ESPEN Guidelines on Parenteral Nutrition:Non-surgical oncology
F.Bozzetti a ,J.Arends b ,K.Lundholm c ,A.Micklewright d ,
G.Zurcher e ,M.Muscaritoli f
a
Department of Surgery,General Hospital of Prato,Prato,Italy
b
Departments of Medical Oncology,Tumor Biology Center,Albert-Ludwigs-University,Freiburg,Germany c
Departments of Surgery,Goteborg University,Goteborg,Sweden d
Department of Dietetics and Nutrition,Queen’s Medical Center,University Hospital NHS Trust,Nottingham,UK e
Departments of Internal Medicine,University of Freiburg,Freiburg,Germany f
难忘的夏天
Departments of Clinical Medicine,University of Rome La Sapienza,Rome,Italy
a r t i c l e i n f o
Article history:
Received 4February 2009Accepted 14April 2009重走红军路
Keywords:Cachexia Cancer
Chemotherapy guideline Clinical practice Energy expenditure Evidence-bad Guideline
Glutamine hematopoietic stem cell transplantation预防事故
Intravenous nutrition Malnutrition Oncology
Parenteral nutrition Radiotherapy Chemotherapy Surgery
Tumor growth Undernutrition
s u m m a r y
Parenteral nutrition offers the possibility of increasing or ensuring nutrient intake in patients in whom
normal food intake is inadequate and enteral nutrition is not feasible,is contraindicated or is not accepted by the patient.
The guidelines are intended to provide evidence-bad recommendations for the u of parenteral nutrition in cancer patients.They were developed by an interdisciplinary expert group in accordance with accepted standards,are bad on the most relevant publications of the last 30years and share many of the conclusions of the ESPEN guidelines on enteral nutrition in oncology.
Under-nutrition and cachexia occur frequently in cancer patients and are indicators of poor prognosis and,per ,responsible for excess morbidity and mortality.Many indications for parenteral nutrition parallel tho for enteral nutrition (weight loss or reduction in food intake for more than 7–10days),but only tho who,for whatever reason cannot be fed orally or enterally,are candidates to receive paren-teral nutrition.A standard nutritional regimen may be recommended for short-term parenteral nutrition,while in cachectic patients receiving intravenous feeding for veral weeks a high fat-to-gluco ratio may be advid becau the patients maintain a high capacity to metabolize fats.The limited nutri-tional respon to the parenteral nutrition reflects more the prence of metabolic derangements which are characteristic of the cachexia syndrome (or merely the short duration of the nutritional support)rather than the inadequacy of the nutritional regimen.Perioperative
parenteral nutrition is only rec-ommended in malnourished patients if enteral nutrition is not feasible.In non-surgical well-nourished oncologic patients routine parenteral nutrition is not recommended becau it has proved to offer no advantage and is associated with incread morbidity.A benefit,however,is reported in patients undergoing hematopoietic stem cell transplantation.Short-term parenteral nutrition is however commonly accepted in patients with acute gastrointestinal complications from chemotherapy and radiotherapy,and long-term (home)parenteral nutrition will sometimes be a life-saving maneuver in patients with sub acute/chronic radiation enteropathy.In incurable cancer patients home parenteral nutrition may be recommended in hypophagic/(sub)obstructed patients (if there is an acceptable performance status)if they are expected to die from starvation/under nutrition prior to tumor spread.
Ó2009European Society for Clinical Nutrition and Metabolism.All rights rerved.
Preliminary remarks
The opportunity has been taken to address what is often considered a controversial area,given the considerable differences in the u of parenteral nutrition (PN)in non-surgical oncology practice around the world.The authors have aimed to prent the data in a format that address common cli
nical problems,and to identify clearly where evidence-bad recommendations can be made.In many cas the evidence ba is not strong and some
recommendations have necessarily been the result of expert connsus.
1.Tumors and nutritional status 1.1.What is cancer cachexia?
From the clinical point of view cancer cachexia is a complex syndrome characterized by a chronic,progressive,involuntary weight loss which is poorly or only partially responsive to stan-dard nutritional support and it is often associated with anorexia,
E-mail address:
.
Contents lists available at ScienceDirect
Clinical Nutrition
journal homepage:
/locate/clnu
0261-5614/$–e front matter Ó2009European Society for Clinical Nutrition and Metabolism.All rights rerved.doi:10.1016/j.clnu.2009.04.011
Clinical Nutrition 28(2009)445–454
early satiety and asthenia.It is usually attributable to two main components:a decread nutrient intake (which may be due to critical involvement of the gastrointestinal tract by the tumor,or to cytoki
nes and similar anorexia-inducing mediators);and metabolic alterations due to the activation of systemic proin-flammatory process .
Resulting metabolic derangements include insulin resistance,incread lipolysis and normal or incread lipid oxidation with loss of body fat,incread protein turnover with loss of muscle mass and an increa in production of acute pha proteins.The systemic inflammatory reaction that develops with many cancers is an important cau of loss of appetite (anorexia)and weight.The syndrome of decread appetite,weight loss,metabolic alterations and an inflammatory state is therefore referred to as cancer cachexia or cancer anorexia-cachexia syndrome.The cytokine-induced metabolic alterations appear to prevent cachectic patients from regaining body cell mass during nutri-tional support,and are associated with a reduced life expectancy,and are not relieved by exogenous nutrients alone .
Attempts to modulate the metabolic changes by other means should be integrated into the management of cancer patients.Nutritional asssment of all cancer patients should begin with tumor diagnosis and be repeated at every visit in order to initiate nutritional intervention early,before the general status is verely compromid and chances to restore a normal condition are few (Grade C).Comments :While weight loss and under-nutrition,both moderate and vere,are frequent
features in patients with malignant dia,many tumor-bearing patients display elevated inflammatory markers.1–4The obrved relea of cytokines,catabolic hormones and further regulatory peptides appears to be a primary reaction of the cancer patient’s host tissues.1–3In addi-tion,substances produced by tumor cells,such as tumor lipid mobilizing factor (LMF)and proteolysis inducing factor (PIF),have been reported to add catabolic signals and further stimulate cytokine production and the acute pha respon.5,6The systemic inflammatory reaction is assumed to be involved in causing loss of appetite 7and body weight 8–11and may facilitate tumor progres-sion.12,13Cytokine-induced metabolic alterations also appear to prevent cachectic patients from regaining body cell mass during nutritional support 14and are associated with a reduced life expectancy.4,6,8,15–17
Impaired gluco tolerance due to insulin resistance was an early finding in cancer patients.18The relation of insulin to catabolic hormones is altered and an incread cortisol cretion as well as a reduced insulin:cortisol ratio are common.2,19As a result,gluco turnover and gluconeogenesis are incread.3Weight loss in cancer patients is accompanied by a loss of fat as well as by enhanced plasma levels of triglycerides.Lipid oxidation can be normal or incread.What caus the alterations in lipid metabolism remains unclear.2However,incread lipolysis is frequently obrved 20,21simultaneously,lipid oxidation is incread 21–23or is in the
high
F.Bozzetti et al./Clinical Nutrition 28(2009)445–454
446
normal range24while gluco oxidation is impaired.The obr-vations may be taken to support recommendations to increa the fat/carbohydrate ratio in feeding cancer patients.
The pro-inflammatory milieu5,25induces skeletal muscle proteolysis3,26resulting in a loss of muscle mass and simulta-neously leads to an incread production of acute pha proteins. The ATP-and ubiquitin-dependent proteosome proteolytic system is activated at an early stage.27,28
Since the metabolic and molecular mechanisms ultimately leading to the phenotypic pattern of the anorexia-cachexia syndrome em to be already operating early in the natural history of the tumor growth and development,oncologists should pay attention to this phenomenon as an event which perhaps could be prevented or at least delayed by means of early pharmacological and nutritional intervention.29
Cachexia cannot be easily differentiated from under-nutrition due to simple starvation:both cachectic
and undernourished patients have lost their body weight and may be anorectic, however,simply undernourished patients show a tendency to save their protein mass,they decrea their resting energy expenditure and they respond quite well to the nutritional support if their general status is not compromid in an irreversible way.On the contrary,cachectic patients have depletion of both the fat and the muscular mass(with prervation of their central protein mass), they fail to adapt their energy requirements to a condition of nutrient deprivation,and they show an inflammatory respon that prevents them from getting substantial benefit from nutri-tional support.Nonetheless a proactive approach can pay divi-dends,as in one study of patients with impending cachexia(weight loss9–10%but nutrient intake>1600kcal/day).Supplementary home PN administered for7–8weeks,when nutrient intake star-ted to decrea to approximately70–80%of the expected level,was associated with a significant expansion of whole body fat, improvement of energy balance and greater exerci capacity if analyzed on the basis of treatment given.30
1.2.Does cancer influence nutritional status?
Yes.Weight loss is frequently thefirst symptom occurring in cancer patients.Depending on the type of primary tumor and stage of dia,weight loss is reported in30%to more than80% of patients and is vere(loss>10%of the usual body weight)in some15%.
Comments:Weight loss preceding tumor diagnosis has been widely reported to occur in31–87%of patients,depending on the site of the primary tumor.31–34A vere involuntary weight loss of more than10%of usual body weight over the previous 6months has already occurred in15%of all patients at the time of diagnosis.31Eighty-five per cent of patients with pancreatic or stomach cancer have lost weight at the time of diagnosis,and in 30%this body weight loss was vere.31Both frequency and verity of weight loss are correlated with tumor stage.35Cancer therapies are associated with anorexia and/or decread food intake and further weight loss if toxicity of treatment outweighs tumor respon,.36,37
1.3.Does nutritional status influence the clinical cour and prognosis?
Yes.Impaired nutritional status is associated with reduced quality of life,lower activity levels,incread treatment-related adver reactions,reduced tumor respon to treatment and reduced survival.Although a cau and effect relationship appears probable this has not yet beenfirmly established.
Comments:Longitudinal studies have demonstrated that the prognosis for cancer patients with weight loss is wor than that for weight-stable patients.Even though tumor stage and unrespon-sive
ness to the oncologic therapy are major prognostic factors for survival,a large body of literature has shown that weight loss is a significant and often independent predictor of decread survival in medical oncologic patients.38–46Depletion of body proteins is also associated with poorer survival.47Malnourished cancer patients have a poorer respon to chemotherapy in respect of both the rate of respon and its duration.34,48–50Furthermore, malnourished cancer patients have higher rates of hospital read-missions,longer hospital stay,51incread symptom distress52and reduced quality of life.34,53In a recent trial total body nitrogen was found to be the most powerful predictor of neutropenia after chemotherapy in breast cancer patients.54Under-nutrition,there-fore,appears to be a marker of dia verity and of poor prog-nosis.A percentage ranging from4to23%of terminal cancer patients ultimately die becau of cachexia.55–58
1.4.Does cancer influence resting energy expenditure?
Frequently yes.Cancer itlf does not have a consistent effect on resting energy expenditure.Oncological treatment,however, may modulate energy expenditure.For practical purpos,and if not measured individually,total daily energy expenditure in cancer patients may be assumed to be similar to healthy subjects, or20–25kcal/kg/day for bedridden and25–30kcal/kg/day for ambulatory patients(Grade C).
Comments:Resting energy expenditure(REE)can be unchanged,incread or decread in relation to the predicted energy expenditure.The energy requirements of cancer patients should therefore be assumed to be normal unless there are specific data showing otherwi.In about25%of patients with active cancer,REE measured by the gold standard method,indirect calo-rimetry,is more than10%higher,and in another25%it is more than 10%lower than predicted energy expenditure.The extent or direction of the error cannot be predicted for individual cas.59,60 In the large experience from the University of Gothenburg, approximately50%of all weight-losing cancer patients were hypermetabolic when compared to appropriate controls with similar physical activity,body composition and age,61and weight loss and hypermetabolism were not compensated by an increa in spontaneous food intake.There is some variability depending on the different types of tumor:some authors report normal REE in patients with gastric and colorectal cancers62,63and higher than expected REE in subjects with pancreatic and lung cancers.63–65 This increa in REE in lung cancer patients is related to the pres-ence of a systemic inflammatory respon.66
However,if we consider the total energy expenditure(TEE) which includes the resting energy expenditure plus the physical activity energy expenditure,this value is usually decread in advanced cancer patients when compared to predicted values for healthy individuals,64,65mainly be
cau of a reduction in physical activity.Recent data67,68from the u of a wearable device,the Sen-Wear armband indicate that TEE of weight-stable leukemic patients and of weight-losing patients with gastrointestinal tumors is about24and28kcal/kg/day,respectively.
There are few and inconsistent data regarding effects of cancer treatments on energy expenditure.Hanll et al.62studied15 patients with colorectal cancer and did not obrve any effects of curative surgery or of hepatic metastas on REE.Fredrix et al.63 compared REE in healthy controls and104patients with gastric or colorectal cancer and40patients with non-small cell lung cancer before and1year after surgery.Subjects with gastrointestinal
F.Bozzetti et al./Clinical Nutrition28(2009)445–454447
cancer had normal REE,which ro slightly after surgery,while lung cancer patients had elevated REE which fell after curative rection,although not if there was tumor recurrence.Chemo-therapy treatment in twelve patients with newly diagnod small cell lung cancer reduced both circulating inflammatory mediators and REE.66
1.5.Do cancer patients require a distinct nutrient profile?
Probably yes.
The majority of ambulatory or hospitalized cancer patients requiring PN for only a short period of time(surgical patients, patients requiring bowel rest for vere gastrointestinal adver effects from chemotherapy or radiation,etc.)do not need any specific formulation.However,special attention should be paid to patients with frank cachexia requiring PN for veral weeks,becau there are abnormalities in energy substrate metabolism in this condition. Pathophysiological and clinical considerations suggest that using a higher than usual percentage of lipid in the 50%of non-protein energy),is beneficial(Grade C).
Comments:Since197169it has been known that fat is efficiently mobilized and utilized as a fuel source in cancer patients.The rationale for the u of fat emulsions in cancer patients stems from veral sophisticated studies reported in the international litera-ture70,71,73–75and relies on the following premis.
Several authors70,71,73,75have reported very efficient mobiliza-tion and oxidation of endogenous fat in the post-absorptive state, ranging from0.7to 1.9g/kg/day,which corresponds to 6.3to 17kcal/kg/day(about60to78%of the resting metabolic expendi-ture)both in weight-stable and weight-losing cancer patients.
After the administration of LCT or LCT/MCT emulsions the lipid clearance(g/kg/day)was reported to be1.4vs.2.3vs.3.5or1.2vs.
1.6vs.
2.1in healthy controls vs.weight-stable vs.weight-losing cancer patients,respectively.
The oxidation rate(g/kg)after infusion of LCT or LCT/MCT emulsions in malnourished cancer patients was reported to be 1.3–1.6or0.62respectively.74
Some investigators are however concerned about the potential toxicity of long-term administration of lipids and suggest limiting administration to no more than1g/kg/day.It is important to point out that the recommendations mainly refer to the experience with soybean oil emulsions,and data with LCT/MCT are more promising.Carpentier et al77reported20patients on HPN receiving mixed emulsions for3–6months and showed good liver tolerance. Simoens et al.78compared plasma triacylglycerol clearance of a lipid emulsion(5:4:1)made of50%MCT,40%LCT,and10%fish oil (wt:wt:wt)to a control(5:5)preparation with50%MCT and50% LCT.Inclusion of10%fish oil in mixed emulsion particles enhanced plasma clearance of infud triacylglycerols(18%,p<0.0001).The faster elimination of5:4:1emulsion appeared related to an enhanced uptake of remnant particles rather tha
n to faster intra-vascular lipolysis.Moreover,each infusion of5:4:1emulsion raid EPA concentration in blood cell phospholipids to reach a7-fold enrichment in platelets and greater than2-fold enrichment in leukocytes after4infusions.
As regards the effects of fat infusion in cancer patients data from literature are scanty.Shaw and Holdaway79reported that the infusion of Intralipid(w29kcal/kg/day)was able to significantly decrea net protein catabolism in patients with lower GI tumors but not upper GI tumors.
梦见被鬼追
A gluco-bad PN may cau positive balance of water and sodium in cancer patients.80–82Insulin,a potent antinaturetic and antidiuretic hormone83is the most probable mediator for this effect.The majority of cancer patients requiring long-term PN are cachectic and hypophagic becau of(sub-acute)intestinal obstruction due to peritoneal carcinomatosis.This condition is often associated with expansion of the extracellular water volume and an overzealous administration of gluco might easily precip-itate a peritoneal effusion which then forces withdrawal of the intravenous nutrition.In addition,the concurrent prence of naua or the administration of morphine,is associated with an excessive production of antidiuretic hormone.
A clinical study in patients undergoing allogeneic bone marrow transplantation for hematologic malig
nancies showed reduced rates of lethal acute graft-versus-host dias when receiving high-LCT parenteral nutrition regimens.84
In conclusion,a one-to-one fat-to-gluco energy ratio might be a nsible standard approach in cancer patients,and higher ratios might be tried when pleural or peritoneal effusions are limiting this approach.
Adver effects reported with LCT emulsions mostly occur when lipid infusion rate are greater than 2.6g/day(that is about 20–24kcal/kg/day),85considerably in excess of the quantities recommended here.
The optimal nitrogen supply for cancer patients cannot be determined at prent.86Recommendations range between a minimum amino acid supply of1g/kg/d86and a target of1.2–2g/ kg/day.87,88
2.Indications for and goals of PN
2.1.What are the specific nutritional goals of PN in cancer patients?
Therapeutic goals for PN in cancer patients are the improve-ment of function and outcome by:
preventing and treating under-nutrition/cachexia,
enhancing compliance with anti-tumor treatments,
controlling some adver effects of anti-tumor therapies,
improving quality of life(Grade C).
PN is ineffective and probably harmful in non-aphagic onco-logical patients in whom there is no gastrointestinal reason for intestinal failure(Grade A).
PN is recommended in patients with vere mucositis or vere radiation enteritis(Grade C).
Comments:There are good reasons for considering PN in cancer care,but its u is justifiable only when there is evidence to demonstrate that it is effective.In general,this evidence is lacking. In the majority of the studies with PN,which failed to achieve nutritional benefit,PN was administered in conventional nutri-tional regimens,and was unable to overcome the metabolic alter-ations characteristic of overt cachexia.PN was generally ud for such limited periods of time(usually in hospitalized patients)that it proved impossible to rever a state of malnutrition which had been prent for many months.In the longer-term studies involving aphagic patients with a non-working gu
t,it would have been ethically unacceptable to have a non-PN control arm,so any prospectively controlled evidence of potential benefit is denied. Therefore it is important to parate the studies investigating the effects of a short-term PN from tho,which are generally more favorable,involving long-term PN.
A widely quoted systematic review and meta-analysis of randomized clinical trials(RCTs)of adjuvant PN versus no PN,per-formed on behalf of the American Gastroenterological Association,89 showed that PN had higher rates of complications and infections and no benefits in oncological outcomes(Level Ia).The conclusions however were criticized becau all the studies dated back to the
F.Bozzetti et al./Clinical Nutrition28(2009)445–454 448
past century,the nutritional regimens were far from what is now considered optimal and,mainly,becau malnutrition and/or aphagia were not absolute criteria for entering the patients in the trials.So the conclusion that PN in cancer patients is uless and probably harmful is valid only if PN is ud as an adjunct to patients who are not malnourished or hypophagic(Level Ia)(Grade A).
No study reported a benefit of PN in preventing side-effects of chemotherapy or radiation therapy,but
when vere mucositis or vere acute radiation enteritis have occurred the efficacy of PN is internationally accepted90(Level II)(Grade C).The value of long-term PN in patients with sub-acute and chronic radiation enter-opathy is well-recognized91,92(Level II)(Grade C)(e also the ESPEN Guidelines on HPN).
2.2.When should PN be started?
Nutritional support should be started if patient is under-nourished or if it is anticipated that the patient will be unable to eat for more than ven days.It should also be started if an inadequate food intake(<60%of estimated energy expenditure)is anticipated for more than10days(Grade C).In such cas if nutritional support for any reason cannot be given through the enteral route,it has to be delivered by vein.A‘‘supplemental’’PN should substitute the difference between the actual oral/enteral intake and the estimated requirements(Grade C).古诗寻隐者不遇
There is no rationale for giving PN if the nutrients intake by oral or enteral route is adequate,and for the reasons PN should not be administered in such conditions(Grade A).
Comments:To demonstrate a reduced intake of normal food, a simple24hour recall is usually sufficient.If this proves difficult in individual cas,it may be appropriate to ask the patient whether hi
s/her nutritional intake is less than50%(low intake)or less than 25%(minimal intake)of their usual intake before the ont of the dia.The u of a visual nutritional atlas is recommended to help the patient quantify his/her daily nutritional intake.
2.3.Can PN maintain or improve nutritional status in cancer patients?
Yes,but only if the nutritional depletion is not extreme.腾讯新闻迷你版
In patients who are losing weight mainly becau of an insufficient nutritional intake,artificial nutritional support should be provided to maintain nutritional status or at least prevent further nutritional deterioration.This may also contribute to the maintenance of quality of life.Any such improvement in the nutritional status is usually modest and is most expected when weight loss is mainly due to hypophagia.In the prence of systemic inflammation,however,it appears to be extremely difficult to achieve whole body protein anabolism in cancer patients.In this situation,in addition to nutritional interventions,pharmacological efforts are recommended to modulate the inflammatory respon(Grade C).
Comments:Short-term experimental studies93–97have shown both the limited efficacy of PN in balancing the metabolism of the cancer patients and the equivalence between PN and EN.Long-ter
m clinical studies are very few,but the experience with HPN98–103 shows that this form of nutritional support is able to maintain the nutritional status of the patients for longer than expected in aphagia.Recent studies by Lundholm et al.30have quantitatively defined some nutritional benefits of long-term PN.Patients who received the planned amounts of energy and nitrogen(given by vein when necessary)had improved energy balance,incread body fat and greater maximum exerci capacity,in addition to prolonged survival when compared to patients randomized to support without PN.
2.4.Is supplementation with special substrates or modulators
beneficial in cancer patients?
Preliminary data suggest a potential positive role of insulin (Grade C).There are no data on n-3fatty acids.
Comments:Lundholm et al.104reported prolonged survival in weight-losing cancer patients who were treated with subcutaneous insulin in addition to optimal nutritional support including PN.
With reference to supplementation with n-3fatty acids,a recent Cochrane systematic review105of the 值得看的小说
published studies on EPA in cancer patients concluded that there was no benefit from the oral administration of EPA in patients with consolidated cachexia.A careful analysis of the studies shows that in at least two of them there were importantflaws(including less EPA administered than prescribed)that could have biad the conclusions according to intention-to-treat.In addition,in another three RCTs the short duration of the study or the inclusion of patients with a primary tumor located in the gastrointestinal tract(and presumably unable to comply with an adequate nutrient intake)could have precluded the demonstration of efficacy of the EPA.It is interesting to speculate that the major restrictions of the oral administration of EPA would be easily overcome if an adequate energy and protein supply combined with n-3fatty acid administration was provided intravenously. Moreover,this review underscores the need for further RCTs addressing the prevention,rather than the treatment of cachexia, with specialized nutritional/pharmacological interventions.
Experience with parenteral EPA is limited to perioperative patients where its short-term administration proved to be safe in respect of hemostasis,106and where it reproduced the expected modulations of the eicosanoids,107,108improved liver and pancre-atic function,109and reduced immunosuppression induced by post-operative chemoradiation therapy.110Furthermore a recent RC
T111 comparing afish oil-containing lipid emulsion with a standard soya-bean oil emulsion reported a significantly shorter length of hospital stay with the enriched PN.
3.PN in special situations
3.1.Is peri-operative PN indicated in cancer patients?
Yes.Perioperative PN is recommended in malnourished candidates for artificial nutrition,when EN is not possible, (Grade A).
Peri-operative PN should not be ud in well-nourished cancer patients(Grade A).
口腔异味的原因和治疗方法
Comments:In weight-losing cancer patients,at least two RCTs112,113have shown that peri-operative EN(with/without immune nutrients)is more effective than perioperative PN. However,if for any reason peri-operative EN is not feasible,peri-operative PN starting7–10days pre-operatively and continuing into the post-operative period,has been shown to be able to decrea complications and/or mortality in two RCTs114,115and in one post hoc analysis116in studies including malnourished cancer patients only.See also ESPEN Guidelines for PN in Surgery.
3.2.Is there an indication for PN during chemotherapy, radiotherapy or combined radio-chemotherap
y?
The routine u of PN during chemotherapy,radiotherapy or combined therapy is not recommended(Grade A).
F.Bozzetti et al./Clinical Nutrition28(2009)445–454449
