A.S.P.E.N. Clinical Guidelines: Nutrition Support Therapy During Adult Anticancer Treatment and in Hematopoietic Cell Transplantation

Nutrition status has an important effect on quality of life and sense of well-being in cancer patients. Malnutrition and weight loss are often contributors to the cause of death in cancer patients.1 Cancer cachexia is a syndrome characterized by progressive, involuntary weight loss. Clinical features include host tissue wasting, anorexia, skeletal muscle atrophy, anergy, fatigue, anemia, and hypoalbuminemia. Causes of cancer cachexia include anorexia, mechanical factors affecting the gastrointestinal tract related to tumor, side effects of surgery, chemotherapy and/or radiation therapy, alterations in intermediary and energy metabolism, and changes in the host cytokine and hormonal milieu. The cancer cachexia syndrome (CCS), which is observed in approximately 50% of cancer patients, involves heterogeneous physiologic and metabolic derangements resulting in potentially life-threatening malnutrition.2 Although often seen in patients with advanced malignancies, CCS may be present in the early stages of tumor growth. Weight loss in cancer patients is of prognostic significance. For any given tumor type, survival is shorter in patients who experience pretreatment weight loss.3-5 Furthermore, CCS is a problematic cause of symptom distress in cancer patients.6,7 Early recognition and intervention to prevent worsening of CCS may afford the best opportunity to prevent its debilitating consequences. Pharmacologic interventions play only a limited role in overcoming the anorexia and metabolic derangements seen in CCS. Research has focused on the use of nutrition support therapy (NST), bypassing oral intake to circumvent CCS related anorexia. Numerous studies, as summarized by Bozetti, have looked at the effect of nutrition support therapy on nutrition parameters in surgical cancer patients.8 Other papers have also examined the use of NST in non-surgical cancer patients.9,10 Parenteral nutrition (PN) consistently causes weight gain, increases body fat, and improves nitrogen balance. The effect of PN on lean body mass is minimal. The effects of enteral nutrition (EN) on body composition are less consistent; EN usually causes weight gain and improves nitrogen balance. Neither EN nor PN, when administered for 7-49 days, have demonstrably beneficial effects on serum proteins. NST has less of an effect on nutrition indices in cancer patients than in non-cancer patients, probably due to the changes that occur in the metabolism of macronutrient substrates in the presence of cancer.8,11 Enthusiasm for the use of NST in cancer patients has historically been tempered by concern that provision of nutrients may stimulate tumor growth and metastasis, as observed in animal studies and cell culture.12 There are few relevant clinical studies.13-17 Most recently, a study of PN in malnourished gastric cancer patients indicated no significant difference in tumor cell proliferation with administration of PN preoperatively.18 Absent any overt effects, it is reasonable to ignore this theoretical consideration when contemplating the use of NST in patients. The purpose of this paper is to examine the literature and develop guidelines only for NST in adult cancer patients (during anticancer treatment and in hematopoietic cell transplantation). Nutrition and cancer prevention or alternative medicine approaches using nutritional supplements in the treatment of cancer is beyond the scope of this paper. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) is an organization comprised of healthcare professionals representing the disciplines of medicine, nursing, pharmacy, dietetics, and nutrition science. The mission of A.S.P.E.N. is to improve patient care by advancing the science and practice of NST. A.S.P.E.N. vigorously works to support quality patient care, education, and research in the fields of nutrition and metabolic support in all healthcare settings. These clinical guidelines were developed under the guidance of the A.S.P.E.N. Board of Directors. Promotion of safe and effective patient care by nutrition support practitioners is a critical role of the A.S.P.E.N. organization. The A.S.P.E.N. Board of Directors has been publishing clinical guidelines since 1986.19-21 Starting in 2007, A.S.P.E.N. has been revising these clinical guidelines on an ongoing basis, reviewing about 20% of the chapters each year in order to keep them as current as possible. These A.S.P.E.N. Clinical Guidelines are based upon general conclusions of health professionals who, in developing such guidelines, have balanced potential benefits to be derived from a particular mode of medical therapy against certain risks inherent with such therapy. However, the professional judgment of the attending health professional is the primary component of quality medical care. Because guidelines cannot account for every variation in circumstances, the practitioners must always exercise professional judgment in their application. These Clinical Guidelines are intended to supplement, but not replace, professional training and judgment. These clinical guidelines were created in accordance with Institute of Medicine recommendations as "systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances."22 These clinical guidelines are for use by healthcare professionals who provide nutrition support services and offer clinical advice for managing adult and pediatric (including adolescent) patients in inpatient and outpatient (ambulatory, home, and specialized care) settings. The utility of the clinical guidelines is attested to by the frequent citation of this document in peer-reviewed publications and their frequent use by A.S.P.E.N. members and other healthcare professionals in clinical practice, academia, research, and industry. They guide professional clinical activities, they are helpful as educational tools, and they influence institutional practices and resource allocation.23 These clinical guidelines are formatted to promote the ability of the end user of the document to understand the strength of the literature used to grade each recommendation. Each guideline recommendation is presented as a clinically applicable statement of care and should help the reader make the best patient care decision. The best available literature was obtained and carefully reviewed. Chapter author(s) completed a thorough literature review using MEDLINE®, the Cochrane Central Registry of Controlled Trials, the Cochrane Database of Systematic Reviews, and other appropriate reference sources. This paper includes older as well as current research related to the use of NST in individuals with cancer. Dates prior to 1990 were not excluded from the analyses, as there are no obvious trends over time to suggest that more modern practice has had an impact on outcome. These results of the literature search and review formed the basis of an evidence-based approach to the clinical guidelines. Chapter editors work with the authors to ensure compliance with the author's directives regarding content and format. Then the initial draft is reviewed internally to ensure consistency with the other A.S.P.E.N. Guidelines and Standards, and externally reviewed (by experts in the field within our organization and/or outside of our organization) for appropriateness of content. The final draft is reviewed and approved by the A.S.P.E.N. Board of Directors. The system used to categorize the level of evidence for each study or article used in the rationale of the guideline statement and to grade the guideline recommendation is outlined in Table 1.24 The grade of a guideline is based on the levels of evidence of the studies used to support the guideline. A randomized controlled trial (RCT), especially one that is double blind in design, is considered to be the strongest level of evidence to support decisions regarding a therapeutic intervention in clinical medicine.25 A systematic review (SR) is a specialized type of literature review that analyzes the results of several RCTs. A high-quality SR usually begins with a clinical question and a protocol that addresses the methodology to answer this question. These methods usually state how the literature is identified and assessed for quality, what data are extracted, how they are analyzed, and whether there were any deviations from the protocol during the course of the study. In most instances, meta-analysis (MA), a mathematical tool to combine data from several sources, is used to analyze the data. However, not all SRs use MA. SR is considered among the most important level of evidence in the field of Evidence-Based Medicine. A level of I, the highest level, will be given to large RCTs where results are clear and the risk of alpha and beta error is low (well-powered). A level of II will be given to RCTs that include a relatively low number of patients or are at moderate-to-high risk for alpha and beta error (under-powered). A level of III is given to cohort studies with contemporaneous controls, while cohort studies with historic controls will receive a level of IV. Case series, uncontrolled studies, and articles based on expert opinion alone will receive a level of V. Table 2 provides the entire set of guidelines recommendations for NST during adult anticancer treatment and in hematopoietic cell transplantation. 1. Patients with cancer are nutritionally-at-risk and should undergo nutrition screening to identify those who require formal nutrition assessment with development of a nutrition care plan. (Grade: D) Rationale: There is clear evidence that nutrition screening with appropriate screening tools will identify cancer patients who are malnourished.26-32 Among the developed screening tools are the patient generated subjective global assessment (PGSGA),27,28 the subjective global assessment (SGA),26,27,30,31 and the nutrition risk index (NRI).30 They all have validated specificity and sensitivity in cancer patients, have been the subjects of prospective clinical trials, and share an emphasis on clinical data. Given the effectiveness of the instruments in detecting malnutrition in cancer patients, it makes sense to utilize these instruments to identify malnutrition and risk of malnutrition. Although there is limited evidence available specifically examining the efficacy of nutrition screening in improving clinical outcomes in cancer patients, the detrimental effects of weight loss on outcomes has been demonstrated.3,33,34 In addition, the benefits of nutrition counseling in cancer patients have been reported.35-38 It seems logical that a formal nutrition screening should be performed in every cancer patient to identify individuals at-risk who require a formal nutrition assessment in an attempt to minimize weight changes and identify individuals who may benefit from further nutrition intervention. Clinical trials are needed to assess the impact of nutrition screening on outcomes in cancer patients. See Table A1. 2. Nutrition support therapy should not be used routinely in patients undergoing major cancer operations. (Grade: A) Rationale: Many studies have investigated the use of NST in patients undergoing major cancer operations, such as resections in the thoracic and abdominal cavities. The use of PN in surgical patients has been studied in prospective, randomized, controlled trials in comparison to standard oral diet (SOD) and EN. Likewise, EN has been examined in relation to SOD. The majority of PN vs SOD41-51 studies find no differences in morbidity41 or mortality,41,48 or even increased morbidity46,47,50 or mortality,42 with the use of PN. Those studies that did indicate benefits from PN tended to include heterogeneous populations43,45 that consisted of both malnourished and well nourished patients. Unfortu nately, some studies reporting benefits also had faulty study designs.44 These studies suggest that PN may be beneficial when used perioperatively in severely malnourished patients; however, PN is not beneficial when used routinely in all patients. Comparisons of PN to EN52-63 also indicate few differences in morbidity53-56,58 or mortality52-54,56 between the modalities. However, EN is favored to preserve gut integrity56,60,64 and immune markers55,57,61,63 and to simplify glycemic management.56,59 Similarly, the majority of studies comparing EN to SOD65-69 indicate no benefit of EN over SOD with respect to morbidity65,66,68,69 and mortality.65,66,68,69 The evidence does not indicate improved outcomes with routine use of NST in all patients undergoing major cancer operations. See Table A2. 3. Perioperative nutrition support therapy may be beneficial in moderately or severely malnourished patients if administered for 7-14 days preoperatively, but the potential benefits of nutrition support must be weighed against the potential risks of the nutrition support therapy itself and of delaying the operation. (Grade: A) Rationale: Studies specifically assessing the use of perioperative NST in moderately or severely malnourished cancer patients, as assessed by the SGA, the PGSGA, or the NRI,41,42,45,46,49,51,52,57 indicate a benefit in morbidity8,45,46,51,52,57 and mortality.8,51,57 These studies began administration of NST 7-14 days preoperatively.46,49,51 See Table A3. 4. Nutrition support therapy should not be used routinely as an adjunct to chemotherapy. (Grade: B) Rationale: Malnutrition can occur in cancer patients starting or receiving chemotherapy as a result of the tumor-induced abnormalities or due to treatment-induced toxicity. Several studies have examined the use of NST during chemotherapy to prevent the development of malnutrition or to mitigate its consequences.64,70-82 When used in this fashion, NST does not reduce chemotherapy-related toxicity70-75,77,78,80,81 and does not improve tumor response70-75,77,78,80,81 or patient survival.70,71,75 All studies were limited by small sample size. Because of an associated increase in the risk of infection with the use of PN in this setting, routine adjunctive use in well-nourished patients receiving chemotherapy is actually deleterious. See Table A4. 5. Nutrition support therapy should not be used routinely in patients undergoing head and neck, abdominal, or pelvic irradiation. (Grade: B) Rationale: Few clinical trials investigating the routine use of NST as an adjunct to radiation therapy in cancer patients have been reported.83-86 One study of upper GI cancer patients indicated less weight loss and fewer treatment interruptions in patients who received EN prior to radiation therapy (XRT).83 Two studies in head and neck cancer patients failed to demonstrate reduced weight loss84; furthermore, worse survival85 was observed in patients who received PN and/or EN before XRT. The role for routine EN, PN, or oral supplement use during head and neck, abdominal, or pelvic irradiation is not clear. The use of NST should be reserved for those patients who are unable to eat as a result of tumor or treatment related side-effects who are becoming progressively malnourished. See Table A5. 6. Nutrition support therapy is appropriate in patients receiving active anticancer treatment who are malnourished and who are anticipated to be unable to ingest and/or absorb adequate nutrients for a prolonged period of time. (Grade: B) Rationale: NST is appropriate in patients receiving active anticancer treatment who are malnourished and who will be unable to absorb adequate nutrients for a prolonged period of time to minimize risk of poor outcomes associated with malnutrition. Seven to fourteen days seems an appropriate definition of "prolonged period of time"; this time period is referred to in many studies, although there are no well designed studies that specifically address this issue. Although no survival benefit with NST intervention has been reported, multiple studies have reported improvements in weight81,83 and nitrogen balance.81,82 The strength of this guideline is tempered by the fact that the best and largest RCT is limited to a head and neck population receiving radiation.85 See Table A6. 7. The palliative use of nutrition support therapy in terminally ill cancer patients is rarely indicated. (Grade: B) Rationale: The palliative use of NST in cancer patients is rarely appropriate, although this issue remains controversial and is emotionally charged. The decision to initiate NST in patients with advanced cancer must include consideration of the patient's and family's wishes, potential risks and benefits, and the patient's estimated survival. The primary objective for initiating NST in advanced cancer patients is to conserve or restore the best possible quality of life and to control any nutrition related symptoms that cause distress.88 There are limited data on the use of PN in palliative care.8,89-96 Although the adverse events caused by PN may actually worsen quality of life and overall palliative care of some patients, home PN may lengthen survival89,92 and improve quality of life in carefully selected patients.90,91,94 Examples of patients who have demonstrated a favorable response to PN include patients with a good performance status, such as Karnofsky score >50, those with inoperable bowel obstruction, those with minimal symptoms from disease involving major organs such as brain, liver, and lungs, and those with indolent disease progression.88,97 If patients are to benefit from this complex, intrusive, and expensive therapy they (1) must be physically and emotionally capable of participating in their own care; (2) should have an estimated life expectancy of >40-60 days; (3) require strong social and financial support at home, including a dedicated in-home lay care provider; and (4) must have failed trials of less invasive medical therapies such as appetite stimulants and enteral feedings.98 Those patients with a life expectancy of <40 days may be palliated with home intravenous fluid therapy, although this is also controversial.88,90,97,99 See Table A7. 8. ω-3 Fatty acid supplementation may help stabilize weight in cancer patients on oral diets experiencing progressive, unintentional weight loss. (Grade: B) Rationale: ω-3 Fatty acids favor production of prostaglandins in the 3-series (PGE3) and leukotrienes in the 5-series (which are associated with improved immunocompetence and reduced inflammatory responses) and reduce levels of the PGE2 and leukotrienes in the 4-series (immunosuppressive and proinflammatory) in comparison with ω-6 fatty acids.100,101ω -3 Fatty acids have been supplemented enterally in pill form102-106 and in liquid nutritional In to the effects of ω-3 fatty acids on and a they also to be effective in in Early studies of ω-3 fatty acids were performed in cancer more studies have looked at other cancer Enteral ω-3 fatty acids to stabilize or the of weight in cancer patients, although this to occur with or no increase in lean body A of 2 of acid This may be administered as available ω-3 liquid nutritional supplements or as ω-3 fatty acid supplements in most Because these supplements are not by health the of this intervention should be See Table Patients should not use therapeutic diets to cancer. (Grade: enteral of and fatty acids may be beneficial in malnourished patients undergoing major cancer operations. (Grade: A) Rationale: of specific for effects beyond their nutrition role may be referred to as nutritional nutrients especially have been the of and fatty Clinical trials nutritional interventions in perioperative cancer patients using an enteral a of substrates including and ω-3 fatty have reported improved immune and clinical the of these studies the ability to the best for of immune EN. The on Enteral recommendations regarding the use of these in surgical It was that individuals undergoing gastrointestinal or major head and neck in there is malnutrition benefit from days studies have examined supplementation with The data on the use of or are limited at this time to make recommendations on the use of these However, based on the studies of use of and ω-3 fatty acids with clinical EN supplemented with these nutrients may be beneficial in malnourished patients undergoing major cancer operations. See Table cell to an of therapies and outcomes are by disease type related of vs cell prior therapy, and nutrition involves chemotherapy with or irradiation to tumor in patients with with of with In the patient's own immune system is to prevent are among the most therapies used in may be used to a with of host tract or are always the for these The of the to the development of during the period of that may as as a result of and effects of patients experience a prolonged period of minimal oral This may well beyond the of cell to the effects of therapy on gastric and 1. All patients undergoing hematopoietic cell with are at nutrition risk and should undergo nutrition screening to identify those who require formal nutrition assessment with development of a nutrition care plan. (Grade: D) Rationale: patients are to developing malnutrition of their the and other in and has been reported in malnourished patients receiving in nutrition status with as many of 50% of patients not to weight at Although evidence the clinical impact of nutrition in patients is appropriate screening of patients should minimize risk of the detrimental effects of weight loss in patients with cancer including those undergoing Clinical trials are needed to assess the impact of nutrition screening on outcomes in cancer patients. See Table 2. Nutrition support therapy is appropriate in patients undergoing hematopoietic cell who are malnourished and who are anticipated to be unable to ingest and/or absorb adequate nutrients for a prolonged period of time for prolonged period of When nutrition is it should be as as have cell (Grade: B) Rationale: NST is appropriate in patients undergoing who are malnourished and who will be unable to absorb adequate nutrients for a prolonged period of time to minimize risk of poor outcomes associated with malnutrition. Seven to days seems an appropriate definition prolonged period of time"; this time period is referred to in many studies, although there are no well designed studies that specifically address this issue. the effect of PN and EN in patients is of patient and treatment The risks and benefits of using PN in have been assessed comparing PN vs or vs PN vs intravenous Studies of PN vs SOD or EN demonstrate increased more more and time to but less weight and less loss of body with PN. There to be no differences in or of of PN to indicate of oral intake with but no difference in A study of and reported a effect of PN on to those who received in patients who received but not There was no difference in between however, the patients had of which with PN. These results have not been The effects of PN composition on has been results indicate no benefit to use of There may be a in the of with the use of PN of from to a of from If PN is used in it should be cell when adequate EN or oral intake is See Table 3. Enteral nutrition should be used in patients with a gastrointestinal tract in oral intake is to nutrition (Grade: Rationale: of EN has been Studies have small of patients receiving enteral or oral intake to PN alone or in of EN or PN, which makes of clinical outcomes In less and less as have been reported in patients receiving The effect on time to is not EN may also be associated with a risk of The of safe enteral are to the risk of and/or abdominal gastric and However, safe enteral has been reported in patients during the and have and gastrointestinal have EN is safe as a from PN to oral diet or when NST is indicated for such as See Table 4. Pharmacologic of may benefit patients undergoing hematopoietic cell (Grade: is not available by the and but as a by a in the on the of in Rationale: The of both and supplementation in have been Studies assessing the impact of enterally administered indicate no in or administered is associated with improved nitrogen shorter of and One study of PN vs PN a in oral intake indicated that patients who received had a shorter with no impact on or overall The results indicated a of in patients receiving These results were not seen with supplemented A Cochrane review that in PN may not be associated with reduced of but a benefit of fewer remains by a of available intravenous research is needed to appropriate and See Table 5. Patients should receive counseling regarding which may risks and safe during the period of (Grade: Rationale: Although the effect of or diets on risk of infection is patients should associated with an increased Several studies have examined the role of diet and risk in with other interventions such as and It is to make between these the were not One study a reduced of infection in patients who received a however, a study indicated no A by that of of Cancer low There were in the cell and used to of low A more small RCT that diet to the guidelines indicated no benefit of the diet in pediatric patients receiving This was also seen in a study of and diets in patients undergoing therapy for there is a for more systematic research on this this is it seems to to provide on during the period of while to the of in these patients. See Table 6. Nutrition support therapy is appropriate for patients undergoing hematopoietic cell who develop to disease by poor oral intake and/or significant (Grade: Rationale: data are available on the impact of NST on the of PN does not to the of in individuals undergoing In PN has been associated with an increased of of to with increased intake in patients or oral nutrition can Although there are no data on the impact of NST on the of it seems logical that NST should be used to nutrition status during prolonged nutrition resulting from See Table