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Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit?
Cancer Treatment Reviews (2008) 34, 568– 575
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/ctrv
GENERAL AND SUPPORTIVE CARE
Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit? ´phane Schneider b, Cyrus Chargari c, Pierre Senesse a,*, Eric Assenat a, Ste ´ c, David Azria d, Xavier He ´buterne b Nicolas Magne a
Department Department c Department d Department b
of Nutrition and Digestive Oncology, Institut Val d’Aurelle, Montpellier, France of Digestive Disease and Nutrition, Centre Hospitalier Universitaire Archet, Nice, France of Radiotherapy, Institut Gustave Roussy, Villejuif, France of Radiotherapy, Institut Val d’Aurelle, Montpellier, France
Received 19 June 2007; received in revised form 10 March 2008; accepted 13 March 2008
KEYWORDS
Summary Introduction: In patients with gastrointestinal (GI) cancer, severe malnutrition is associated with increased morbidity and mortality, reduction of treatment efficacy, and increased length of hospital stay. Therefore, systematic screening and care of malnutrition is mandatory. Materials and methods: Data for this review were identified by searches of Medline with and without MeSH database and Cancerlit. Studies were selected only if they were randomised clinical trials or historical reports. References were also identified from reference lists in relevant preciously published articles. Recent guidelines and meta-analyses were included. Only articles published in English were taken into consideration. Results: For surgical patients, practical information such as weight loss or subjective global assessment would provide a better basis for deciding whether or not to delay surgery. At least 10 days of nutritional support is recommended in severely malnourished patients before major digestive surgery. In non-severely malnourished patients, preoperative oral immunonutrition is associated with a 50% decrease in postoperative complications. The benefit of immune-enhancing diets in severely malnourished patients remains to be proven. For patients undergoing radiochemotherapy, dietary counselling should be proposed to all patients. In cases of severely malnourished patients or if dietary counselling suffers a setback, enteral nutrition should be recommended. Parenteral nutrition should be reserved for patients with severe digestive intolerance when enteral nutrition is not possible.
Diet therapy; Gastrointestinal neoplasms; Adult; Weight loss; Enteral nutrition; Parenteral nutrition; Nutritional support; Malnutrition; Food; Formulated
* Corresponding author. Tel.: +33 467 618 554; fax: +33 467 613 729. E-mail address: [email protected] (P. Senesse).
0305-7372/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2008.03.003
Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit?
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Conclusion: Propose an adaptive nutritional support at each step of a multimodal GI oncological treatment is essential. These recommendations should be used in daily practice but should also be included in all clinical research protocols. c 2008 Elsevier Ltd. All rights reserved.
Introduction
Several recent publications and guidelines have pointed out the benefit of nutritional support for patients suffering from gastrointestinal (GI) cancer. Therefore, even if most clinicians commonly agree that malnutrition is a risk factor for increased morbidity and mortality, nutrition management of these patients remains insufficient. Among the many reasons for this clinical circumspection, the following can be mentioned: the lack of useful practicable criteria, the multiplicity of these criteria, the lack of publications on large series, and the complexity of current guidelines. While this list may be continued, in daily oncological practice, nutrition is often relegated to the bottom of the list of priorities. Spiro and colleagues,1 on the basis of two case scenarios in patients with GI cancer and a specific questionnaire, gathered views and practices of oncologists on nutritional support. Their study showed that oncologists lacked identifying factors for classifying patients at risk of malnutrition. Indeed, 48% failed to specify height and/or BMI (body weight in kg/height in m2) and 55% failed to determine weight loss over 1 month, indicative of the need for nutritional support. Nutritional assessment concerns all the actors of the treatment strategy and should not be restricted just to the nutrition expert. Nutritional support is particularly relevant in GI cancer for which recent studies and guidelines have been published and the benefits proven. The aim of this target review is to sensitise oncologists and surgeons to the problem of nutritional assessment and support for GI cancer patients undergoing curative treatment.
Review of the literature Data for this review were identified by searches of Medline with and without MeSH database and Cancerlit. End of literature search was December 2006. Studies were selected only if they were randomised clinical trials or historical reports. Only articles published in English were taken into consideration. The terms ‘‘enteral feeding’’, ‘‘parenteral nutrition’’, ‘‘surgery’’, ‘‘radiotherapy’’, ‘‘neoadjuvant therapy’’, ‘‘perioperative care’’, ‘‘chemotherapy, adjuvant’’, ‘‘dietary supplements’’, ‘‘meta-analysis’’, ‘‘guidelines’’, ‘‘clinical trials’’, ‘‘prospective studies’’, ‘‘gastrointestinal neoplasms’’, ‘‘immunonutrition’’, ‘‘eicosapentaenoic acid’’ were used.
Consequences of malnutrition in GI cancer patients Malnutrition is a well-recognized and significant source of postoperative morbidity and high rate toxicities during chemotherapy or radiotherapy, resulting in increased hospital length of stay, increased treatment costs, decreased performance status, and altered quality of life.
For patients undergoing surgery, Malone and colleagues2 reported that malnutrition (defined as a weight loss of more than 10% over 6 consecutive months) has to be considered as a significant preoperative risk factor of nosocomial infections (12.3 vs 7.1% infections in the surgical site, p = 0.011). In GI cancer patients, malnutrition is also associated with a poor prognosis. In a randomised control study of localized oesophageal cancers, Kelsen and colleagues3 reported the negative role of weight loss greater than 10% of body weight in the outcome (p = 0.03). Alves and colleagues4 reported similar data in a prospective multicentre study of 1421 patients undergoing colon surgery (colorectal cancers and diverticular disease). In this study, weight loss of more than 10% was an independent preoperative risk factor of mortality. Nutritional assessment or more precisely malnutrition screening is thus an essential step in the global management of all cancer patients. In fact, this screening allows clinicians to distinguish two subgroups of patients: malnourished and non-malnourished patients. The American Society for Parenteral and Enteral Nutrition guidelines5 defined malnutrition as an involuntary loss or gain P10% of usual body weight in 6 months or P5% of usual body weight in 1 month. The recent European guidelines6 for surgical patients suggest a systematic screening of malnourished patients on additional criteria: severe nutritional risk defined by weight loss greater than 10–15% in 6 months, BMI less than 18.5, a subjective global assessment (SGA)7,8 grade C, or a serum albumin concentration less than 30 g/L. In addition to these criteria, the Nutritional Ratio Index9,10 [NRI: 15.9 · serum albumin (g/dL) + 41.7 · (current weight/usual weight)] could predict morbidity in perioperative patients. For patients undergoing chemotherapy and/or radiotherapy, minor malnutrition (weight loss <10%) is also a significant source of toxicities and poor prognosis. In a multicentre cooperative study of 3047 patients prior to chemotherapy,11 weight loss was associated with a poor median survival for colorectal cancer patients (weight loss compared with no weight loss, p < 0.01). Andreyev and colleagues,12 indicated in a retrospective review of 1555 patients for GI malignancies undergoing chemotherapy that weight loss at presentation may be an independent prognostic variable of developing more severe dose-limiting toxicities (p < 0.0001), decreased response (p = 0.006), and shorter overall survival (gastric and colorectal neoplasms, p < 0.0001). Weight loss P5% was associated with a poor prognostic factor (9 months vs 12 months, p = 0.006) in 350 patients with advanced oesophageal cancer who were treated in six consecutive prospective trials.13 Recently, Mitry and colleagues14 analyzed predictive factors of survival in patients with advanced colorectal cancer included in irinotecan phase III trials. By multivariate analysis, weight loss <5% was independently associated with a better overall survival (odds ratio 1.67, 95% CI 1.29–2.14). One hypothesis to explain these side effects is modification of xenobiotic
570 detoxification associated with inflammatory mediators and/ or nuclear receptors.15–18 In summary, severe malnutrition in patients undergoing curative treatment in GI cancer is clearly associated with increased morbidity and mortality, reduced efficacy of treatment, and increased length of hospital stay. Systematic screening for malnutrition should be instituted and then an appropriate and efficient nutritional support proposed if necessary.
Benefits of nutritional support for patients undergoing surgery Severely malnourished patients In this situation, the European guidelines6 indicate that ‘‘patients with severe nutritional risk benefit from nutritional support for 10–14 days prior to major surgery even if surgery is delayed. Whenever feasible, the enteral route should be preferred’’. To support these recommendations, further studies have been published. The impact of total parenteral nutrition (TPN) in patients undergoing surgery (not only GI cancer patients) was evaluated in four meta-analyses of prospective randomised trials.19–22 Three of these19,20,22 confirmed the benefits of preoperative nutrition in terms of a lower rate of postoperative morbidity. More precisely, Koretz and colleagues21 combined the trials that only included patients with stomach and oesophageal carcinoma. A reduction of major complications was demonstrated (estimated risk difference of 18%). Nevertheless, pooled data did not confirm that perioperative nutrition improves postoperative mortality rate. However, these meta-analyses were associated with a significant heterogeneity due to poor methodology, particularly considering the small number of patients, the short duration of the preoperative nutrition, and the unsuitable caloric intake in some studies. In 1982, Mu ¨ller and colleagues23 suggested that patients with GI neoplasms might benefit from preoperative parenteral nutrition, with fewer major complications and a significant lower mortality rate (18.6% vs 4.5%). In a control study, the Veterans Affairs Cooperative Study Group24 studied 395 malnourished (moderately and severe) patients (51% with GI cancer) and randomised between perioperative TPN (7–15 days before and 3 days after surgery) and no TPN. Only severely malnourished patients (NRI < 83.5) who received TPN had significantly fewer non-infectious complications than controls (5.3% vs 42.9%, p = 0.03). More recently, Bozzetti and colleagues25 presented the impact of perioperative TPN on reducing the risk of surgery in malnourished cancer patients (weight loss P10%). Ninety elective surgical patients with gastric or colorectal tumours were randomly assigned to perioperative parenteral nutrition or no TPN (control group). Postoperative morbidity was reduced by 20% (p = 0.03) for the patients receiving TPN. On the other hand, Heyland and colleagues20 suggested that enteral nutrition significantly reduces the complication rate compared with parenteral nutrition. In a meta-analysis, Braunschweig and colleagues26 presented the effects of enteral or parenteral nutrition in adults suffering from GI cancer and undergoing surgery.
P. Senesse et al. Pooled analysis suggested that tube feeding was associated with a lower risk of infection than parenteral nutrition (relative risk 0.66, 95% CI 0.56–0.79) but mortality and infectious complications are higher in studies reporting patients with severe protein calorie malnutrition. A recent systematic review27 (concerning a majority of GI cancer patients receiving postoperative nutrition) confirmed these data. Enteral tube feeding compared with parenteral nutrition was associated with a significantly shorter length of hospital stay and a lower incidence of all complications, namely, infections. Nevertheless, this review did not show a difference in terms of mortality. The main multicentre randomised trial28 compared postoperative enteral (surgical jejunostomy) and parenteral nutrition in 317 malnourished patients (weight loss P10%) with GI cancer and candidates for major elective surgery. Postoperative complications occurred in 54 (34%) and 78 (49%) of the patients fed enterally and parenterally, respectively (p = 0.005). Respective adverse effects appeared in 56 (35%) and 22 (14%) patients (p < 0.0001), respectively. A large prospective study,29 published in 2006, showed that artificial nutrition could reduce significantly surgical morbidity and mortality in malnourished GI cancer patients. Complications occurred in 18.3% of the patients receiving nutrition and in 33.5% of the control patients (p = 0.012). Fourteen patients died in the control group and five in the group receiving artificial nutrition (6.0% vs 2.1%, p = 0.003). The total length of hospitalization of control patients was significantly longer (29 vs 22 days, p = 0.014) than those for the patients receiving artificial nutrition. This large study confirms the interest and the necessity of proposing artificial nutrition to every severely malnourished patient undergoing major surgery for GI cancer. Another interest of this study is that it also proposes an artificial nutrition regimen with a pragmatic choice, namely, either enteral or parenteral nutrition, as determined by the clinician. After surgery, early enteral feeding is recommended. In fact, a meta-analysis30 was performed to compare the potential beneficial effects of early feeding vs nil by mouth after gastrointestinal surgery. Results (n = 837 patients) showed that early feeding (within 24 h after surgery) reduced significantly both the risk of infection and the mean length of hospital stay. Nevertheless, in proximal digestive tract surgery, early feeding may even be harmful. To improve the immunologic, metabolic, and clinical outcome in patients with GI malignancies, some researchers have studied an enteral immune-enhancing diet instead of a standard enteral diet. In severe malnourished patient, however, the use of perioperative immunonutrition remains, at least, debatable. In a review on enteral nutritional support and eicosapentaenoic acid (EPA) supplementation in patients with cancer,27 no significant difference in the incidence of infectious complications (odds ratio 0.84, 95% CI 0.39–1.82) following nutritional support was noted when compared with standard enteral feeding.
Non-malnourished patients For GI cancer patients undergoing abdominal surgery, preoperative oral immunonutrition (arginine, omega-3 fatty acids, and nucleotides) is now recommended.6 To support these recommendations, first, three meta-analyses have
Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit? been published.31–33 In summary, these meta-analyses demonstrated that a perioperative immunonutrition in surgical patients reduced the risk of infectious complications,31 and overall hospital stay but had no effect on mortality. The same results were obtained for surgical GI cancer patients with a significant reduction of infectious complications (odds ratio 0.47, 95% CI 0.30–0.73) and overall hospital stay ( 2.4 days, 95% CI 4.00 to 0.8).32 Second, three prospective studies demonstrated that a preoperative immunonutrition (arginine, omega-3 fatty acids, and nucleotides) in GI cancer patients reduced significantly the incidence of postoperative infections (Table 1).34–36 In the most important study,36 a total of 305 non or moderately malnourished patients (weight loss <10%) with cancer of the GI tract (gastrooesophageal, pancreatic, and colorectal surgery) were randomised to receive (1) oral supplementation for 5 days before surgery with 1 L/day of an immunonutrition, with no nutritional support given after surgery (preoperative group, n = 102); (2) the same preoperative treatment plus postoperative jejunal infusion with the same immunonutrition (perioperative group, n = 101); and (3) no artificial nutrition before and after surgery (conventional group; n = 102). Analysis showed a 13.7% incidence of postoperative infections in the preoperative group, 15.8% in the perioperative group, and 30.4% in the conventional group (p = 0.006 conventional vs preoperative group and p = 0.02 conventional vs perioperative group). In summary, for patients undergoing GI surgery, it seems essential to screen for severe malnutrition (Fig. 1). Numer-
Table 1
571
ous criteria or indices of malnutrition are available and could be a source of confusion. Consequently, in our opinion, even if the NRI or serum albumin levels help to establish the nutritional status of the patients, practical information like weight loss (>10% since the beginning of the disease) and the SGA would provide a better basis for deciding whether or not to delay surgery and to feed the patients more efficiently in the preoperative period. A severely malnourished patient (defined by a weight loss >10% or an SGA grade C) should have preoperative artificial nutrition for at leas, 10 days prior to major surgery and 7 days after surgery. Enteral nutrition is the best support for these patients, especially when there is no central venous access. Standard products should be proposed. In our opinion, the benefit of immune-enhancing diets in severely malnourished patients remains to be proven. Preoperative oral nutrition should be ad libitum (if possible) and provide an average 25 nonprotein kcal/kg per day and 0.25 g nitrogen/kg per day. On the other hand, preoperative oral immunonutrition (arginine, omega-3 fatty acids, and nucleotides) is indicated in non-malnourished patients (weight loss 610% or SGA grade A and B) 5 days prior to major GI cancer surgery.
Benefits of nutritional support for patients undergoing chemotherapy and/or radiotherapy According to the ESPEN guidelines on enteral nutrition of patients with extern beam radiotherapy or chemoradiation, every effort should be made to increase dietary intake and
Preoperative immunonutrition for non malnourished patients with gastrointestinal (GI) cancer: randomised trials
References
Patients
Nutritional status
Immunonutrition dose and schedule
Postoperative infectious complications
Braga et al.34
206 patients with neoplasm of stomach, pancreas, and colorectum randomised vs control enteral formula vs enteral immunonutrition
Well nourished (weight loss <10%) = 76% Malnourished patients (weight loss P 10%) = 24%
1 L/d for 7 consecutive days before and 7 days after surgery
Infectious complication rate: 14% vs 30% in the control group (p = 0.009)
Senkal et al.35
154 patients with neoplasm of oesophagus, stomach, and pancreas randomised preoperatively vs control oral formula vs oral immunonutrition
Nutrition Risk Index: 91 ± 15 in the control group 97 ± 12 in the immunonutrition group
1 L/d for 5 consecutive days before and 10 days after surgery by a jejunostomy
Infectious complication rate: 14% vs 27% in the control group (p = 0.05)
Gianotti et al.36
305 patients with neoplasm of oesophagus, stomach, pancreas, and colorectum randomised either preoperative oral formula vs pre or postoperative immunonutrition vs no artificial nutrition
Weight loss <10%
1 L/d for five consecutive days before surgery and 1 L/d for 5 days before and after surgery
Infectious complication rate: 13.7% (preoperative group) vs 15.8% (pre and postoperative group) vs 30.4% (p = 0.006 vs preoperative; p = 0.02 vs perioperative)
572
P. Senesse et al.
to prevent therapy associated weight loss and interruption of radiation therapy. Although routine enteral nutrition is not indicated during radiation therapy or chemotherapy, intensive dietary advice and oral nutritional supplements are recommended. Enteral nutrition should be delivered only if severe local mucositis is expected for oesophagus irradiation.37 However, there are no randomised controlled trial comparing PEG with nasogastric tube feeding and most of retrospective reports assessed nutritional supports in patients with head and neck cancers. Oral nutritional support should be proposed for all patients receiving neoadjuvant treatment. However, few studies are available, particularly, with regard to GI cancer. A recent review showed no difference in mortality between oral nutritional support or enteral tube feeding compared with routine care in patients undergoing chemotherapy or radiotherapy, but in patients undergoing radiotherapy, oral nutritional support significantly increased dietary intake compared with routine care.27 Recently, 60 patients (SGA grade A and B) with GI or head and neck neoplasms (12% rectal or abdominal radiotherapy, 13% oesophagus, and 75% head and neck) were randomised into two groups to compare standard care with an intensive oral nutritional intervention.38 The results showed a significant reduction in nutritional status (compared with the SGA grade, p = 0.02) and quality of life (p = 0.009) alterations when intensive nutritional intervention and oral nutritional supplementation were offered. Similarly, Ravasco and colleagues39,40
published two randomised studies. One hundred and eleven patients with colorectal cancer treated by radiotherapy were randomly assigned: dietary counselling (n = 37), two cans per day of a high-protein liquid supplement in addition to their usual diet (n = 37) and ad libitum intake (n = 37).39 After radiotherapy and at 3 months, the rates of anorexia, nausea, vomiting, and diarrhoea were higher in the group with ad libitum intake (p < 0.05). At radiotherapy completion, in the dietary counselling group, all quality of life function scores improved proportionally to adequate intake or nutritional status (p < 0.05). In the dietary counselling and protein supplement groups, improvement or deterioration of quality of life correlated with better or poorer intake of nutritional status (p < 0.003). In the other study by these investigators,40 75 randomised patients with head and neck tumours treated by radiotherapy were given either dietary counselling (n = 25), two cans per day of a high-protein liquid supplement in addition to their usual diet (n = 25) or allowed ad libitum intake (n = 25). After radiotherapy, quality of life function scores improved (p < 0.003) proportionally with nutritional intake and status in the dietary counselling and protein supplement groups (p < 0.05) but worsened in the ad libitum intake group (p < 0.05). At 3 months, the reduction of incidence and severity of grades 1 and 2 (anorexia, nausea, vomiting, xerostomia, and dysgeusia) was significantly decreased in the oral supplement group. Only patients in the dietary counselling group maintained or improved their overall
Surgery with morbidity >25–30% (oesophageal, stomach, pancreas, colorectal surgery)
NO
YES
No nutritional support Weekly follow-up
Body weight >10% or SGA grade C
NO
YES
No severe malnutrition
Oral immunonutrition (arginine, omega-3 fatty acids and nucleotides) 5 days prior to surgery Figure 1
Severe malnutrition
Artificial nutrition for, at least, 10 days prior to major surgery and 7 days after surgery
Nutritional support step-by-step for GI surgical patients.
Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit? quality of life. A complementary approach was published on patients with unresectable pancreatic cancer. Fearon and colleagues41 randomised, in a multicentre study, 200 patients with weight loss greater than 5% who consumed two cans per day of either a special diet with n 3 fatty acids or the identical supplement without the n 3 fatty acids. In an intention to treat analysis, comparisons indicated that both supplements were equally effective. Patients in both groups stopped losing weight (p < 0.001) but, at 8 weeks, 90 patients were lost to follow-up (death, withdrawal, and disease progression). In another multicentre trial42 over an 8-week period, 200 patients were randomised to drink 2 cans per day of an oral nutritional supplement with or without n 3 fatty acids. After 8 weeks, there was a significant improvement of body weight only (p < 0.001). There was no significant change in spontaneous food consumption. Over the 8 week period, only 53.6% of the patients were compliant to the treatment and drank 1.5 cans or more per day. In cases of severely malnourished patients or if the dietary counselling suffers a setback, artificial nutrition should then be proposed. Nevertheless, a meta-analysis showed a significantly increased rate of infectious complications, by 16%, when parenteral nutrition was used during radiochemotherapy.21 A recent review suggests that parenteral nutrition could be used only when enteral nutrition is contraindicated.43 However, few studies are available on enteral nutrition during neoadjuvant or adjuvant treatment. The most striking example is for upper GI tract malignancies before and during neoadjuvant treatment. Odelli and colleagues44 in a retrospective study, compared outcomes of two groups of patients: no nutritional support (n = 24) and nutritional support (n = 24). At the initial consultation, nutritional support included a systematic nutritional counselling. High energy intake was proposed for patients with anorexia, dysphagia or weight loss less than 10%; for severely malnourished patients (weight loss P10%, BMI <18), percutaneous endoscopic gastrostomy (PEG) was organised before starting treatment. Patients with a nutritional support had significantly greater radiotherapy completion rates (92% vs 50%), fewer hospital admissions (46% vs 75%) and shorter hospital stay (3.2 days vs 13.5 days). Other studies have shown that PEG is a feasible method even for oesophageal cancer patients and neoadjuvant treatment.45,46 In cases of oesophagectomy and stomach mobilization in particular, PEG placement requires an experienced team because of the risk of vascular stomach lesions. Further studies are needed to improve this method. In view of these results, dietary counselling should be proposed to all patients with neoadjuvant or adjuvant treatment by radiotherapy or chemotherapy as soon as possible. This counselling does not rule out oral supplements. However, to enhance compliance, Bauer and colleagues42 proposed a weekly contact with patients by either face-toface interview or telephone contact. It is very important that clinicians be convinced of this strategy. All patients should consider the dietary counselling and oral supplements as an essential component of their treatment. This is all the more urgent since a recent study47 showed that only 36% of patients with GI malignancies were referred to a dietician. One-third of the patients with more than 10% weight loss were not referred for dietary assessment. The authors concluded the following: ‘‘This study suggests that
573
an out-patient dietetic screening tool is urgently required. Such screening is likely to result in considerable improvements to the clinical care of cancer patients with weight loss.’’ If dietary counselling suffers a setback or in cases of severely malnourished patients, enteral nutrition should be provided.
A question of timing Patients undergoing surgery (and a fortiori when flanked by neoadjuvant or adjuvant treatment) require early nutritional management. There is consequently great interest in having practical tools for nutritional evaluation (involuntary weight loss, SGA) applicable at the time of the patient’s first consultation with the surgeon, anaesthetist, or oncologist. Thus, regarding the recent guidelines for malnourished patients, a delay of 10 days prior to major surgery and a period of at least 7 days after surgery should be respected.6 Any proof of benefit should be noted from artificial nutritional support when administered for less than 7 days before surgery. In fact, it has not been investigated sufficiently whether short-term preoperative nutritional support. Moreover, if adjuvant treatment is needed (for example, radiochemotherapy after gastrectomy with a necessary caloric intake greater than 1500 kcal per day),48 the duration and the route of nutritional support administration must be considered. To prove this point, a study on 23 patients after total gastrectomy (without adjuvant oncologic treatment) showed that their average daily energy intake was 1457.9 kcal in the first postoperative month.49 In this case, postoperative jejunostomy enteral feeding was shown to be necessary in a substantial number of patients (pre- and postoperative enteral feeding for severe malnourished patients)50 and led to better management and outcome. Poor evaluation of this timing could lead to potentially ineffective and dangerous nutritional support protocols. On this subject, it is interesting to stress that the immediate preoperative period should not necessarily be a period of ‘‘urgent nutritional compensation’’ but, on the contrary, a period during which it is necessary to reduce salt and water intake, particularly during and after surgery. Lobo and colleagues51 studied the effect of salt and water balance on recovery of GI function in 21 patients after elective colonic resection in a randomised controlled trial. Positive salt and water balance sufficient to cause a 3 kg weight gain after surgery delayed return of GI function and prolonged hospital stay in patients undergoing elective colonic resection. Only one complication (hypokalaemia) was noted in the restriction group (p < 0.001). These data have recently been confirmed on a large trial, underlining the interest of restricted perioperative intake on metabolic and pulmonary complications and on cicatrisation.52 Although this approach might be valid, another 2006 randomised trial blunted our emphasis on postoperative intravenous fluid restriction on recovery after elective colorectal surgery and showed no significant reduction on hospital stay.53 In a recent review of randomised controlled trials, Holte and colleagues assessed the place of fluid therapy in surgical patients. Although perioperative fluid administration of greater than 1 L may improve recovery after minor or moderately
574 sized operations, care should be taken to avoid fluid overload in major surgical procedures.54
Conclusion Knowledge of the nutritional status of patients with GI cancer is essential, not only for screening malnourished or nonmalnourished patients, but especially to propose an adaptive treatment at each step of a multimodal oncological treatment. Numerous studies are available and convincing. In any cases, the earlier, the better. In clinical practice, the subjective global assessment appears relevant in trained teams but not easily adaptable for a generalized use (subjective tools). For this reason, it seems to us that weight loss is the best tools for screening nutritional status. Whatever the treatment procedure, surgical or not, all patients could benefit from nutritional support during oncologic treatments. An immunonutrition for 5 days before surgery must be proposed for non-malnourished patients and artificial nutrition for 10 days prior to major surgery for severely malnourished patients. Dietary counselling should be proposed for all patients receiving radiotherapy or chemotherapy. In our opinion, these recommendations should be used in daily practice but should also be included in all clinical research protocols concerning GI cancer patients receiving oncologic treatment.
Conflicts of interest statement We declare that we have no conflicts of interest.
Acknowledgement The authors wish to thank Dr. S.L. Salhi for critical comments and excellent editorial assistance.
References 1. Spiro A, Baldwin C, Patterson A, Thomas J, Andreyev HJ. The views and practice of oncologists towards nutritional support in patients receiving chemotherapy. Br J Cancer 2006;95:431–4. 2. Malone DL, Genuit T, Tracy JK, Gannon C, Napolitano LM. Surgical site infections: reanalysis of risk factors. J Surg Res 2002;103:89–95. 3. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 1998;339:1979–84. 4. Alves A, Panis Y, Mathieu P, Mantion G, Kwiatkowski F, Slim K. Postoperative mortality and morbidity in French patients undergoing colorectal surgery: results of a prospective multicenter study. Arch Surg 2005;140:278–83. [discussion]. 5. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr 2002;26:1SA–138SA. 6. Weimann A, Braga M, Harsanyi L, et al. ESPEN guidelines on enteral nutrition: surgery including organ transplantation. Clin Nutr 2006;25:224–44. 7. Detsky AS, Baker JP, O’Rourke K, et al. Predicting nutritionassociated complications for patients undergoing gastrointestinal surgery. J Parenter Enteral Nutr 1987;11:440–6.
P. Senesse et al. 8. Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S, Mendelson RA, et al. What is subjective global assessment of nutritional status? J Parenter Enteral Nutr 1987;11:8–13. 9. Mullen J, Buzby G, Waldman T, Gertner MH, Hobbs CL, Rosato EF. Prediction of operative morbidity and mortality by preoperative nutritional assessment. Surg Forum 1979;30:80–2. 10. Buzby GP, Knox LS, Crosby LO, et al. Study protocol: a randomized clinical trial of total parenteral nutrition in malnourished surgical patients. Am J Clin Nutr 1988;47:366–81. 11. Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med 1980;69:491–7. 12. Andreyev HJ, Norman AR, Oates J, Cunningham D. Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur J Cancer 1998;34:503–9. 13. Polee MB, Hop WC, Kok TC, et al. Prognostic factors for survival in patients with advanced oesophageal cancer treated with cisplatin-based combination chemotherapy. Br J Cancer 2003;89:2045–50. 14. Mitry E, Douillard JY, Van Cutsem E, et al. Predictive factors of survival in patients with advanced colorectal cancer: an individual data analysis of 602 patients included in irinotecan phase III trials. Ann Oncol 2004;15:1013–7. 15. Ding X, Lichti K, Kim I, Gonzalez FJ, Staudinger JL. Regulation of constitutive androstane receptor and its target genes by fasting, cAMP, hepatocyte nuclear factor alpha, and the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha. J Biol Chem 2006;281:26540–51. 16. Morley JE, Thomas DR, Wilson MM. Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr 2006;83:735–43. 17. Shiraki T, Sakai N, Kanaya E, Jingami H. Activation of orphan nuclear constitutive androstane receptor requires subnuclear targeting by peroxisome proliferator-activated receptor gamma coactivator-1 alpha. A possible link between xenobiotic response and nutritional state. J Biol Chem 2003;278: 11344–50. 18. Scripture CD, Sparreboom A, Figg WD. Modulation of cytochrome P450 activity: implications for cancer therapy. Lancet Oncol 2005;6:780–9. 19. Torosian MH. Perioperative nutrition support for patients undergoing gastrointestinal surgery: critical analysis and recommendations. World J Surg 1999;23:565–9. 20. Heyland DK, Montalvo M, MacDonald S, Keefe L, Su XY, Drover JW. Total parenteral nutrition in the surgical patient: a metaanalysis. Can J Surg 2001;44:102–11. 21. Koretz RL, Lipman TO, Klein S. AGA technical review on parenteral nutrition. Gastroenterology 2001;121:970–1001. 22. Klein S, Kinney J, Jeejeebhoy K, et al. Nutrition support in clinical practice: review of published data and recommendations for future research directions. Summary of a conference sponsored by the National Institutes of Health, American Society for Parenteral and Enteral Nutrition, and American Society for Clinical Nutrition. Am J Clin Nutr 1997;66:683–706. 23. Muller JM, Brenner U, Dienst C, Pichlmaier H. Preoperative parenteral feeding in patients with gastrointestinal carcinoma. Lancet 1982;1:68–71. 24. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group. Perioperative total parenteral nutrition in surgical patients. N Engl J Med 1991;325:525–32. 25. Bozzetti F, Gavazzi C, Miceli R, et al. Perioperative total parenteral nutrition in malnourished, gastrointestinal cancer patients: a randomized, clinical trial. J Parenter Enteral Nutr 2000;24:7–14. 26. Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr 2001;74:534–42.
Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit? 27. Elia M, van Bokhorst-de van der Schueren MA, Garvey J, et al. Enteral (oral or tube administration) nutritional support and eicosapentaenoic acid in patients with cancer: a systematic review. Int J Oncol 2006;28:5–23. 28. Bozzetti F, Braga M, Gianotti L, Gavazzi C, Mariani L. Postoperative enteral versus parenteral nutrition in malnourished patients with gastrointestinal cancer: a randomised multicentre trial. Lancet 2001;358:1487–92. 29. Wu GH, Liu ZH, Wu ZH, Wu ZG. Perioperative artificial nutrition in malnourished gastrointestinal cancer patients. World J Gastroenterol 2006;12:2441–4. 30. Lewis SJ, Egger M, Sylvester PA, Thomas S. Early enteral feeding versus ‘‘nil by mouth’’ after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. BMJ 2001;323:773–6. 31. Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA 2001;286:944–53. 32. Heys SD, Walker LG, Smith I, Eremin O. Enteral nutritional supplementation with key nutrients in patients with critical illness and cancer: a meta-analysis of randomized controlled clinical trials. Ann Surg 1999;229:467–77. 33. Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med 1999;27:2799–805. 34. Braga M, Gianotti L, Radaelli G, Vignalli A, Mari G, Gentilini O, et al. Perioperative immunonutrition in patients undergoing cancer surgery: results of a randomized double-blind phase 3 trial. Arch Surg 1999;134:428–33. 35. Senkal M, Zumtobel V, Bauer KH, Marpe B, Wolfram G, Frei A, et al. Outcome and cost-effectiveness of perioperative enteral immunonutrition in patients undergoing elective upper gastrointestinal tract surgery: a prospective randomized trial. Arch Surg 1999;134:1309–16. 36. Gianotti L, Braga M, Nespoli L, Radaelli G, Beneduce A, Di Carlo V. A randomized controlled trial of preoperative oral supplementation with a specialized diet in patients with gastrointestinal cancer. Gastroenterology 2002;122:1763–70. 37. Arends J, Bodoky G, Bozzetti F, et al. ESPEN guidelines on enteral nutrition: non-surgical oncology. Clin Nutr 2006;25:245–59. 38. Isenring EA, Capra S, Bauer JD. Nutrition intervention is beneficial in oncology outpatients receiving radiotherapy to the gastrointestinal or head and neck area. Br J Cancer 2004;91:447–52. 39. Ravasco P, Monteiro-Grillo I, Vidal PM, Camilo ME. Dietary counseling improves patient outcomes: a prospective, randomized, controlled trial in colorectal cancer patients undergoing radiotherapy. J Clin Oncol 2005;23:1431–8. 40. Ravasco P, Monteiro-Grillo I, Marques VP, Camilo ME. Impact of nutrition on outcome: a prospective randomized controlled trial in patients with head and neck cancer undergoing radiotherapy. Head Neck 2005;27:659–68.
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41. Fearon KC, von Meyenfeldt MF, Moses AG, et al. Effect of a protein and energy dense N 3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut 2003;52:1479–86. 42. Bauer J, Capra S, Battistutta D, Davidson W, Ash S. Compliance with nutrition prescription improves outcomes in patients with unresectable pancreatic cancer. Clin Nutr 2005;24:998–1004. 43. Zaloga GP. Parenteral nutrition in adult inpatients with functioning gastrointestinal tracts: assessment of outcomes. Lancet 2006;367:1101–11. 44. Odelli C, Burgess D, Bateman L, et al. Nutrition support improves patient outcomes, treatment tolerance and admission characteristics in oesophageal cancer. Clin Oncol (R Coll Radiol) 2005;17:639–45. 45. Margolis M, Alexander P, Trachiotis GD, Gharagozloo F, Lipman T. Percutaneous endoscopic gastrostomy before multimodality therapy in patients with esophageal cancer. Ann Thorac Surg 2003;76:1694–7. 46. Stockeld D, Fagerberg J, Granstrom L, Backman L. Percutaneous endoscopic gastrostomy for nutrition in patients with oesophageal cancer. Eur J Surg 2001;167:839–44. 47. Baldwin C, McGough C, Norman AR, Frost GS, Cunningham DC, Andreyev HJ. Failure of dietetic referral in patients with gastrointestinal cancer and weight loss. Eur J Cancer 2006;42:2504–9. 48. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–30. 49. Braga M, Zuliani W, Foppa L, Di Carlo V, Cristallo M. Food intake and nutritional status after total gastrectomy: results of a nutritional follow-up. Br J Surg 1988;75:477–80. 50. Daly JM, Weintraub FN, Shou J, Rosato EF, Lucia M. Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients. Ann Surg 1995;221:327–38. 51. Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet 2002;359:1812–8. 52. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al. Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg 2003;238:641–8. 53. MacKay G, Fearon K, McConnachie A, Serpell MG, Molloy RG, O’Dwyer PJ. Randomized clinical trial of the effect of postoperative intravenous fluid restriction on recovery after elective colorectal surgery. Br J Surg 2006;93:1469–74. 54. Holte K, Kehlet H. Fluid therapy and surgical outcomes in elective surgery: a need for reassessment in fast-track surgery. J Am Coll Surg 2006;202:971–89.
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GENERAL AND SUPPORTIVE CARE
Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit? ´phane Schneider b, Cyrus Chargari c, Pierre Senesse a,*, Eric Assenat a, Ste ´ c, David Azria d, Xavier He ´buterne b Nicolas Magne a
Department Department c Department d Department b
of Nutrition and Digestive Oncology, Institut Val d’Aurelle, Montpellier, France of Digestive Disease and Nutrition, Centre Hospitalier Universitaire Archet, Nice, France of Radiotherapy, Institut Gustave Roussy, Villejuif, France of Radiotherapy, Institut Val d’Aurelle, Montpellier, France
Received 19 June 2007; received in revised form 10 March 2008; accepted 13 March 2008
KEYWORDS
Summary Introduction: In patients with gastrointestinal (GI) cancer, severe malnutrition is associated with increased morbidity and mortality, reduction of treatment efficacy, and increased length of hospital stay. Therefore, systematic screening and care of malnutrition is mandatory. Materials and methods: Data for this review were identified by searches of Medline with and without MeSH database and Cancerlit. Studies were selected only if they were randomised clinical trials or historical reports. References were also identified from reference lists in relevant preciously published articles. Recent guidelines and meta-analyses were included. Only articles published in English were taken into consideration. Results: For surgical patients, practical information such as weight loss or subjective global assessment would provide a better basis for deciding whether or not to delay surgery. At least 10 days of nutritional support is recommended in severely malnourished patients before major digestive surgery. In non-severely malnourished patients, preoperative oral immunonutrition is associated with a 50% decrease in postoperative complications. The benefit of immune-enhancing diets in severely malnourished patients remains to be proven. For patients undergoing radiochemotherapy, dietary counselling should be proposed to all patients. In cases of severely malnourished patients or if dietary counselling suffers a setback, enteral nutrition should be recommended. Parenteral nutrition should be reserved for patients with severe digestive intolerance when enteral nutrition is not possible.
Diet therapy; Gastrointestinal neoplasms; Adult; Weight loss; Enteral nutrition; Parenteral nutrition; Nutritional support; Malnutrition; Food; Formulated
* Corresponding author. Tel.: +33 467 618 554; fax: +33 467 613 729. E-mail address: [email protected] (P. Senesse).
0305-7372/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2008.03.003
Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit?
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Conclusion: Propose an adaptive nutritional support at each step of a multimodal GI oncological treatment is essential. These recommendations should be used in daily practice but should also be included in all clinical research protocols. c 2008 Elsevier Ltd. All rights reserved.
Introduction
Several recent publications and guidelines have pointed out the benefit of nutritional support for patients suffering from gastrointestinal (GI) cancer. Therefore, even if most clinicians commonly agree that malnutrition is a risk factor for increased morbidity and mortality, nutrition management of these patients remains insufficient. Among the many reasons for this clinical circumspection, the following can be mentioned: the lack of useful practicable criteria, the multiplicity of these criteria, the lack of publications on large series, and the complexity of current guidelines. While this list may be continued, in daily oncological practice, nutrition is often relegated to the bottom of the list of priorities. Spiro and colleagues,1 on the basis of two case scenarios in patients with GI cancer and a specific questionnaire, gathered views and practices of oncologists on nutritional support. Their study showed that oncologists lacked identifying factors for classifying patients at risk of malnutrition. Indeed, 48% failed to specify height and/or BMI (body weight in kg/height in m2) and 55% failed to determine weight loss over 1 month, indicative of the need for nutritional support. Nutritional assessment concerns all the actors of the treatment strategy and should not be restricted just to the nutrition expert. Nutritional support is particularly relevant in GI cancer for which recent studies and guidelines have been published and the benefits proven. The aim of this target review is to sensitise oncologists and surgeons to the problem of nutritional assessment and support for GI cancer patients undergoing curative treatment.
Review of the literature Data for this review were identified by searches of Medline with and without MeSH database and Cancerlit. End of literature search was December 2006. Studies were selected only if they were randomised clinical trials or historical reports. Only articles published in English were taken into consideration. The terms ‘‘enteral feeding’’, ‘‘parenteral nutrition’’, ‘‘surgery’’, ‘‘radiotherapy’’, ‘‘neoadjuvant therapy’’, ‘‘perioperative care’’, ‘‘chemotherapy, adjuvant’’, ‘‘dietary supplements’’, ‘‘meta-analysis’’, ‘‘guidelines’’, ‘‘clinical trials’’, ‘‘prospective studies’’, ‘‘gastrointestinal neoplasms’’, ‘‘immunonutrition’’, ‘‘eicosapentaenoic acid’’ were used.
Consequences of malnutrition in GI cancer patients Malnutrition is a well-recognized and significant source of postoperative morbidity and high rate toxicities during chemotherapy or radiotherapy, resulting in increased hospital length of stay, increased treatment costs, decreased performance status, and altered quality of life.
For patients undergoing surgery, Malone and colleagues2 reported that malnutrition (defined as a weight loss of more than 10% over 6 consecutive months) has to be considered as a significant preoperative risk factor of nosocomial infections (12.3 vs 7.1% infections in the surgical site, p = 0.011). In GI cancer patients, malnutrition is also associated with a poor prognosis. In a randomised control study of localized oesophageal cancers, Kelsen and colleagues3 reported the negative role of weight loss greater than 10% of body weight in the outcome (p = 0.03). Alves and colleagues4 reported similar data in a prospective multicentre study of 1421 patients undergoing colon surgery (colorectal cancers and diverticular disease). In this study, weight loss of more than 10% was an independent preoperative risk factor of mortality. Nutritional assessment or more precisely malnutrition screening is thus an essential step in the global management of all cancer patients. In fact, this screening allows clinicians to distinguish two subgroups of patients: malnourished and non-malnourished patients. The American Society for Parenteral and Enteral Nutrition guidelines5 defined malnutrition as an involuntary loss or gain P10% of usual body weight in 6 months or P5% of usual body weight in 1 month. The recent European guidelines6 for surgical patients suggest a systematic screening of malnourished patients on additional criteria: severe nutritional risk defined by weight loss greater than 10–15% in 6 months, BMI less than 18.5, a subjective global assessment (SGA)7,8 grade C, or a serum albumin concentration less than 30 g/L. In addition to these criteria, the Nutritional Ratio Index9,10 [NRI: 15.9 · serum albumin (g/dL) + 41.7 · (current weight/usual weight)] could predict morbidity in perioperative patients. For patients undergoing chemotherapy and/or radiotherapy, minor malnutrition (weight loss <10%) is also a significant source of toxicities and poor prognosis. In a multicentre cooperative study of 3047 patients prior to chemotherapy,11 weight loss was associated with a poor median survival for colorectal cancer patients (weight loss compared with no weight loss, p < 0.01). Andreyev and colleagues,12 indicated in a retrospective review of 1555 patients for GI malignancies undergoing chemotherapy that weight loss at presentation may be an independent prognostic variable of developing more severe dose-limiting toxicities (p < 0.0001), decreased response (p = 0.006), and shorter overall survival (gastric and colorectal neoplasms, p < 0.0001). Weight loss P5% was associated with a poor prognostic factor (9 months vs 12 months, p = 0.006) in 350 patients with advanced oesophageal cancer who were treated in six consecutive prospective trials.13 Recently, Mitry and colleagues14 analyzed predictive factors of survival in patients with advanced colorectal cancer included in irinotecan phase III trials. By multivariate analysis, weight loss <5% was independently associated with a better overall survival (odds ratio 1.67, 95% CI 1.29–2.14). One hypothesis to explain these side effects is modification of xenobiotic
570 detoxification associated with inflammatory mediators and/ or nuclear receptors.15–18 In summary, severe malnutrition in patients undergoing curative treatment in GI cancer is clearly associated with increased morbidity and mortality, reduced efficacy of treatment, and increased length of hospital stay. Systematic screening for malnutrition should be instituted and then an appropriate and efficient nutritional support proposed if necessary.
Benefits of nutritional support for patients undergoing surgery Severely malnourished patients In this situation, the European guidelines6 indicate that ‘‘patients with severe nutritional risk benefit from nutritional support for 10–14 days prior to major surgery even if surgery is delayed. Whenever feasible, the enteral route should be preferred’’. To support these recommendations, further studies have been published. The impact of total parenteral nutrition (TPN) in patients undergoing surgery (not only GI cancer patients) was evaluated in four meta-analyses of prospective randomised trials.19–22 Three of these19,20,22 confirmed the benefits of preoperative nutrition in terms of a lower rate of postoperative morbidity. More precisely, Koretz and colleagues21 combined the trials that only included patients with stomach and oesophageal carcinoma. A reduction of major complications was demonstrated (estimated risk difference of 18%). Nevertheless, pooled data did not confirm that perioperative nutrition improves postoperative mortality rate. However, these meta-analyses were associated with a significant heterogeneity due to poor methodology, particularly considering the small number of patients, the short duration of the preoperative nutrition, and the unsuitable caloric intake in some studies. In 1982, Mu ¨ller and colleagues23 suggested that patients with GI neoplasms might benefit from preoperative parenteral nutrition, with fewer major complications and a significant lower mortality rate (18.6% vs 4.5%). In a control study, the Veterans Affairs Cooperative Study Group24 studied 395 malnourished (moderately and severe) patients (51% with GI cancer) and randomised between perioperative TPN (7–15 days before and 3 days after surgery) and no TPN. Only severely malnourished patients (NRI < 83.5) who received TPN had significantly fewer non-infectious complications than controls (5.3% vs 42.9%, p = 0.03). More recently, Bozzetti and colleagues25 presented the impact of perioperative TPN on reducing the risk of surgery in malnourished cancer patients (weight loss P10%). Ninety elective surgical patients with gastric or colorectal tumours were randomly assigned to perioperative parenteral nutrition or no TPN (control group). Postoperative morbidity was reduced by 20% (p = 0.03) for the patients receiving TPN. On the other hand, Heyland and colleagues20 suggested that enteral nutrition significantly reduces the complication rate compared with parenteral nutrition. In a meta-analysis, Braunschweig and colleagues26 presented the effects of enteral or parenteral nutrition in adults suffering from GI cancer and undergoing surgery.
P. Senesse et al. Pooled analysis suggested that tube feeding was associated with a lower risk of infection than parenteral nutrition (relative risk 0.66, 95% CI 0.56–0.79) but mortality and infectious complications are higher in studies reporting patients with severe protein calorie malnutrition. A recent systematic review27 (concerning a majority of GI cancer patients receiving postoperative nutrition) confirmed these data. Enteral tube feeding compared with parenteral nutrition was associated with a significantly shorter length of hospital stay and a lower incidence of all complications, namely, infections. Nevertheless, this review did not show a difference in terms of mortality. The main multicentre randomised trial28 compared postoperative enteral (surgical jejunostomy) and parenteral nutrition in 317 malnourished patients (weight loss P10%) with GI cancer and candidates for major elective surgery. Postoperative complications occurred in 54 (34%) and 78 (49%) of the patients fed enterally and parenterally, respectively (p = 0.005). Respective adverse effects appeared in 56 (35%) and 22 (14%) patients (p < 0.0001), respectively. A large prospective study,29 published in 2006, showed that artificial nutrition could reduce significantly surgical morbidity and mortality in malnourished GI cancer patients. Complications occurred in 18.3% of the patients receiving nutrition and in 33.5% of the control patients (p = 0.012). Fourteen patients died in the control group and five in the group receiving artificial nutrition (6.0% vs 2.1%, p = 0.003). The total length of hospitalization of control patients was significantly longer (29 vs 22 days, p = 0.014) than those for the patients receiving artificial nutrition. This large study confirms the interest and the necessity of proposing artificial nutrition to every severely malnourished patient undergoing major surgery for GI cancer. Another interest of this study is that it also proposes an artificial nutrition regimen with a pragmatic choice, namely, either enteral or parenteral nutrition, as determined by the clinician. After surgery, early enteral feeding is recommended. In fact, a meta-analysis30 was performed to compare the potential beneficial effects of early feeding vs nil by mouth after gastrointestinal surgery. Results (n = 837 patients) showed that early feeding (within 24 h after surgery) reduced significantly both the risk of infection and the mean length of hospital stay. Nevertheless, in proximal digestive tract surgery, early feeding may even be harmful. To improve the immunologic, metabolic, and clinical outcome in patients with GI malignancies, some researchers have studied an enteral immune-enhancing diet instead of a standard enteral diet. In severe malnourished patient, however, the use of perioperative immunonutrition remains, at least, debatable. In a review on enteral nutritional support and eicosapentaenoic acid (EPA) supplementation in patients with cancer,27 no significant difference in the incidence of infectious complications (odds ratio 0.84, 95% CI 0.39–1.82) following nutritional support was noted when compared with standard enteral feeding.
Non-malnourished patients For GI cancer patients undergoing abdominal surgery, preoperative oral immunonutrition (arginine, omega-3 fatty acids, and nucleotides) is now recommended.6 To support these recommendations, first, three meta-analyses have
Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit? been published.31–33 In summary, these meta-analyses demonstrated that a perioperative immunonutrition in surgical patients reduced the risk of infectious complications,31 and overall hospital stay but had no effect on mortality. The same results were obtained for surgical GI cancer patients with a significant reduction of infectious complications (odds ratio 0.47, 95% CI 0.30–0.73) and overall hospital stay ( 2.4 days, 95% CI 4.00 to 0.8).32 Second, three prospective studies demonstrated that a preoperative immunonutrition (arginine, omega-3 fatty acids, and nucleotides) in GI cancer patients reduced significantly the incidence of postoperative infections (Table 1).34–36 In the most important study,36 a total of 305 non or moderately malnourished patients (weight loss <10%) with cancer of the GI tract (gastrooesophageal, pancreatic, and colorectal surgery) were randomised to receive (1) oral supplementation for 5 days before surgery with 1 L/day of an immunonutrition, with no nutritional support given after surgery (preoperative group, n = 102); (2) the same preoperative treatment plus postoperative jejunal infusion with the same immunonutrition (perioperative group, n = 101); and (3) no artificial nutrition before and after surgery (conventional group; n = 102). Analysis showed a 13.7% incidence of postoperative infections in the preoperative group, 15.8% in the perioperative group, and 30.4% in the conventional group (p = 0.006 conventional vs preoperative group and p = 0.02 conventional vs perioperative group). In summary, for patients undergoing GI surgery, it seems essential to screen for severe malnutrition (Fig. 1). Numer-
Table 1
571
ous criteria or indices of malnutrition are available and could be a source of confusion. Consequently, in our opinion, even if the NRI or serum albumin levels help to establish the nutritional status of the patients, practical information like weight loss (>10% since the beginning of the disease) and the SGA would provide a better basis for deciding whether or not to delay surgery and to feed the patients more efficiently in the preoperative period. A severely malnourished patient (defined by a weight loss >10% or an SGA grade C) should have preoperative artificial nutrition for at leas, 10 days prior to major surgery and 7 days after surgery. Enteral nutrition is the best support for these patients, especially when there is no central venous access. Standard products should be proposed. In our opinion, the benefit of immune-enhancing diets in severely malnourished patients remains to be proven. Preoperative oral nutrition should be ad libitum (if possible) and provide an average 25 nonprotein kcal/kg per day and 0.25 g nitrogen/kg per day. On the other hand, preoperative oral immunonutrition (arginine, omega-3 fatty acids, and nucleotides) is indicated in non-malnourished patients (weight loss 610% or SGA grade A and B) 5 days prior to major GI cancer surgery.
Benefits of nutritional support for patients undergoing chemotherapy and/or radiotherapy According to the ESPEN guidelines on enteral nutrition of patients with extern beam radiotherapy or chemoradiation, every effort should be made to increase dietary intake and
Preoperative immunonutrition for non malnourished patients with gastrointestinal (GI) cancer: randomised trials
References
Patients
Nutritional status
Immunonutrition dose and schedule
Postoperative infectious complications
Braga et al.34
206 patients with neoplasm of stomach, pancreas, and colorectum randomised vs control enteral formula vs enteral immunonutrition
Well nourished (weight loss <10%) = 76% Malnourished patients (weight loss P 10%) = 24%
1 L/d for 7 consecutive days before and 7 days after surgery
Infectious complication rate: 14% vs 30% in the control group (p = 0.009)
Senkal et al.35
154 patients with neoplasm of oesophagus, stomach, and pancreas randomised preoperatively vs control oral formula vs oral immunonutrition
Nutrition Risk Index: 91 ± 15 in the control group 97 ± 12 in the immunonutrition group
1 L/d for 5 consecutive days before and 10 days after surgery by a jejunostomy
Infectious complication rate: 14% vs 27% in the control group (p = 0.05)
Gianotti et al.36
305 patients with neoplasm of oesophagus, stomach, pancreas, and colorectum randomised either preoperative oral formula vs pre or postoperative immunonutrition vs no artificial nutrition
Weight loss <10%
1 L/d for five consecutive days before surgery and 1 L/d for 5 days before and after surgery
Infectious complication rate: 13.7% (preoperative group) vs 15.8% (pre and postoperative group) vs 30.4% (p = 0.006 vs preoperative; p = 0.02 vs perioperative)
572
P. Senesse et al.
to prevent therapy associated weight loss and interruption of radiation therapy. Although routine enteral nutrition is not indicated during radiation therapy or chemotherapy, intensive dietary advice and oral nutritional supplements are recommended. Enteral nutrition should be delivered only if severe local mucositis is expected for oesophagus irradiation.37 However, there are no randomised controlled trial comparing PEG with nasogastric tube feeding and most of retrospective reports assessed nutritional supports in patients with head and neck cancers. Oral nutritional support should be proposed for all patients receiving neoadjuvant treatment. However, few studies are available, particularly, with regard to GI cancer. A recent review showed no difference in mortality between oral nutritional support or enteral tube feeding compared with routine care in patients undergoing chemotherapy or radiotherapy, but in patients undergoing radiotherapy, oral nutritional support significantly increased dietary intake compared with routine care.27 Recently, 60 patients (SGA grade A and B) with GI or head and neck neoplasms (12% rectal or abdominal radiotherapy, 13% oesophagus, and 75% head and neck) were randomised into two groups to compare standard care with an intensive oral nutritional intervention.38 The results showed a significant reduction in nutritional status (compared with the SGA grade, p = 0.02) and quality of life (p = 0.009) alterations when intensive nutritional intervention and oral nutritional supplementation were offered. Similarly, Ravasco and colleagues39,40
published two randomised studies. One hundred and eleven patients with colorectal cancer treated by radiotherapy were randomly assigned: dietary counselling (n = 37), two cans per day of a high-protein liquid supplement in addition to their usual diet (n = 37) and ad libitum intake (n = 37).39 After radiotherapy and at 3 months, the rates of anorexia, nausea, vomiting, and diarrhoea were higher in the group with ad libitum intake (p < 0.05). At radiotherapy completion, in the dietary counselling group, all quality of life function scores improved proportionally to adequate intake or nutritional status (p < 0.05). In the dietary counselling and protein supplement groups, improvement or deterioration of quality of life correlated with better or poorer intake of nutritional status (p < 0.003). In the other study by these investigators,40 75 randomised patients with head and neck tumours treated by radiotherapy were given either dietary counselling (n = 25), two cans per day of a high-protein liquid supplement in addition to their usual diet (n = 25) or allowed ad libitum intake (n = 25). After radiotherapy, quality of life function scores improved (p < 0.003) proportionally with nutritional intake and status in the dietary counselling and protein supplement groups (p < 0.05) but worsened in the ad libitum intake group (p < 0.05). At 3 months, the reduction of incidence and severity of grades 1 and 2 (anorexia, nausea, vomiting, xerostomia, and dysgeusia) was significantly decreased in the oral supplement group. Only patients in the dietary counselling group maintained or improved their overall
Surgery with morbidity >25–30% (oesophageal, stomach, pancreas, colorectal surgery)
NO
YES
No nutritional support Weekly follow-up
Body weight >10% or SGA grade C
NO
YES
No severe malnutrition
Oral immunonutrition (arginine, omega-3 fatty acids and nucleotides) 5 days prior to surgery Figure 1
Severe malnutrition
Artificial nutrition for, at least, 10 days prior to major surgery and 7 days after surgery
Nutritional support step-by-step for GI surgical patients.
Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit? quality of life. A complementary approach was published on patients with unresectable pancreatic cancer. Fearon and colleagues41 randomised, in a multicentre study, 200 patients with weight loss greater than 5% who consumed two cans per day of either a special diet with n 3 fatty acids or the identical supplement without the n 3 fatty acids. In an intention to treat analysis, comparisons indicated that both supplements were equally effective. Patients in both groups stopped losing weight (p < 0.001) but, at 8 weeks, 90 patients were lost to follow-up (death, withdrawal, and disease progression). In another multicentre trial42 over an 8-week period, 200 patients were randomised to drink 2 cans per day of an oral nutritional supplement with or without n 3 fatty acids. After 8 weeks, there was a significant improvement of body weight only (p < 0.001). There was no significant change in spontaneous food consumption. Over the 8 week period, only 53.6% of the patients were compliant to the treatment and drank 1.5 cans or more per day. In cases of severely malnourished patients or if the dietary counselling suffers a setback, artificial nutrition should then be proposed. Nevertheless, a meta-analysis showed a significantly increased rate of infectious complications, by 16%, when parenteral nutrition was used during radiochemotherapy.21 A recent review suggests that parenteral nutrition could be used only when enteral nutrition is contraindicated.43 However, few studies are available on enteral nutrition during neoadjuvant or adjuvant treatment. The most striking example is for upper GI tract malignancies before and during neoadjuvant treatment. Odelli and colleagues44 in a retrospective study, compared outcomes of two groups of patients: no nutritional support (n = 24) and nutritional support (n = 24). At the initial consultation, nutritional support included a systematic nutritional counselling. High energy intake was proposed for patients with anorexia, dysphagia or weight loss less than 10%; for severely malnourished patients (weight loss P10%, BMI <18), percutaneous endoscopic gastrostomy (PEG) was organised before starting treatment. Patients with a nutritional support had significantly greater radiotherapy completion rates (92% vs 50%), fewer hospital admissions (46% vs 75%) and shorter hospital stay (3.2 days vs 13.5 days). Other studies have shown that PEG is a feasible method even for oesophageal cancer patients and neoadjuvant treatment.45,46 In cases of oesophagectomy and stomach mobilization in particular, PEG placement requires an experienced team because of the risk of vascular stomach lesions. Further studies are needed to improve this method. In view of these results, dietary counselling should be proposed to all patients with neoadjuvant or adjuvant treatment by radiotherapy or chemotherapy as soon as possible. This counselling does not rule out oral supplements. However, to enhance compliance, Bauer and colleagues42 proposed a weekly contact with patients by either face-toface interview or telephone contact. It is very important that clinicians be convinced of this strategy. All patients should consider the dietary counselling and oral supplements as an essential component of their treatment. This is all the more urgent since a recent study47 showed that only 36% of patients with GI malignancies were referred to a dietician. One-third of the patients with more than 10% weight loss were not referred for dietary assessment. The authors concluded the following: ‘‘This study suggests that
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an out-patient dietetic screening tool is urgently required. Such screening is likely to result in considerable improvements to the clinical care of cancer patients with weight loss.’’ If dietary counselling suffers a setback or in cases of severely malnourished patients, enteral nutrition should be provided.
A question of timing Patients undergoing surgery (and a fortiori when flanked by neoadjuvant or adjuvant treatment) require early nutritional management. There is consequently great interest in having practical tools for nutritional evaluation (involuntary weight loss, SGA) applicable at the time of the patient’s first consultation with the surgeon, anaesthetist, or oncologist. Thus, regarding the recent guidelines for malnourished patients, a delay of 10 days prior to major surgery and a period of at least 7 days after surgery should be respected.6 Any proof of benefit should be noted from artificial nutritional support when administered for less than 7 days before surgery. In fact, it has not been investigated sufficiently whether short-term preoperative nutritional support. Moreover, if adjuvant treatment is needed (for example, radiochemotherapy after gastrectomy with a necessary caloric intake greater than 1500 kcal per day),48 the duration and the route of nutritional support administration must be considered. To prove this point, a study on 23 patients after total gastrectomy (without adjuvant oncologic treatment) showed that their average daily energy intake was 1457.9 kcal in the first postoperative month.49 In this case, postoperative jejunostomy enteral feeding was shown to be necessary in a substantial number of patients (pre- and postoperative enteral feeding for severe malnourished patients)50 and led to better management and outcome. Poor evaluation of this timing could lead to potentially ineffective and dangerous nutritional support protocols. On this subject, it is interesting to stress that the immediate preoperative period should not necessarily be a period of ‘‘urgent nutritional compensation’’ but, on the contrary, a period during which it is necessary to reduce salt and water intake, particularly during and after surgery. Lobo and colleagues51 studied the effect of salt and water balance on recovery of GI function in 21 patients after elective colonic resection in a randomised controlled trial. Positive salt and water balance sufficient to cause a 3 kg weight gain after surgery delayed return of GI function and prolonged hospital stay in patients undergoing elective colonic resection. Only one complication (hypokalaemia) was noted in the restriction group (p < 0.001). These data have recently been confirmed on a large trial, underlining the interest of restricted perioperative intake on metabolic and pulmonary complications and on cicatrisation.52 Although this approach might be valid, another 2006 randomised trial blunted our emphasis on postoperative intravenous fluid restriction on recovery after elective colorectal surgery and showed no significant reduction on hospital stay.53 In a recent review of randomised controlled trials, Holte and colleagues assessed the place of fluid therapy in surgical patients. Although perioperative fluid administration of greater than 1 L may improve recovery after minor or moderately
574 sized operations, care should be taken to avoid fluid overload in major surgical procedures.54
Conclusion Knowledge of the nutritional status of patients with GI cancer is essential, not only for screening malnourished or nonmalnourished patients, but especially to propose an adaptive treatment at each step of a multimodal oncological treatment. Numerous studies are available and convincing. In any cases, the earlier, the better. In clinical practice, the subjective global assessment appears relevant in trained teams but not easily adaptable for a generalized use (subjective tools). For this reason, it seems to us that weight loss is the best tools for screening nutritional status. Whatever the treatment procedure, surgical or not, all patients could benefit from nutritional support during oncologic treatments. An immunonutrition for 5 days before surgery must be proposed for non-malnourished patients and artificial nutrition for 10 days prior to major surgery for severely malnourished patients. Dietary counselling should be proposed for all patients receiving radiotherapy or chemotherapy. In our opinion, these recommendations should be used in daily practice but should also be included in all clinical research protocols concerning GI cancer patients receiving oncologic treatment.
Conflicts of interest statement We declare that we have no conflicts of interest.
Acknowledgement The authors wish to thank Dr. S.L. Salhi for critical comments and excellent editorial assistance.
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