3
a
mean value.
WLa
npkcal/ kg/d
Methodology
Gastroenteric
22%
36
L-[
11 12
2 H5] phenylalanine and L-[2H4]tyrosine 15 Oesophagus 16.1% 36 N glycine Miscellaneous 13.6% 26 / 44 L-[U-14C] tyrosine
5
Gastroenteric
18%
29
15
N glycine
43
Miscellaneous 8.4%
24
14
C-leucine
1.4e2.0
¼ 1.25e2.0 Catabolism ¼ 1.4e1.7
nr: not reported. [ means increase; Y means decrease; ¼ means no change.
(BCAA)-enriched PN in gastrointestinal cancer patients who were not receiving any kind of oncologic therapy and presented with a severe weight loss (12.6% and 16% respectively). In these randomized trials Tayek et al.15 and Hunter et al.16 compared a BCAA-enriched (50%) solution (1.2 g total AA/kg/day, 0.6 g BCAA/ kg/day) with an equivalent total AA solution including however only 19% of BCAA (0.2 g BCAA/kg/day). Energy was at 1.3 daily basal energy expenditure. At the end of the infusion period flow rates and volume of infusate were calculated and then the patients were switched to the second formula depending upon the order of randomization. In the first study15 whole body protein turnover was determined by a 10-h continuous infusion of [14C] leucine, whereas in the second study16 both [13C] leucine and [14C] tyrosine were employed as tracers to avoid the potential bias to the different composition of the two parenteral nutrition solutions. The investigators reported that the fractional albumin synthetic rate increased significantly on BCAA-PN from 4.3 2.9 on AA to 8.0 5.1 per cent per day, while the reduction in tyrosine oxidation suggested improved protein synthesis and utilization. These data would seem partially conflicting with the findings by McNurlan et al.17 who reported that the BCAA infused at 0.3 g/kg/day were less effective than conventional intravenous nutrition containing 0.5 g BCAA/kg/day in stimulating protein synthesis in muscle. These last results, however, were obtained in non-malnourished patients. 3.2. Clinical studies These studies include two types of trials: one, aiming to assess a potential nonspecific benefit (lower toxicity, lower morbidity, better compliance and oncologic outcome) of PN in patients receiving aggressive chemotherapy (so called “permissive” PN).18 These patients were not necessarily malnourished or hypophagic and comparisons could be performed in a randomized fashion. In the second type of studies, the authors mainly administered PN to weight-losing and hypophagic patients, consequently randomization was rare and the main end-point of the study was to assess whether PN was able to improve survival together with some parameters of quality of life and of nutritional status (so called “supplemental” PN).18 The first reports investigating the potential efficacy of permissive PN in cancer patients to allow them to receive chemotherapy date back to the early seventies.2,19e23 Unfortunately in these
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papers there is no mention not only of the quantity and type of amino acid infused but also the energy for unit of body weight was not expressed: PN was still “hyperalimentation”! During the following years a series of RCTs were performed, mainly in the United States and data were subsequently summarized in a metaanalysis24 which represented the basis for a position paper of the American Gastroenterological Association.25 On the whole the results were negative (the main reason being that patients receiving PN were not malnourished and possibly they did not need it) and very few of these papers reported the quantities of the infused AA which ranged from 1.026 to 1.327e29 to 1.630,31 g/kg/day. Interestingly, De Cicco et al.32 compared randomly both wellnourished and malnourished cancer patients who receive PN (35 kcal/kg/day, 1.4 g AA/kg/day) or a standard oral diet for a mean period of 13 days during chemotherapy. They found a benefit in prealbumin, retinol-binding protein and nitrogen balance only in the malnourished group receiving PN. Geibig et al.33 studied the effect of 13 days of PN (40 kcal/kg/day) with 1.6 or 2.0 g AA/kg/day in non(severely) malnourished marrow transplants recipients: there was no benefit in clinical outcome but a significantly better nitrogen balance was observed in the patients with higher nitrogen load without a difference in blood urea nitrogen or serum creatinine levels. Finally, Sikora et al.34 showed that patients with esophageal cancer receiving PN support (1e1.5 g AA/kg/day) for 20 days were able to tolerate higher doses of chemoradiation therapy without increased toxicity as compared with a historical group which did not receive PN. More recently two RCTs on long term supplemental home parenteral nutrition (HPN) were published.35,36 In the first Swedish study35 33 non-malnourished patients with testicular carcinoma were randomized to receive HPN (1.5 times their measured caloric need and 1.26 g AA/kg/day) for 2 months during chemotherapy. Total AA intake in HPN group was 1.5 g/kg/day versus 0.7 g/kg/day in the control patients. Despite a significant weight gain in the HPN group there was no improvement in the maximal exercise capacity and in sparing the whole body nitrogen comparing with the control patients. On the contrary the second Swedish study36 involved 309 patients with a mean weight loss 9e10% and with progressive cachexia, who were randomized to HPN or no-HPN when their daily food intake started to decline from 30 to 21e24 kcal/kg. The supplemented group had an estimated total AA intake of 1.4e1.7 g/ kg/day (about 0.8 orally and 0.6e0.9 intravenously) for a median period of 46 days. On an intention-to-treat basis the HPN patients had a significant improvement in energy balance while the astreated analysis demonstrated also a prolonged survival (p < 0.01), improved energy balance (p < 0.001), increased body fat (p < 0.05) and a greater maximum exercise capacity (p < 0.04). In conclusion, it would appear that a long-term intravenous supplementation with 1.5 g AA/kg/day or more in malnourished and hypophagic patients is able to achieve a nutritional and clinical benefit. 4. Discussion In the literature data concerning the relationship between quantity and quality of infused AA and metabolic-nutritional or oncological outcome are scanty and sparse. Our analysis has allowed us to collect two sets of information regarding this issue, those produced by very sophisticated shortterm metabolic studies and those due to clinical trials. The studies on protein kinetics are undoubtedly the most accurate from the metabolic-nutritional point of view because they explore the two components of protein turnover and can also explain which metabolic processes are affected by the
administration of AA. However they are like a snapshot and we have no guarantee that repeating the same measurements after a further period of AA administration would allow us to find the same results. However, some studies have shown that when acute intake of specific nutritional supplements increases muscle protein synthesis, intake of these nutritional supplements for longer periods correlates with improved muscle function.37,38 Hence such approach is preferable to other methods used in the evaluation of the metabolic response of cancer patients to PN. Nitrogen balance is penalized by systematic measurement errors due to underestimation of nitrogen losses (because of incomplete collections of feces and urine and insensible skin losses), while nitrogen intake is commonly overestimated because of unconsumed nutrients especially when they are administered orally.39,40 As a matter of fact data derived from net nitrogen metabolism are only weakly correlated with more direct isotopic studies of protein turnover.41 The use of urinary 3-methylhistidine excretion too, as a research tool, is limited because its tissue specificity has not been defined in man, it does not evaluate protein synthesis, and cannot be used to acutely evaluate factors regulating protein turnover. Clinical studies are obviously also important, but, since in the supplemental PN studies the intravenous AA were added to an unspecified quantity of oral intake of proteins, these results are less accurate than those from studies where the AA intake was exclusively intravenous. However, it should be considered that, thanks to the intravenous extra-supplementation of AA, a higher intake, approaching the ideal protein requirement,6,7 was probably reached in the patients receiving AA by the combined route. Taken together these results seem to suggest that an adequate AA intake could be around 1.8e2 g AA/kg/day because such amount was able to increase WBPS and MPS while maintaining (probably) unchanged the protein catabolism e (Table 2). As regards the composition of the AA solution, data would suggest that BCAA should be given at 0.6 g AA/kg/day and the dosage of EAA should be increased to 1.2 g EAA/kg/day. A recent experimental study (Winter et al, in press in Clinical Nutrition) has confirmed that hyperaminoacidemia due to the intravenous administration of AA is able to activate a normal protein anabolic response in cachectic patients lung cancer patients. A further reason to increase the load of EAA is the observation that the plasma levels of these AA is quite often lower than normal in cancer patients. In fact a recent extensive collective review by Lai et al.42 on 189 patients with cancer of head and neck or of the gastrointestinal tract, that is the patients population which more often requires a nutritional support, showed that the plasma level of all the EAA (except threonine) was always decreased. Finally, these findings are in keeping with the few reports concerning the effect of an oral load of AA. In a short-term metabolic experiment Dillon et al.43 administered 40 g AA (0.67 g/kg) orally in 3 h to six patients with FIGO stage IIIC ovarian cancer having lost more than 10% body weight and reported that despite ongoing therapy and an enhanced inflammatory burden, amino acids were capable of acutely stimulating muscle protein synthesis. Quite recently Deutz et al.44 reported that the oral administration of 40 g of AA (0.48 g/kg) as an oral supplement of a leucine-enriched medical food to advanced non-malnourished cancer patients, significantly increased muscle protein fractional synthesis rate in comparison with the arm randomized to receive 24 g of a conventional medical food. In conclusion, it is well known that the trajectory of the cancer patient towards an overt cachexia evolves through different phases45: initially there is only a mild weight loss, which subsequently worsens and is associated with the presence of systemic symptoms (fatigue, anorexia and early satiety) caused by the same mediators
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which are involved in the metabolic derangements including an excessive protein catabolism. When weight loss exceeds 10% of the usual body weight, systemic symptoms are almost invariably present.46 Even if hard data on the optimal protein intake in weight-losing cancer patients are not available in the literature, however the overall findings of the above-mentioned papers would suggest that when patients are severely depleted, as those investigated in shortterm preclinical studies, very high AA intakes (about 2 g/kg/day) according to Shaw et al.14 and Hyltander et al.12 are required to achieve protein replenishment. In less malnourished patients (as those reported in the clinical studies), lower doses, ranging from 1.25 to 1.7 g/kg/day,32,34e36 even if higher than those usually administered, are necessary to compensate for a decline in nutrient intake and to achieve a clinical benefit. This picture parallels the findings in elderly frail patients where increasing protein intake from an average of 0.87 g AA/kg/day to 1.23 g AA/kg/day increased muscle mass47 and increasing dietary protein intake from 0.5 to 1.0, 1.5, and 2.0 g protein/kg/day in elderly malnourished hospitalized patients resulted in progressively greater rates of whole body protein synthesis and improved nitrogen balance.48 Hence, not necessarily the same nutritional regimen applies to both conditions but the worse the nutritional deterioration of the patients, the higher might be the requirement of large amounts of BCAA- and EAA-enriched solutions. It may be that an explanation for the frequent administration of a relatively low quantity of AA in the current standard practice is due both to the poor attention paid to this issue and/or to the unavailability of proper parenteral admixtures: these should have a non-protein calorie to nitrogen ratio 100 to comply with the relatively low resting metabolic expenditure/urinary nitrogen ratio reported in cancer patients during the postabsorbitive status49e52 and an energy density of about 1 kcal/ml to meet the total energy expenditure53e56 and water4 requirements reported in the literature for the advanced oncologic population. This approach might be a reasonable working hypothesis for future specific investigations on this topic both in experimental conditions and in clinical research. Conflict of interest None. References 1. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE. Long-term total parenteral nutrition with growth, development, and positive nitrogen balance. Surgery 1968;64:134e42. 2. Copeland EM, Macfayden Jr BV, Dudrick SJ. Intravenous hyperalimentation in cancer patients. J Surg Res 1974;16:241e7. 3. August DA, Huhmann MB, American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. J Parenter Enteral Nutr 2009 SepeOct;33(5):472e500. 4. Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M. ESPEN guidelines on parenteral nutrition: non-surgical oncology. Clin Nutr 2009 Aug;28(4):445e54 [Epub 2009 May 23]. 5. Nitenberg G, Raynard B. Nutritional support of the cancer patient: issues and dilemmas. Crit Rev Oncol Hematol 2000;34(3):137e68. 6. Barrera R. Nutritional support in cancer patients. J Parenter Enteral Nutr 2002;26(5 Suppl.):563e71. 7. Baracos VE. Meeting the aminoacid requirements for protein anabolism in cancer cachexia. In: Mantovani G, editor. Cachexia and wasting. A modern approach. Milan: Springer; 2006. p. 631e4. 8. Bozzetti F, Gavazzi C, Ferrari P, Dworzak F. Effect of total parenteral nutrition on the protein kinetics of patients with cancer cachexia. Tumori 2000 Sepe Oct;86(5):408e11. 9. Burt ME, Gorschboth CM, Brennan MF. A controlled, prospective randomized trial evaluating the metabolic effects of enteral and parenteral nutrition in the cancer patient. Cancer 1982;49:1092e105.
145
10. Burt ME, Stein TP, Brennan MF. A controlled, randomized trial evaluating the effects of enteral and parenteral nutrition on protein metabolism in cancerbearing man. J Surg Res 1983;34:303e14. 11. Burt ME, Stein TP, Schwade JG, Brennan MF. Whole-body protein metabolism in cancer-bearing patients. Effect of total parenteral nutrition and associated serum insulin response. Cancer 1984;53:1246e52. 12. Hyltander A, Warnold I, Eden E, Lundholm K. Effect on whole-body protein synthesis after institution of intravenous nutrition in cancer. Eur J Cancer 1991;27:16e21. 13. Jeevanandam M, Legaspi A, Lowry SF, Horowitz GD, Brennan MF. Effect of total parenteral nutrition on whole body protein kinetics in cachectic patients with benign or malignant disease. J Parenter Enteral Nutr 1988;12:229e36. 14. Shaw JHF, Humberstone DA, Douglas RG, Korea J. Leucine kinetics in patients with benign disease, non-weight-losing cancer, and cancer cachexia: studies at the whole-body and tissue level and the response to nutritional support. Surgery 1991;109:37e50. 15. Tayek JA, Bistrian BR, Hehir DJ, Martin R, Moldawer LL, Blackburn GL. Improved protein kinetics and albumin synthesis by branched chain amino acid-enriched total parenteral nutrition in cancer cachexia. A prospective randomized crossover trial. Cancer 1986 Jul 1;58(1):147e57. 16. Hunter DC, Weintraub M, Blackburn GL, Bistrian BR. Branched chain amino acids as the protein component of parenteral nutrition in cancer cachexia. Br J Surg 1989 Feb;76(2):149e53. 17. McNurlan MA, Heys SD, Park KG, Broom J, Brown DS, Eremin O, et al. Tumour and host tissue responses to branched-chain amino acid supplementation of patients with cancer. Clin Sci (Lond) 1994 Mar;86(3):339e45. 18. Bozzetti F. Nutritional support in oncologic patients: where we are and where we are going. Clin Nutr 2011 Jul 28;30:714e7. 19. Schwartz GF, Green HL, Bendon ML, Graham 3rd WP, Blakemore WS. Combined parenteral hyperalimentation and chemotherapy in the treatment of disseminated solid tumors. Am J Surg 1971 Feb;121(2):169e73. 20. Lanzotti VJ, Copeland 3rd EM, George SL, Dudrick SJ, Samuels ML. Cancer chemotherapeutic response and intravenous hyperalimentation. Cancer Chemother Rep 1975 MareApr;59(2 Pt 1):437e9. Copeland EM, Macfayden BV Jr., Dudrick SJ. Intravenous hyperalimentation in cancer patients. J Surg Res 1974 Mar;16(3):241e7. 21. Souchon EA, Copeland EM, Watson P, Dudrick SJ. Intravenous hyperalimentation as an adjunct to cancer chemotherapy with 5-fluorouracil. J Surg Res 1975 Apr;18(4):451e4. 22. Copeland 3rd EM, MacFadyen Jr BV, Lanzotti VJ, Dudrick SJ. Intravenous hyperalimentation as an adjunct to cancer chemotherapy. Am J Surg 1975 Feb;129(2):167e73. 23. Copeland 3rd EM, Daly JM, Dudrick SJ. Nutrition as an adjunct to cancer treatment in the adult. Cancer Res 1977 Jul;37:2451e6. 24. Koretz RL, Lipman TO, Klein S. AGA technical review on parenteral nutrition. Gastroenterology 2001;121:970e1001. 25. American Gastroenterological Association medical position statement: parenteral nutrition. Gastroenterology 2001;121:966e9. 26. Clamon GH, Feld R, Evans WK, Weiner RS, Moran EM, Blum RH, et al. Effect of adjuvant central Iv hyperalimentation on the survival and response to treatment of patients with small cell lung cancer: a randomized trial. Cancer Treat Rep 1985;69:167e77. 27. Popp MB, Fisher RI, Wesley R, Aamodt R, Brennan MF. A prospective randomized study of adjuvant parenteral nutrition in the treatment of advanced diffuse lymphoma: influence on survival. Surgery 1981;90:195e203. 28. Popp MB, Fisher RI, Simon RM, Brennan MF. A prospective randomized study of adjuvant parenteral nutrition in the treatment of diffuse lymphoma: effect on drug tolerance. Cancer Treat Rep 1981;65(Suppl. 5):129e35. 29. Samuels ML, Selig DE, Ogden S, Grant C, Brown B. IV hyperalimentation and chemotherapy for stage III testicular cancer: a randomized study. Cancer Treat Rep 1981;65:615e6. 30. Evans WK, Makuch R, Clamon GH, Feld R, Weiner RS, Moran E, et al. Limited impact of total parenteral nutrition on nutritional status during treatment for small cell lung cancer. Cancer Res 1985;45:3347e53. 31. Lawson DH, Nixon DW, Kutner MH, Heymsfield SB, Rudman D, Moffitt S, et al. Enteral versus parenteral nutritional support in cancer patients. Cancer Treat Rep 1981;65(Suppl. 5):101e6. 32. De Cicco M, Panarello G, Fantin D, Veronesi A, Pinto A, Zagonel V, et al. Parenteral nutrition in cancer patients receiving chemotherapy: effects on toxicity and nutritional status. J Parenter Enteral Nutr 1993 NoveDec;17(6): 513e8. 33. Geibig CB, Owens JP, Mirtallo JM, Bowers D, Nahikian-Nelms M, Tutschka P. Parenteral nutrition for marrow transplant recipients: evaluation of an increased nitrogen dose. J Parenter Enteral Nutr 1991 MareApr;15(2):184e8. 34. Sikora SS, Ribeiro U, Kane 3rd JM, Landreneau RJ, Lembersky B, Posner MC. 31. Role of nutrition support during induction chemoradiation therapy in esophageal cancer. J Parenter Enteral Nutr 1998;22:18e21. 35. Hyltander A, Drott C, Unsgaard B, Tölli J, Körner U, Arfvidsson B, et al. The effect on body composition and exercise performance of home parenteral nutrition when given as adjunct to chemotherapy of testicular carcinoma. Eur J Clin Invest 1991 Aug;21(4):413e20. 36. Lundholm K, Daneryd P, Bosaeus I, Korner U, Lindholm E. Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: effects on survival, metabolism and function. Cancer 2004;100:1967e77.
146
F. Bozzetti, V. Bozzetti / Clinical Nutrition 32 (2013) 142e146
37. Ferrando AA, Paddon-Jones D, Hays NP, Kortebein P, Ronsen O, Williams RH, et al. EAA supplementation to increase nitrogen intake improves muscle function during bed rest in the elderly. Clin Nutr 2010;29:18e23. 38. Borsheim E, Bui QU, Tissier S, Kobayashi H, Ferrando AA, Wolfe RR. Effect of amino acid supplementation on muscle mass, strength and physical function in elderly. Clin Nutr 2008;27(2):189e95. PMCID: PMC2430042. 39. Kopple JD. Uses and limitations of the balance technique. J Parenter Enteral Nutr 1987;11:79Se85S. 40. Bier DM. Intrinsically difficult problems: the kinetics of body proteins and amino acids in man. Diabetes Metab Rev 1989;5(11):1e32. 41. Golden M, Waterlow JC, Picou D. The relationship between dietary intake, weight change, nitrogen balance and protein turnover in man. Am J Clin Nutr 1977;30:1345e8. 42. Lai HS, Lee JC, Lee PH, Wang ST, Chen WJ. Plasma free amino acid profile in cancer patients. Semin Cancer Biol 2005 Aug;15(4):267e76. 43. Dillon EL, Volpi E, Wolfe RR, Sinha S, Sanford AP, Arrastia CD, et al. Amino acid metabolism and inflammatory burden in ovarian cancer patients undergoing intense oncological therapy. Clin Nutr 2007 Dec;26(6):736e43. 44. Deutz NE, Safar A, Schutzler S, Memelink R, Ferrando A, Spencer H, et al. Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food. Clin Nutr 2011 Dec;30(6):759e68. 45. Bozzetti F, Mariani L. Defining and classifying cancer cachexia: a proposal by the SCRINIO Working Group. J Parenter Enteral Nutr 2009 JuleAug;33(4):361e7 [Epub 2008 Dec 24]. 46. 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. Support Care Cancer 2012 Feb;20(2):301e9 [Epub 2011 Jan 6]. 47. Chevalier S, Gougeon R, Nayar K, Morais JA. Frailty amplifies the effects of aging on protein metabolism: role of protein intake. Am J Clin Nutr 2003;78:422e9.
48. Bos C, Benamouzig R, Bruhat A, Roux C, Valensi P, Ferriere F, et al. Nutritional status after short-term dietary supplementation in hospitalized malnourished geriatric patients. Clin Nutr 2001;20:225e33. 49. Eden E, Edstrom S, Bennegard K, Schersten T, Lundholm K. Glucose flux in relation to energy expenditure in malnourished patients with and without cancer during periods of fasting and feeding. Cancer Res 1984;44: 1718e24. 50. Lindmark L, Eden E, Ternell M, Bennegard K, Svaninger G, Lundholm K. Thermic effect and substrate oxidation in response to intravenous nutrition in cancer patients who lose weight. Ann Surg 1986;204:628e36. 51. Pirat A, Tucker AM, Taylor KA, Jinnah R, Finch CG, Canada TD, et al. Comparison of measured versus predicted energy requirements in critically ill cancer patients. Respir Care 2009;54:487e94. 52. Richards EW, Long CL, Nelson KM, Tohver OK, Pinkston JA, Navari RM, et al. Protein turnover in advanced lung cancer patients. Metabolism 1993;42: 291e6. 53. Bencini L, Di Leo A, Pozzessere D, Bozzetti F. Total energy expenditure in patients with advanced solid tumours: a preliminary report. Nutr Ther Met 2008;26:45e7. 54. Cereda E, Turrini M, Ciapanna D, Marbello L, Pietrobelli A, Corradi E. Assessing energy expenditure in cancer patients: a pilot validation of a new wearable device. J Parenter Enteral Nutr 2007;31:502e7. 55. Gibney E, Elia M, Jebb SA, Murgatroyd P, Jennings G. Total energy expenditure in patients with small-cell lung cancer: results of a validated study using the bicarbonate-urea method. Metabolism 1997;46(12):1412e7. 56. Moses AW, Slater C, Preston T, Barber MD, Fearon KC. Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids. Br J Cancer 2004;90(5):996e1002.