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Impact of home enteral nutrition in malnourished patients with upper gastrointestinal cancer: A multicentre randomised clinical trial
European Journal of Cancer 64 (2016) 107e112
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Original Research
Impact of home enteral nutrition in malnourished patients with upper gastrointestinal cancer: A multicentre randomised clinical trial Cecilia Gavazzi a,*, Silvia Colatruglio a, Filippo Valoriani b, Vincenzo Mazzaferro c, Annarita Sabbatini b, Roberto Biffi b, Luigi Mariani d, Rosalba Miceli d a
Unit of Nutrition Therapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Division of Abdominal-Pelvic Surgery, European Institute of Oncology, Milan, Italy c Department of Surgery, Liver Transplantation and Gastroenterology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy d Unit of Medical Statistics, Biometry, Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy b
Received 1 February 2016; received in revised form 11 May 2016; accepted 20 May 2016
KEYWORDS Gastrointestinal cancer; Malnutrition; Home enteral nutrition; Nutritional counselling
Abstract Background: Weight loss is frequent in patients with gastrointestinal (GI) cancer. Nutritional status deteriorates throughout anti-cancer treatment, mostly after major surgery, increasing complications, reducing tolerance and worsening the final prognosis. Enteral nutrition is safe and effective in malnourished patients undergoing major GI surgery. Randomised trials aimed at investigating the effects of home enteral nutrition (HEN) in post-surgical patients with GI cancer are lacking. This study compares HEN and counselling in limiting weight loss during oncologic treatment. Patients and methods: Patients with upper GI cancer and candidate to major surgery were included in the protocol when the nutritional risk screening (NRS 2002) score was 3. All patients were supported with enteral nutrition through a jejunostomy after surgery and randomly assigned to continue enteral nutrition or receiving nutritional counselling after discharge. Nutritional and performance status, quality of life (QoL) and tolerance to cancer treatment have been evaluated at 2 and 6 months after discharge. Results: Seventy-nine patients were randomised; 38 continued enteral nutrition at home and 41 patients received nutritional counselling only. After 2 months, patients on HEN maintained their mean body weight, while patients in the nutritional counselling group showed a weight loss of 3.6 kg. Patients supported on HEN had a higher chance to complete chemotherapy as planned (48% versus 34%). QoL was not worsened by HEN. No complications were reported. Conclusions: HEN is a simple and feasible treatment to support malnourished patients with
* Corresponding author: Head Unit of Nutrition Therapy, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. E-mail address: [email protected] (C. Gavazzi). http://dx.doi.org/10.1016/j.ejca.2016.05.032 0959-8049/Published by Elsevier Ltd.
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upper GI cancer after major surgery and during chemotherapy in order to limit further weight loss. Published by Elsevier Ltd.
1. Introduction Malnutrition in gastrointestinal (GI) cancer patients negatively affects all different phases of oncologic treatment and represents an independent prognostic factor for worse clinical outcomes [1,2]. In more detail, malnutrition increases surgical morbidity and mortality, enhances the incidence and severity of chemo- or radiotherapy-associated toxicities, prolongs hospital staying and decreases performance status and quality of life (QoL) [2]. Weight loss is the most frequent sign of malnutrition, often present since diagnosis [3], with a prevalence in GI cancer patients ranging from 49.5% to 69.2% [4,5]. It is associated with shorter survival [6,7]. Of note, standard treatment approaches for GI cancer such as surgery and chemoradiotherapy further deteriorates nutritional status [8,9]. In order to maintain an adequate nutritional status over the oncological treatment period, regular assessment of nutritional indicators and specific nutrition interventions should be instituted from diagnosis [10e12]. Body mass index, recent weight loss and change in food intake correlate with impaired organ function and clinical outcome; these parameters, together with assessment of clinical conditions, are used to calculate the nutritional risk score with the NRS 2002 tool and therefore to identify patients who are more likely to benefit from nutritional intervention [13]. Enteral nutrition is safe and effective in malnourished patients undergoing major GI surgery [12,14e16]. After hospital discharge, the continuation of home enteral nutrition (HEN) and regular monitoring of nutritional status might prevent further deterioration of nutritional status and allow patients to complete scheduled anticancer treatment [17,18]. However, to our knowledge, prospective evidence specifically aimed at investigating the effects of HEN in post-surgical patients with GI cancer is lacking. This randomised study evaluates the impact of HEN on nutritional status, QoL and chemotherapy feasibility in malnourished patients affected by upper GI cancer who underwent major surgery.
(Milan, Italy) and at the European Institute of Oncology (Milan, Italy). Patients were randomly assigned e by a computer-generated list e in a 1:1 ratio stratified according to centre by following a random permuted block design to receive either HEN (treatment group) or nutritional counselling only (control group). Each row of the list contained the randomisation number (progressive number) and the randomisation arm. One interim and one final efficacy analyses were planned, with the interim analysis to be performed when half of the patients had been followed for at least 6 months. The study was conducted in line with the Helsinki declaration; its design was approved by the local Ethical Committees and all patients signed an informed consent before inclusion. During the study, the patients will not be blinded as to which random arm they are in. The trial was registered at clinicaltrials.gov (registration number NCT02664974). 2.2. Patients Adult (>18 years) patients with documented cancer of the upper GI tract (oesophagus, stomach, pancreas, biliary tract) who were candidate for major elective surgery and presented a preoperative nutritional risk score 3 according to the NRS 2002 tool [13] were eligible. Exclusion criteria were as follows: Karnofsky index <60, renal insufficiency (ongoing haemodialysis or plasma creatinine >3 mg/dl), respiratory insufficiency (arterial blood PaO2 <70 mmHg), American Society of Anaesthesiology score 4e5, ChildePugh liver function class C, short bowel syndrome, pregnancy or need for emergency or palliative surgery. Patients with foreign residence, residents in an Italian region with no specific regulation for HEN or those unable to be regularly followed-up were excluded as well from accrual. Patients were free to leave the study at any time. The investigators also could withdraw subjects from the study in case of administrative issues related to HEN product delivery or repeated absence to planned followup controls.
2. Patients and methods 2.3. Interventions 2.1. Design This was a multicentre, controlled, open-label, two-parallel groups, randomised clinical trial conducted at the Fondazione IRCCS Istituto Nazionale dei Tumori
The study was conducted from December 2008 to June 2011; the minimum treatment period was 2 months. All patients continued observation until 6 months after discharge.
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In all patients, a fine needle catheter jejunostomy was implanted at the end of scheduled surgery. Enteral nutrition was started on post-operative day 1 and it was progressively increased, oral intake was allowed from post-operative day 2, and when it was regularly reassumed, enteral nutrition was reduced or stopped. Randomisation was performed before discharge, and in HEN group, enteral nutrition was planned to cover the basal energy requirement calculated with HarriseBenedict equation [19]. It was administrated preferentially overnight as an integration of oral diet. HEN included any standard polymeric formula providing 1e1.5 kcal/ml with 50e60% carbohydrates, 25e35% lipids and 12e20% proteins. HEN could be withdrawn after 2 months from discharge whenever a weight gain 5% was reported and oral diet was regular and adequate. Before discharge, patients and/or caregivers were trained for the correct use of HEN, and all required materials were provided by the regional healthcare system. In the control group, specific nutritional indications including total energy and protein requirements were provided to patients by an experienced dietitian working with cancer patients; oral nutritional supplements could be prescribed as necessary. The same HEN protocol described above could be started in patients assigned to the control group, not before 2 months from discharge if a further weight loss 5% was reported. All patients continued their oncological treatment according to the standard practice of the participating centres. 2.4. Evaluations After initial assessment, aiming at identifying nutritional risk according to the NRS 2002 tool, patients were reevaluated for nutritional status at hospital discharge (baseline) and after 2 and 6 months. Patients were evaluated, by the treating physician and a trained dietitian, for nutritional status (body weight and biochemical nutritional indicators including serum levels of total protein, albumin, prealbumin, transferrin and lymphocytes and muscle strength, measured on the dominant arm by a hand grip dynamometer, according to manufacturer’s instruction [Bolingbrook, IL, USA]) and Karnofsky performance status (KPS). Caloric intake (expressed as kcal/kg) was assessed at 2 and 6 months using a diet history technique referred to the week prior to the evaluation. Mean caloric intake was determined using Food Composition Database for Epidemiological Studies in Italy [20]. QoL was evaluated by the self-administrated Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire [21] at discharge (baseline) and after 2 months. The actual completion of the planned cancer treatment was evaluated at 6 months after discharge. Patients and caregivers were encouraged to report any mechanical (e.g. tube obstruction) or clinical (e.g.
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diarrhoea and constipation) complications associated with HEN, and complications were evaluated by investigators. Caregivers were specifically instructed on how to handle those events. 2.5. Statistical methods The primary study objective was to investigate a favourable effect of HEN on nutritional status. The treatment effect corresponded to the difference between the mean ‘weight change’ (difference between the weight after 2 months after discharge and baseline weight) in the HEN and nutritional counselling arms. The efficacy analyses were performed considering the eligible patients as randomised, according to the intent-to-treat principle. In order not to exceed an overall type I error of 5%, the nominal significance level required by each analysis was 2.94%, according to Pocok’s procedure. If this threshold was reached at the interim analysis, the trial had to be stopped. To evaluate the main end-point, a univariable linear model was fitted, including only treatment arm as covariate. The model results are reported in terms of difference between the mean weight loss in the two randomisation arms, the corresponding 95% confidence interval (CI), and two-sided Wald test p value. The main analysis was performed on the subset of patients for whom information on 2-month weight was available (evaluable set). In addition, missing information on weight loss were filled in by applying a multiple imputation procedure, according to the model-based approach by Van Buuren and Oudshoorn [22] and using the R library MICE (multivariate imputation by chained equations. The MI model predictors were as follows: centre, randomised arm, patient gender and age, tumour characteristic (site, histology, T, N and M stage), usual weight, weight loss at randomisation, body mass index, and NRS. The arm-specific pooled mean weight loss and corresponding standard error were obtained by combining the estimates obtained in each of the 10 multiply imputed data sets by using the Rubin’s method [23]. As a secondary end-point, it was also planned to evaluate treatment success defined as the possibility to undergo chemotherapy as planned. The analysis was performed by fitting a multivariable binary logistic model in which the response variable took the value of 1 when a patient was submitted to therapy as planned and 0 otherwise; the model included as covariates the actual treatment arm (treatment actually received), together with potential confounding factors such as patients age, modelled as continuous variable by using a three-knot restricted cubic spline to obtain flexible fit [24], and tumour site. The model results are reported in terms of odds ratio, corresponding 95% CI, and two-sided Wald test p value. The SASä software (SAS/STAT Software: Changes and Enhancements through Release 6.11, Cary, NC:
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SAS Institute Inc., 2000) and the R software (http:// www.r-project.org/, last accessed on 18th September 2015) were used to perform all modelling and statistical calculations. 3. Results 3.1. Patient population In total, 79 patients were enrolled; of these, 38 were assigned to HEN group. Their baseline characteristics are reported in Table 1. Fig. S1 shows patients’ disposition throughout the study. No complications associated with HEN were reported. In the HEN group, mean body weight was 61.0 11.2 kg before surgery and 60.2 11.9 at discharge; these figures were 63.1 12.1 and 61.7 11.4 in the control group, respectively. In total, 16 patients were switched from the control group to the HEN group 2 months from discharge, due to further weight loss 5%. 3.2. Weight change
the trial was stopped since HEN showed increased efficacy over counselling only. Similar results were obtained with the multiple imputation of missing data on weight loss. At 6 months, the variation in body weight was 0.4 5.6 kg in the treated group ( 0.6%) and 2.4 5.0 kg in the control group ( 3.8%). 3.3. Other nutritional parameters
At 2 months, patients in HEN group had maintained their body weight ( 0.3 3.9 kg, e0.5% compared with baseline) as compared with control group, in which a reduction of body weight was observed ( 3.6 4.8 kg, e5.8% as compared with baseline) (Fig. 1 and Tables S1 and S2). This corresponded to a treatment effect of 3.2 kg (95% CI: 1.1e5.3), with a significant advantage for the HEN group (p Z 0.0031, lower than 0.0294, that was the nominal significance for the evaluation of efficacy, as established for the interim analysis). Therefore, Table 1 Patients and disease characteristics at baseline CG N Total Patients’ age (years) Median (IQ range) Gender Female Male Tumour site Oesophagus Pancreas Stomach Biliary tract Tumour histology Adenocarcinoma Squamocellular Other Tumour stage I II >II
Fig. 1. Percentage variation in body weight over the study.
HEN %
N
At 2 months, the mean total caloric intake was significantly higher in HEN patients, as compared with the nutritional counselling group (40.6 versus 30.2 kcal/kg, p Z 0.0001). On the other hand, no differences were observed in terms of caloric intake per os (26.0 versus 28.2 kcal/kg, p Z 0.3746) at the same time point (Table S1). Similarly, no differences in the serum concentration of biochemical nutritional indicators over the study period were reported in either group, although a trend towards an increased concentration of transferrin at 6 months was disclosed in the HEN group (baseline: 185 41 mg/dl, 6 months: 296 86 mg/dl); no differences between groups were detected (Table S1).
%
41
38
3.4. Hand grip
69 (58e76)
67 (62e74)
In both groups, hand grip strength did not change over the study period; no differences between groups were reported (Table S1).
15 26
36.6 63.4
15 23
39.5 60.5
7 5 26 3
17.1 12.2 63.4 7.3
7 8 19 4
18.4 21.1 50.0 10.5
37 3 1
90.2 7.3 2.4
34 2 2
89.5 5.3 5.3
6 14 21
14.6 34.1 51.2
2 12 24
5.3 31.6 63.2
CG: control group; HEN: home enteral nutrition; IQ: interquartile range.
3.5. Treatment success Information on planned/received chemotherapy (CT) was not available for 7 patients; thus, the analysis was performed on 72 patients, 37 (51%) of whom were in the HEN group. Chemotherapy was planned for 50 patients; 30 subjects regularly received treatment, 18 of which actually received HEN. There was a trend for a greater treatment success for HEN compared with the control group (18 of 37, 48% versus 12 of 35, 34%; chisquare test, p Z 0.217). This trend was confirmed at the multivariable logistic analysis (Table S3). Specifically,
C. Gavazzi et al. / European Journal of Cancer 64 (2016) 107e112
the chance to have CT administered as planned was approximately 2.5 times greater with HEN than with nutritional counselling only, as indicated by the odds ratio estimate; however, this difference was not statistically significant (p Z 0.103). 3.6. QoL Overall, the FAACT score improved at two months, with respect to baseline values, in both groups; no differences between groups were reported (Table S1). 4. Discussion Weight loss and malnutrition represent a major issue in the management of patients with upper GI cancer [16]. In fact, surgery and chemotherapy can cause malabsorption, increased metabolism and reduced food intake, thus increasing the risk of deterioration of nutritional status and ultimately affecting clinical outcomes. The importance of oral supplements for reducing weight loss in post-surgical patients with GI cancer has already been suggested by Beattie et al. [8], but randomised studies evaluating the impact of long term use of enteral nutrition in this setting are lacking. In our randomised study, we compared the effect of HEN with another intervention, i.e. nutritional counselling including oral supplements, in post-surgical malnourished patients with upper GI cancers. We showed that patients supported with HEN succeeded in maintaining a stable body weight at 2 months after surgery (primary end-point). On the other hand, patients in the control group, despite receiving nutritional counselling with oral supplements, experienced a further weight loss of 3.5 kg. This figure is overall comparable with the result reported by Beattie et al. [8] in the treated group. The statistically significant advantage observed in the HEN at the interim analysis e which led to trial interruption as prespecified in the protocol e was still evident at 6 months. Noteworthy, HEN was not associated with any adverse effect. This maintenance of weight can be attributed to the increased total caloric intake reported in the HEN group, compared with the control group. In fact, total caloric intake was significantly higher in patients supported with HEN compared with patients who received nutritional counselling only (40.6 versus 30.2 kcal/kg) while oral caloric intake was similar in the two groups. The administration of standardised HEN resulted in a caloric surplus, higher than current recommendations [12], but probably necessary in patients with increased metabolism and malabsorption. Interestingly, both groups maintained stable and in normal range functional strength (hand grip) and biochemical nutritional indicators, suggesting that the main cause for malnutrition was reduced dietary intake
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more than altered metabolic demand as for inflammatory state. Previous studies have suggested that nutritional counselling plus oral supplementation do not positively influence survival [17]. HEN might provide advantage to this respect. In fact, patients assigned to HEN had a z2.5-fold higher probability of completing the adjuvant chemotherapy treatment as planned e which was our definition of treatment success in this protocol e with respect to the nutritional counselling group, with potential advantages in terms of clinical outcomes. We acknowledge that chemotherapy interruption or modification of scheduling may have been due to a number of reasons other than nutritional status (e.g. occurrence of unacceptable toxicities). When comparing treatment success between the two groups, statistical significance was not reached likely due to small sample sizes. In the present study, sample size was calculated in order to evaluate the overall treatment effect and subgroup analyses were not pre-planned, thus reporting of results by tumour type or age group is not appropriate. Future randomised studies, possibly with a larger sample size, are warranted for analysing the effect of HEN on nutritional status separately for oesophagus, stomach, pancreas, or biliary tract cancers, possibly preplanning subgroup analyses by age groups. Remarkably, in our study QoL, as assessed by the FAACT score, was not worsened by HEN. This finding is in line with other studies, which suggest neutral, if not beneficial, effect of HEN on QoL, although further evidence appears necessary to fully investigate this issue [25,26]. The functional status of the patients, assessed by the KPS, remained unchanged as well. Our study is not without limitations other than limited sample size. For instance, we did not collect detailed information about nutritional support in the peri-operative setting, since it was the objective of other studies conducted in similar, but mixed, population of patients undergoing GI surgery [27,28]. On the other hand, the main focus of our study was on the 2 months after major surgery discharge. Nutritional support was similar in the two groups during the post-operative period and no statistical difference in body weight was recorded before surgery and at discharge. Another limitation is that we did not collect information on changes in body composition over the study period. We are currently investigating this parameter e which may have a potential impact on prognosis e in a dedicated study. In conclusion, our randomised study lends support to the importance of HEN in upper GI cancer patients, after major surgery, as it helps maintain body weight without any safety concern or detrimental impact on QoL. This effect can translate into a higher probability to start and complete scheduled chemotherapy. More trials are required to confirm this preliminary evidence.
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Conflict of interest statement None declared.
Acknowledgements Data management was supported by Tiziana Camerini; editorial assistance for the preparation of this manuscript was provided by Luca Giacomelli, PhD; and this assistance was supported by internal funds.
[12]
[13]
[14]
[15]
Appendix A. Supplementary data [16]
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejca.2016.05.032. [17]
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Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Original Research
Impact of home enteral nutrition in malnourished patients with upper gastrointestinal cancer: A multicentre randomised clinical trial Cecilia Gavazzi a,*, Silvia Colatruglio a, Filippo Valoriani b, Vincenzo Mazzaferro c, Annarita Sabbatini b, Roberto Biffi b, Luigi Mariani d, Rosalba Miceli d a
Unit of Nutrition Therapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Division of Abdominal-Pelvic Surgery, European Institute of Oncology, Milan, Italy c Department of Surgery, Liver Transplantation and Gastroenterology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy d Unit of Medical Statistics, Biometry, Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy b
Received 1 February 2016; received in revised form 11 May 2016; accepted 20 May 2016
KEYWORDS Gastrointestinal cancer; Malnutrition; Home enteral nutrition; Nutritional counselling
Abstract Background: Weight loss is frequent in patients with gastrointestinal (GI) cancer. Nutritional status deteriorates throughout anti-cancer treatment, mostly after major surgery, increasing complications, reducing tolerance and worsening the final prognosis. Enteral nutrition is safe and effective in malnourished patients undergoing major GI surgery. Randomised trials aimed at investigating the effects of home enteral nutrition (HEN) in post-surgical patients with GI cancer are lacking. This study compares HEN and counselling in limiting weight loss during oncologic treatment. Patients and methods: Patients with upper GI cancer and candidate to major surgery were included in the protocol when the nutritional risk screening (NRS 2002) score was 3. All patients were supported with enteral nutrition through a jejunostomy after surgery and randomly assigned to continue enteral nutrition or receiving nutritional counselling after discharge. Nutritional and performance status, quality of life (QoL) and tolerance to cancer treatment have been evaluated at 2 and 6 months after discharge. Results: Seventy-nine patients were randomised; 38 continued enteral nutrition at home and 41 patients received nutritional counselling only. After 2 months, patients on HEN maintained their mean body weight, while patients in the nutritional counselling group showed a weight loss of 3.6 kg. Patients supported on HEN had a higher chance to complete chemotherapy as planned (48% versus 34%). QoL was not worsened by HEN. No complications were reported. Conclusions: HEN is a simple and feasible treatment to support malnourished patients with
* Corresponding author: Head Unit of Nutrition Therapy, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. E-mail address: [email protected] (C. Gavazzi). http://dx.doi.org/10.1016/j.ejca.2016.05.032 0959-8049/Published by Elsevier Ltd.
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C. Gavazzi et al. / European Journal of Cancer 64 (2016) 107e112
upper GI cancer after major surgery and during chemotherapy in order to limit further weight loss. Published by Elsevier Ltd.
1. Introduction Malnutrition in gastrointestinal (GI) cancer patients negatively affects all different phases of oncologic treatment and represents an independent prognostic factor for worse clinical outcomes [1,2]. In more detail, malnutrition increases surgical morbidity and mortality, enhances the incidence and severity of chemo- or radiotherapy-associated toxicities, prolongs hospital staying and decreases performance status and quality of life (QoL) [2]. Weight loss is the most frequent sign of malnutrition, often present since diagnosis [3], with a prevalence in GI cancer patients ranging from 49.5% to 69.2% [4,5]. It is associated with shorter survival [6,7]. Of note, standard treatment approaches for GI cancer such as surgery and chemoradiotherapy further deteriorates nutritional status [8,9]. In order to maintain an adequate nutritional status over the oncological treatment period, regular assessment of nutritional indicators and specific nutrition interventions should be instituted from diagnosis [10e12]. Body mass index, recent weight loss and change in food intake correlate with impaired organ function and clinical outcome; these parameters, together with assessment of clinical conditions, are used to calculate the nutritional risk score with the NRS 2002 tool and therefore to identify patients who are more likely to benefit from nutritional intervention [13]. Enteral nutrition is safe and effective in malnourished patients undergoing major GI surgery [12,14e16]. After hospital discharge, the continuation of home enteral nutrition (HEN) and regular monitoring of nutritional status might prevent further deterioration of nutritional status and allow patients to complete scheduled anticancer treatment [17,18]. However, to our knowledge, prospective evidence specifically aimed at investigating the effects of HEN in post-surgical patients with GI cancer is lacking. This randomised study evaluates the impact of HEN on nutritional status, QoL and chemotherapy feasibility in malnourished patients affected by upper GI cancer who underwent major surgery.
(Milan, Italy) and at the European Institute of Oncology (Milan, Italy). Patients were randomly assigned e by a computer-generated list e in a 1:1 ratio stratified according to centre by following a random permuted block design to receive either HEN (treatment group) or nutritional counselling only (control group). Each row of the list contained the randomisation number (progressive number) and the randomisation arm. One interim and one final efficacy analyses were planned, with the interim analysis to be performed when half of the patients had been followed for at least 6 months. The study was conducted in line with the Helsinki declaration; its design was approved by the local Ethical Committees and all patients signed an informed consent before inclusion. During the study, the patients will not be blinded as to which random arm they are in. The trial was registered at clinicaltrials.gov (registration number NCT02664974). 2.2. Patients Adult (>18 years) patients with documented cancer of the upper GI tract (oesophagus, stomach, pancreas, biliary tract) who were candidate for major elective surgery and presented a preoperative nutritional risk score 3 according to the NRS 2002 tool [13] were eligible. Exclusion criteria were as follows: Karnofsky index <60, renal insufficiency (ongoing haemodialysis or plasma creatinine >3 mg/dl), respiratory insufficiency (arterial blood PaO2 <70 mmHg), American Society of Anaesthesiology score 4e5, ChildePugh liver function class C, short bowel syndrome, pregnancy or need for emergency or palliative surgery. Patients with foreign residence, residents in an Italian region with no specific regulation for HEN or those unable to be regularly followed-up were excluded as well from accrual. Patients were free to leave the study at any time. The investigators also could withdraw subjects from the study in case of administrative issues related to HEN product delivery or repeated absence to planned followup controls.
2. Patients and methods 2.3. Interventions 2.1. Design This was a multicentre, controlled, open-label, two-parallel groups, randomised clinical trial conducted at the Fondazione IRCCS Istituto Nazionale dei Tumori
The study was conducted from December 2008 to June 2011; the minimum treatment period was 2 months. All patients continued observation until 6 months after discharge.
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In all patients, a fine needle catheter jejunostomy was implanted at the end of scheduled surgery. Enteral nutrition was started on post-operative day 1 and it was progressively increased, oral intake was allowed from post-operative day 2, and when it was regularly reassumed, enteral nutrition was reduced or stopped. Randomisation was performed before discharge, and in HEN group, enteral nutrition was planned to cover the basal energy requirement calculated with HarriseBenedict equation [19]. It was administrated preferentially overnight as an integration of oral diet. HEN included any standard polymeric formula providing 1e1.5 kcal/ml with 50e60% carbohydrates, 25e35% lipids and 12e20% proteins. HEN could be withdrawn after 2 months from discharge whenever a weight gain 5% was reported and oral diet was regular and adequate. Before discharge, patients and/or caregivers were trained for the correct use of HEN, and all required materials were provided by the regional healthcare system. In the control group, specific nutritional indications including total energy and protein requirements were provided to patients by an experienced dietitian working with cancer patients; oral nutritional supplements could be prescribed as necessary. The same HEN protocol described above could be started in patients assigned to the control group, not before 2 months from discharge if a further weight loss 5% was reported. All patients continued their oncological treatment according to the standard practice of the participating centres. 2.4. Evaluations After initial assessment, aiming at identifying nutritional risk according to the NRS 2002 tool, patients were reevaluated for nutritional status at hospital discharge (baseline) and after 2 and 6 months. Patients were evaluated, by the treating physician and a trained dietitian, for nutritional status (body weight and biochemical nutritional indicators including serum levels of total protein, albumin, prealbumin, transferrin and lymphocytes and muscle strength, measured on the dominant arm by a hand grip dynamometer, according to manufacturer’s instruction [Bolingbrook, IL, USA]) and Karnofsky performance status (KPS). Caloric intake (expressed as kcal/kg) was assessed at 2 and 6 months using a diet history technique referred to the week prior to the evaluation. Mean caloric intake was determined using Food Composition Database for Epidemiological Studies in Italy [20]. QoL was evaluated by the self-administrated Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire [21] at discharge (baseline) and after 2 months. The actual completion of the planned cancer treatment was evaluated at 6 months after discharge. Patients and caregivers were encouraged to report any mechanical (e.g. tube obstruction) or clinical (e.g.
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diarrhoea and constipation) complications associated with HEN, and complications were evaluated by investigators. Caregivers were specifically instructed on how to handle those events. 2.5. Statistical methods The primary study objective was to investigate a favourable effect of HEN on nutritional status. The treatment effect corresponded to the difference between the mean ‘weight change’ (difference between the weight after 2 months after discharge and baseline weight) in the HEN and nutritional counselling arms. The efficacy analyses were performed considering the eligible patients as randomised, according to the intent-to-treat principle. In order not to exceed an overall type I error of 5%, the nominal significance level required by each analysis was 2.94%, according to Pocok’s procedure. If this threshold was reached at the interim analysis, the trial had to be stopped. To evaluate the main end-point, a univariable linear model was fitted, including only treatment arm as covariate. The model results are reported in terms of difference between the mean weight loss in the two randomisation arms, the corresponding 95% confidence interval (CI), and two-sided Wald test p value. The main analysis was performed on the subset of patients for whom information on 2-month weight was available (evaluable set). In addition, missing information on weight loss were filled in by applying a multiple imputation procedure, according to the model-based approach by Van Buuren and Oudshoorn [22] and using the R library MICE (multivariate imputation by chained equations. The MI model predictors were as follows: centre, randomised arm, patient gender and age, tumour characteristic (site, histology, T, N and M stage), usual weight, weight loss at randomisation, body mass index, and NRS. The arm-specific pooled mean weight loss and corresponding standard error were obtained by combining the estimates obtained in each of the 10 multiply imputed data sets by using the Rubin’s method [23]. As a secondary end-point, it was also planned to evaluate treatment success defined as the possibility to undergo chemotherapy as planned. The analysis was performed by fitting a multivariable binary logistic model in which the response variable took the value of 1 when a patient was submitted to therapy as planned and 0 otherwise; the model included as covariates the actual treatment arm (treatment actually received), together with potential confounding factors such as patients age, modelled as continuous variable by using a three-knot restricted cubic spline to obtain flexible fit [24], and tumour site. The model results are reported in terms of odds ratio, corresponding 95% CI, and two-sided Wald test p value. The SASä software (SAS/STAT Software: Changes and Enhancements through Release 6.11, Cary, NC:
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SAS Institute Inc., 2000) and the R software (http:// www.r-project.org/, last accessed on 18th September 2015) were used to perform all modelling and statistical calculations. 3. Results 3.1. Patient population In total, 79 patients were enrolled; of these, 38 were assigned to HEN group. Their baseline characteristics are reported in Table 1. Fig. S1 shows patients’ disposition throughout the study. No complications associated with HEN were reported. In the HEN group, mean body weight was 61.0 11.2 kg before surgery and 60.2 11.9 at discharge; these figures were 63.1 12.1 and 61.7 11.4 in the control group, respectively. In total, 16 patients were switched from the control group to the HEN group 2 months from discharge, due to further weight loss 5%. 3.2. Weight change
the trial was stopped since HEN showed increased efficacy over counselling only. Similar results were obtained with the multiple imputation of missing data on weight loss. At 6 months, the variation in body weight was 0.4 5.6 kg in the treated group ( 0.6%) and 2.4 5.0 kg in the control group ( 3.8%). 3.3. Other nutritional parameters
At 2 months, patients in HEN group had maintained their body weight ( 0.3 3.9 kg, e0.5% compared with baseline) as compared with control group, in which a reduction of body weight was observed ( 3.6 4.8 kg, e5.8% as compared with baseline) (Fig. 1 and Tables S1 and S2). This corresponded to a treatment effect of 3.2 kg (95% CI: 1.1e5.3), with a significant advantage for the HEN group (p Z 0.0031, lower than 0.0294, that was the nominal significance for the evaluation of efficacy, as established for the interim analysis). Therefore, Table 1 Patients and disease characteristics at baseline CG N Total Patients’ age (years) Median (IQ range) Gender Female Male Tumour site Oesophagus Pancreas Stomach Biliary tract Tumour histology Adenocarcinoma Squamocellular Other Tumour stage I II >II
Fig. 1. Percentage variation in body weight over the study.
HEN %
N
At 2 months, the mean total caloric intake was significantly higher in HEN patients, as compared with the nutritional counselling group (40.6 versus 30.2 kcal/kg, p Z 0.0001). On the other hand, no differences were observed in terms of caloric intake per os (26.0 versus 28.2 kcal/kg, p Z 0.3746) at the same time point (Table S1). Similarly, no differences in the serum concentration of biochemical nutritional indicators over the study period were reported in either group, although a trend towards an increased concentration of transferrin at 6 months was disclosed in the HEN group (baseline: 185 41 mg/dl, 6 months: 296 86 mg/dl); no differences between groups were detected (Table S1).
%
41
38
3.4. Hand grip
69 (58e76)
67 (62e74)
In both groups, hand grip strength did not change over the study period; no differences between groups were reported (Table S1).
15 26
36.6 63.4
15 23
39.5 60.5
7 5 26 3
17.1 12.2 63.4 7.3
7 8 19 4
18.4 21.1 50.0 10.5
37 3 1
90.2 7.3 2.4
34 2 2
89.5 5.3 5.3
6 14 21
14.6 34.1 51.2
2 12 24
5.3 31.6 63.2
CG: control group; HEN: home enteral nutrition; IQ: interquartile range.
3.5. Treatment success Information on planned/received chemotherapy (CT) was not available for 7 patients; thus, the analysis was performed on 72 patients, 37 (51%) of whom were in the HEN group. Chemotherapy was planned for 50 patients; 30 subjects regularly received treatment, 18 of which actually received HEN. There was a trend for a greater treatment success for HEN compared with the control group (18 of 37, 48% versus 12 of 35, 34%; chisquare test, p Z 0.217). This trend was confirmed at the multivariable logistic analysis (Table S3). Specifically,
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the chance to have CT administered as planned was approximately 2.5 times greater with HEN than with nutritional counselling only, as indicated by the odds ratio estimate; however, this difference was not statistically significant (p Z 0.103). 3.6. QoL Overall, the FAACT score improved at two months, with respect to baseline values, in both groups; no differences between groups were reported (Table S1). 4. Discussion Weight loss and malnutrition represent a major issue in the management of patients with upper GI cancer [16]. In fact, surgery and chemotherapy can cause malabsorption, increased metabolism and reduced food intake, thus increasing the risk of deterioration of nutritional status and ultimately affecting clinical outcomes. The importance of oral supplements for reducing weight loss in post-surgical patients with GI cancer has already been suggested by Beattie et al. [8], but randomised studies evaluating the impact of long term use of enteral nutrition in this setting are lacking. In our randomised study, we compared the effect of HEN with another intervention, i.e. nutritional counselling including oral supplements, in post-surgical malnourished patients with upper GI cancers. We showed that patients supported with HEN succeeded in maintaining a stable body weight at 2 months after surgery (primary end-point). On the other hand, patients in the control group, despite receiving nutritional counselling with oral supplements, experienced a further weight loss of 3.5 kg. This figure is overall comparable with the result reported by Beattie et al. [8] in the treated group. The statistically significant advantage observed in the HEN at the interim analysis e which led to trial interruption as prespecified in the protocol e was still evident at 6 months. Noteworthy, HEN was not associated with any adverse effect. This maintenance of weight can be attributed to the increased total caloric intake reported in the HEN group, compared with the control group. In fact, total caloric intake was significantly higher in patients supported with HEN compared with patients who received nutritional counselling only (40.6 versus 30.2 kcal/kg) while oral caloric intake was similar in the two groups. The administration of standardised HEN resulted in a caloric surplus, higher than current recommendations [12], but probably necessary in patients with increased metabolism and malabsorption. Interestingly, both groups maintained stable and in normal range functional strength (hand grip) and biochemical nutritional indicators, suggesting that the main cause for malnutrition was reduced dietary intake
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more than altered metabolic demand as for inflammatory state. Previous studies have suggested that nutritional counselling plus oral supplementation do not positively influence survival [17]. HEN might provide advantage to this respect. In fact, patients assigned to HEN had a z2.5-fold higher probability of completing the adjuvant chemotherapy treatment as planned e which was our definition of treatment success in this protocol e with respect to the nutritional counselling group, with potential advantages in terms of clinical outcomes. We acknowledge that chemotherapy interruption or modification of scheduling may have been due to a number of reasons other than nutritional status (e.g. occurrence of unacceptable toxicities). When comparing treatment success between the two groups, statistical significance was not reached likely due to small sample sizes. In the present study, sample size was calculated in order to evaluate the overall treatment effect and subgroup analyses were not pre-planned, thus reporting of results by tumour type or age group is not appropriate. Future randomised studies, possibly with a larger sample size, are warranted for analysing the effect of HEN on nutritional status separately for oesophagus, stomach, pancreas, or biliary tract cancers, possibly preplanning subgroup analyses by age groups. Remarkably, in our study QoL, as assessed by the FAACT score, was not worsened by HEN. This finding is in line with other studies, which suggest neutral, if not beneficial, effect of HEN on QoL, although further evidence appears necessary to fully investigate this issue [25,26]. The functional status of the patients, assessed by the KPS, remained unchanged as well. Our study is not without limitations other than limited sample size. For instance, we did not collect detailed information about nutritional support in the peri-operative setting, since it was the objective of other studies conducted in similar, but mixed, population of patients undergoing GI surgery [27,28]. On the other hand, the main focus of our study was on the 2 months after major surgery discharge. Nutritional support was similar in the two groups during the post-operative period and no statistical difference in body weight was recorded before surgery and at discharge. Another limitation is that we did not collect information on changes in body composition over the study period. We are currently investigating this parameter e which may have a potential impact on prognosis e in a dedicated study. In conclusion, our randomised study lends support to the importance of HEN in upper GI cancer patients, after major surgery, as it helps maintain body weight without any safety concern or detrimental impact on QoL. This effect can translate into a higher probability to start and complete scheduled chemotherapy. More trials are required to confirm this preliminary evidence.
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Conflict of interest statement None declared.
Acknowledgements Data management was supported by Tiziana Camerini; editorial assistance for the preparation of this manuscript was provided by Luca Giacomelli, PhD; and this assistance was supported by internal funds.
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Appendix A. Supplementary data [16]
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejca.2016.05.032. [17]
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