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Effects of artificial nutrition and hydration on survival in patients with head and neck cancer and esophageal cancer admitted to palliative care units

Open AccessPublished:December 03, 2021DOI:https://doi.org/10.1016/j.nutos.2021.11.008

      Summary

      Background

      The benefits of artificial nutrition and hydration in patients with head and neck cancer and esophageal cancer in the late stage remain unknown. We performed a secondary analysis of a cohort study to investigate the effects of enteral tube feeding (ETF) and parenteral nutrition and hydration (PNH) on survival in this population.

      Methods

      Patients with head and neck cancer and esophageal cancer admitted to palliative care units were included. Information on primary nutritional administration routes during the first week of admission and data on the averaged calorie sufficiency rate/total calorie intake, e.g., 75%≤/750 kcal/day≤ and <25%/<250 kcal/day, were obtained. Patients were divided into oral intake-, ETF-, and PNH-groups. We performed time-to-event analyses using the Kaplan-Meier method, Log-rank test, and univariate and multivariate Cox regression analyses.

      Results

      There were 33 patients in the oral intake-group, 25 in the ETF-group, and 44 in the PNH-group. A significant difference was observed in survival rates between these groups (Log-rank P = 0.002), and median survival times were 54.0 (95% CI 33–75), 26.0 (95% CI 13–39), and 18.0 (95% CI 14–22) days, respectively. In the multivariate-adjusted model, the oral intake-group had a significantly lower risk of mortality than the PNH-group [HR 0.46 (95% CI 0.28–0.76), P = 0.002], while the ETF-group had a markedly lower risk of mortality than the PNH-group [HR 0.60 (95% CI 0.34–1.06), P = 0.077].

      Conclusions

      These results indicate the potentially beneficial effects of ETF for patients with head and neck cancer and esophageal cancer in palliative care.

      Keywords

      Introduction

      Patients with head and neck cancer and esophageal cancer are at a high risk of malnutrition because tumors may not only obstruct the digestive tract, they may also cause swallowing disorders, i.e., oropharyngeal or esophageal dysphagia, based on their location and size [
      • Arends J.
      • Bachmann P.
      • Baracos V.
      • Barthelemy N.
      • Bertz H.
      • Bozzetti F.
      • et al.
      ESPEN guidelines on nutrition in cancer patients.
      ,
      • Arends J.
      • Baracos V.
      • Bertz H.
      • Bozzetti F.
      • Calder P.C.
      • Deutz N.E.P.
      • et al.
      ESPEN expert group recommendations for action against cancer-related malnutrition.
      ,
      • Einarsson S.
      • Laurell G.
      • Tiblom Ehrsson Y.
      Mapping the frequency of malnutrition in patients with head and neck cancer using the GLIM Criteria for the Diagnosis of Malnutrition.
      ,
      • Curtin P.
      • Akbar A.
      • Kramer H.
      • Iqbal A.
      • Markossian T.
      The Status of Nutritional Management Guidelines for Head and Neck Cancer Patients.
      ,
      • Findlay M.
      • Purvis M.
      • Venman R.
      • Luong R.
      • Carey S.
      Nutritional management of patients with oesophageal cancer throughout the treatment trajectory: benchmarking against best practice.
      ]. Malnutrition may have profound adverse effects on cancer treatment and survival [
      • Arends J.
      • Bachmann P.
      • Baracos V.
      • Barthelemy N.
      • Bertz H.
      • Bozzetti F.
      • et al.
      ESPEN guidelines on nutrition in cancer patients.
      ,
      • Arends J.
      • Baracos V.
      • Bertz H.
      • Bozzetti F.
      • Calder P.C.
      • Deutz N.E.P.
      • et al.
      ESPEN expert group recommendations for action against cancer-related malnutrition.
      ]. The main treatment for head and neck cancer and esophageal cancer involves surgery, radiotherapy, and/or chemotherapy, which may have severe adverse effects and late sequelae, e.g., pain in the mouth and throat, mucositis, dry mouth, and dysphagia, leading to malnutrition [
      • Findlay M.
      • Purvis M.
      • Venman R.
      • Luong R.
      • Carey S.
      Nutritional management of patients with oesophageal cancer throughout the treatment trajectory: benchmarking against best practice.
      ,
      • Trotti A.
      Toxicity in head and neck cancer: a review of trends and issues.
      ,
      • Vissink A.
      • Jansma J.
      • Spijkervet F.K.
      • Burlage F.R.
      • Coppes R.P.
      Oral sequelae of head and neck radiotherapy.
      ,
      • Argiris A.
      • Karamouzis M.V.
      • Raben D.
      • Ferris R.L.
      Head and neck cancer.
      ,
      • Bozzetti F.
      Nutritional support in patients with oesophageal cancer.
      ]. These effects are regarded as nutrition impact symptoms and may persist beyond the completion or cessation of the main treatment [
      • Kubrak C.
      • Olson K.
      • Jha N.
      • Jensen L.
      • McCargar L.
      • Seikaly H.
      • et al.
      Nutrition impact symptoms: key determinants of reduced dietary intake, weight loss, and reduced functional capacity of patients with head and neck cancer before treatment.
      ,
      • Kubrak C.
      • Olson K.
      • Baracos V.E.
      The head and neck symptom checklist©: an instrument to evaluate nutrition impact symptoms effect on energy intake and weight loss.
      ,
      • Anandavadivelan P.
      • Martin L.
      • Djärv T.
      • Johar A.
      • Lagergren P.
      Nutrition Impact Symptoms Are Prognostic of Quality of Life and Mortality after Surgery for Oesophageal Cancer.
      ,
      • Einarsson S.
      • Laurell G.
      • Tiblom Ehrsson Y.
      Experiences and coping strategies related to food and eating up to two years after the termination of treatment in patients with head and neck cancer.
      ,
      • Guyer D.L.
      • Almhanna K.
      • McKee K.Y.
      Palliative care for patients with esophageal cancer: a narrative review.
      ]. Recent expert opinions/guidance on the use of clinically assisted nutrition in patients with advanced cancer edited by the Multinational Association of Supportive Care in Cancer (MASCC) suggest that clinically assisted nutrition needs to be considered for patients with an inability (reversible/irreversible) to ingest sufficient nutrients, and also recommend enteral tube feeding (ETF) over parenteral nutrition and hydration (PNH) [
      • Alderman B.
      • Allan L.
      • Amano K.
      • Bouleuc C.
      • Davis M.
      • Lister-Flynn S.
      • et al.
      Multinational Association of Supportive Care in Cancer (MASCC) expert opinion/guidance on the use of clinically assisted nutrition in patients with advanced cancer.
      ].
      An observational study on patients with various types of advanced cancer in palliative care settings in Italy reported that oral issues may have a significant impact on the physical, social, and psychological well-being of patients and need to be assessed in the early stages in order to prevent their progression to an inability to eat or drink [
      • Mercadante S.
      • Aielli F.
      • Adile C.
      • Ferrera P.
      • Valle A.
      • Fusco F.
      • et al.
      Prevalence of oral mucositis, dry mouth, and dysphagia in advanced cancer patients.
      ]. This study also demonstrated that mucositis and dysphagia correlated with head and neck cancer and showed a strong relationship between mucositis, dry mouth, and dysphagia [
      • Mercadante S.
      • Aielli F.
      • Adile C.
      • Ferrera P.
      • Valle A.
      • Fusco F.
      • et al.
      Prevalence of oral mucositis, dry mouth, and dysphagia in advanced cancer patients.
      ]. A recent large prospective multicenter cohort study conducted in palliative care units in Japan demonstrated the potentially beneficial effects of artificial nutrition and hydration (ANH) on survival in patients with various types of advanced cancer with a mean survival of 5 weeks [
      • Amano K.
      • Maeda I.
      • Ishiki H.
      • Miura T.
      • Hatano Y.
      • Tsukuura H.
      • et al.
      Effects of enteral nutrition and parenteral nutrition on survival in patients with advanced cancer cachexia: Analysis of a multicenter prospective cohort study.
      ]. The findings obtained also indicated the superiority of enteral nutrition (oral intake and ETF) over PNH; however, only 7.0% of all patients had head and neck cancer or esophageal cancer [
      • Amano K.
      • Maeda I.
      • Ishiki H.
      • Miura T.
      • Hatano Y.
      • Tsukuura H.
      • et al.
      Effects of enteral nutrition and parenteral nutrition on survival in patients with advanced cancer cachexia: Analysis of a multicenter prospective cohort study.
      ]. An observational retrospective cohort study using data from the last 30 days of life of patients with advanced cancer in Brazil reported that the use of ANH was associated with head and neck cancer in a non-palliative care hospital and palliative care unit [
      • Wiegert E.V.M.
      • da Costa Rosa K.S.
      • Dos Santos R.T.F.
      • Dos Santos D.A.
      • de Freitas R.
      • de Oliveira L.C.
      The use of nutrition support near the end of life for hospitalized patients with advanced cancer at a reference center: Two realities.
      ].
      Limited information is currently available on the prevalence of malnutrition in patients with head and neck cancer and esophageal cancer admitted to palliative care units. Furthermore, it remains unknown whether ANH are beneficial for survival in this population. Therefore, we herein conducted a secondary analysis of the cohort study described above [
      • Amano K.
      • Maeda I.
      • Ishiki H.
      • Miura T.
      • Hatano Y.
      • Tsukuura H.
      • et al.
      Effects of enteral nutrition and parenteral nutrition on survival in patients with advanced cancer cachexia: Analysis of a multicenter prospective cohort study.
      ] to assess the effects of ETF and PNH on survival in patients with head and neck cancer and esophageal cancer who cannot orally consume a sufficient amount of calories.

      Methods

      Study design and subjects

      The present study was a secondary analysis of a large prospective multicenter cohort study investigating the beneficial effects of ANH on survival in patients with various types of advanced cancer in 23 palliative care units across Japan between January 2017 and June 2018 [
      • Amano K.
      • Maeda I.
      • Ishiki H.
      • Miura T.
      • Hatano Y.
      • Tsukuura H.
      • et al.
      Effects of enteral nutrition and parenteral nutrition on survival in patients with advanced cancer cachexia: Analysis of a multicenter prospective cohort study.
      ]. In brief, consecutive patients newly referred to palliative care units in all institutions were enrolled. Each institution obtained data up to the number of patients according to the size of the institution without depending on high-volume centers. The inclusion criteria of the present study were as follows: (1) 18 years of age or older, (2) head and neck cancer and esophageal cancer, and (3) locally advanced or metastatic cancer. Patients who planned to be discharged within 1 week or those who declined to be enrolled were excluded from the original study.

      Measurements

      Data on patient characteristics, including age, sex, the primary cancer site, metastasis, surgery to remove tumors, chemotherapy or targeted therapy in 1 month, the Eastern Cooperative Oncology Group Performance Status (ECOG PS) [
      • Oken M.M.
      • Creech R.H.
      • Tormey D.C.
      • Horton J.
      • Davis T.E.
      • McFadden E.T.
      • et al.
      Toxicity and response criteria of the Eastern Cooperative Oncology Group.
      ], body mass index (kg/m2), and body weight loss in 1 month, were obtained on the first day of admission. Physicians obtained information on physical findings, such as the presence of dysphagia, edema, pleural effusion, and ascites. Laboratory data on serum levels of albumin and C-reactive protein, which were measured within 7 days before admission or 3 days after admission, were collected. Data on the primary nutritional administration route and averaged calorie sufficiency rate/total calorie intake per day during the first week were also recorded on the 7th day. However, there was no information on how the calories administered were calculated for patients receiving ANH and no data on the location of the initiation of ANH. We defined survival days as the time from baseline to death or discharge, and patients who were discharged had been followed up for 180 days from admission to palliative care units.

      Ethical approval

      In the present study, we adhered to the ethical standards of the Declaration of Helsinki and the ethical guidelines for epidemiological research presented by the Ministry of Health, Labour, and Welfare in Japan. This study was examined and approved by the individual local Institutional Review Boards in all institutions. We employed an opt-out method without obtaining written or oral informed consent because individual informed consent from participants is not necessary in a non-invasive observational trial according to Japanese law.

      Statistical analysis

      Patient characteristics were shown as a number (%) or the mean ± standard deviation where appropriate. Patients were divided into the following three groups using the primary nutritional administration route categories based on the previous study: oral intake-, ETF-, and PNH-groups [
      • Amano K.
      • Maeda I.
      • Ishiki H.
      • Miura T.
      • Hatano Y.
      • Tsukuura H.
      • et al.
      Effects of enteral nutrition and parenteral nutrition on survival in patients with advanced cancer cachexia: Analysis of a multicenter prospective cohort study.
      ]. Comparisons were performed using the Kruskal-Wallis test or a trend test (the Mantel-Haenszel method).
      The proportions of the four levels of the averaged calorie sufficiency rate/total calorie intake per day, i.e., 75%≤ or 750 kcal/day≤, 50–75% or 500–750 kcal/day, 25–50% or 250–500 kcal/day, and <25% or <250 kcal/day, in each group were calculated. Calories from amino acids and fat emulsions were included in the calculation of calories administered in the PNH-group.
      The Kaplan-Meier method using the Log-rank test was performed to analyze survival after enrollment, and the P-value for the Log-rank test was employed to investigate whether there was a difference in survival times between the groups.
      Univariate and multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models. Variables, i.e., age (<70/70 years≤), sex (male/female), the primary cancer site (head and neck/esophagus), ECOG PS (0–2/3/4), and calorie sufficiency rate/total calorie intake (50%≤ or 500 kcal/day≤/<50% or <500 kcal/day), were included as covariates in the multivariate model. These variables were considered to be predictors of the initiation of ANH in previous studies [
      • Amano K.
      • Maeda I.
      • Ishiki H.
      • Miura T.
      • Hatano Y.
      • Tsukuura H.
      • et al.
      Effects of enteral nutrition and parenteral nutrition on survival in patients with advanced cancer cachexia: Analysis of a multicenter prospective cohort study.
      ,
      • Arakawa S.
      • Amano K.
      • Oyamada S.
      • Maeda I.
      • Ishiki H.
      • Miura T.
      • et al.
      Effects of parenteral nutrition and hydration on survival in advanced cancer patients with malignant bowel obstruction: Secondary analysis of a multicenter prospective cohort study.
      ].
      We considered all results to be significant when the P-value was less than 0.05, and we analyzed all data using SPSS version 27.0 (IBM, Tokyo, Japan).

      Results

      Among the original cohort of 1453 patients, 102 (7.0%) who had head and neck cancer or esophageal cancer were included in the present study. The mean age of all patients was 71.5 ± 12.1 years. The percentage of male patients was 70.6%, and that of head and neck cancer was 47.1% in all groups. The percentages of patients with ECOG PS 3 and 4 were 55.9 and 31.4%, respectively. The mean body mass index was 18.2 ± 2.8 kg/m2, and percent body weight loss in 1 month was 82.4%. Dysphagia was present in 61.8% of all patients. The mean serum level of albumin was 2.6 ± 0.6 g/dL.
      Patients were divided into the following three groups according to the primary nutritional administration routes: the oral intake-group (n = 33), ETF-group (n = 25), and PNH-group (n = 44). Patient characteristics in the three groups are shown in Table 1. The numbers of males were significantly higher in the ETF- and PNH-groups (p = 0.008). The number of patients with esophageal cancer was significantly higher in the ETF-group, and that of patients with head and neck cancer in the PNH-group (p = 0.044). The prevalence of dysphagia was significantly higher in the ETF- and PNH-groups (p < 0.001). Each group was then subdivided into the four levels of the averaged calorie sufficiency rate/total calorie intake per day (Table 2).
      Table 1Patient characteristics (n = 102)
      Primary nutritional administration routeOral intake (n = 33)Enteral tube feeding (n = 25)Parenteral nutrition and hydration (n = 44)P
      Age
       Years, mean (SD)70.6 (13.6)70.6 (8.5)72.7 (12.9)0.68
       70≤ years, n (%)17 (51.5)13 (52.0)28 (63.6)0.49
      Sex, n (%)
       Male18 (54.5)23 (92.0)31 (70.5)0.008
       Female15 (45.5)2 (8.0)13 (29.5)
      Primary cancer site, n (%)
       Head and neck15 (45.5)7 (28.0)26 (59.1)0.044
       Esophagus18 (54.5)18 (72.0)18 (40.9)
      Metastasis, yes, n (%)23 (69.7)18 (72.0)25 (56.8)0.34
      Surgery to remove tumors, yes, n (%)15 (45.5)13 (52.0)14 (31.8)0.22
      Chemotherapy or targeted therapy in 1 month, yes, n (%)3 (9.1)2 (8.0)2 (4.5)0.71
      ECOG performance status, n (%)
       0-24 (12.1)6 (24.0)3 (6.8)0.17
       321 (63.6)13 (52.0)23 (52.3)
       48 (24.2)6 (24.0)18 (40.9)
      Body mass index (kg/m2), mean (SD)18.1 (2.9)18.4 (2.6)18.1 (3.0)0.82
      Body weight loss in 1 month, yes, n (%)24 (72.7)21 (84.0)39 (88.6)0.19
      Dysphagia, yes, n (%)10 (30.3)21 (84.0)32 (72.7)< 0.001
      Edema, yes, n (%)10 (30.3)2 (8.0)8 (18.2)0.10
      Pleural effusion, yes, n (%)7 (21.2)2 (8.0)11 (25.0)0.22
      Ascites, yes, n (%)0 (0.0)0 (0.0)3 (6.8)0.13
      Serum levels, mean (SD)
       Albumin (g/dL)2.7 (0.6)2.6 (0.6)2.5 (0.5)0.12
       C-reactive protein (mg/dL)5.9 (5.6)8.5 (6.2)7.8 (6.4)0.18
      SD, standard deviation; ECOG, Eastern Cooperative Oncology Group.
      Table 2Primary nutritional administration route and calorie sufficiency rate/total calorie intake (n = 102)
      Primary nutritional administration routeOral intakeEnteral tube feedingParenteral nutrition and hydrationTotal
      75%≤ or 750 kcal/day≤6 (5.8)11 (10.8)7 (6.9)24 (23.5)
      50–75% or 500–750 kcal/day9 (8.8)8 (7.8)9 (8.8)26 (25.4)
      25–50% or 250–500 kcal/day11 (10.8)6 (5.8)6 (5.8)23 (22.5)
      <25% or <250 kcal/day7 (6.9)0 (0.0)22 (21.6)29 (28.4)
      Total33 (32.4)25 (24.5)44 (43.1)102 (100.0)
      Values represent n (%).
      The survival curves for 102 patients in the three groups are shown in Fig. 1. A significant difference was observed in survival rates among the groups (Log-rank P = 0.002). Survival was longer in the oral intake-(54 days) and ETF-(26 days) groups than in the PNH-group (18 days).
      Fig. 1
      Fig. 1Kaplan-Meier plot. Survival curves for patients in the oral intake (OI)-group (n = 33), enteral tube feeding (ETF)-group (n = 25), and parenteral nutrition and hydration (PNH)-group (n = 44). A significant difference was observed in survival rates among the groups (Log-rank P = 0.002). Median survival times were 54.0 (95% CI 33–75), 26.0 (95% CI 13–39), and 18.0 (95% CI 14–22) days, respectively.
      The relationships between the mortality risk and the three groups, i.e., the oral intake-, ETF-, and PNH-groups, and HRs for mortality are shown in Table 3. In the multivariate-adjusted model, a significantly lower risk of mortality was observed in the Cox proportional hazard model for the oral intake-group [HR 0.46 (95% CI 0.28–0.76), P = 0.002] than for the PNH-group. A markedly lower risk of mortality was observed in the Cox proportional hazard model for the ETF-group [HR 0.60 (95% CI 0.34–1.06), P = 0.077] than for the PNH-group. Furthermore, a significantly lower risk of mortality was observed in the Cox proportional hazard model for the higher calorie-group (50%≤ or 500 kcal/day≤) [HR 0.51 (95% CI 0.31–0.82), P = 0.005] than for the lower calorie-group (<50% or <500 kcal/day).
      Table 3Primary nutritional administration route and hazard ratio for mortality (n = 102)
      HR (95% CI)P
      Univariate model
       Primary nutritional administration route
       Parenteral nutrition and hydration1.00 (reference)
       Enteral tube feeding0.53 (0.31–0.89)0.017
       Oral intake0.48 (0.30–0.76)0.002
      Calorie sufficiency rate/total calorie intake
       <50% or <500 kcal/day1.00 (reference)
       50%≤ or 500 kcal/day≤0.53 (0.35–0.81)0.003
      Multivariate model
      Primary nutritional administration route
       Parenteral nutrition and hydration1.00 (reference)
       Enteral tube feeding0.60 (0.34–1.06)0.077
       Oral intake0.46 (0.28–0.76)0.002
      Calorie sufficiency rate/total calorie intake
       <50% or <500 kcal/day1.00 (reference)
       50%≤ or 500 kcal/day≤0.51 (0.31–0.82)0.005

      Discussion

      This is the first study suggesting the beneficial effects of ETF on survival in patients with head and neck cancer and esophageal cancer with an insufficient oral calorie intake in palliative care units. The risk of mortality was markedly lower in the ETF-group than in the PNH-group. Due to the small number of patients examined, these results may be attributed to a lack of power.
      Evidence-based clinical practice guidelines recommend nutritional risk screening and nutritional support for all cancer patients because an insufficient nutritional intake is frequently observed and associated with body weight loss and total or supplemental ANH need to be indicated when an insufficient nutritional intake persists [
      • Arends J.
      • Bachmann P.
      • Baracos V.
      • Barthelemy N.
      • Bertz H.
      • Bozzetti F.
      • et al.
      ESPEN guidelines on nutrition in cancer patients.
      ,
      • Arends J.
      • Baracos V.
      • Bertz H.
      • Bozzetti F.
      • Calder P.C.
      • Deutz N.E.P.
      • et al.
      ESPEN expert group recommendations for action against cancer-related malnutrition.
      ]. In addition, expert opinions/guidance on the use of clinically assisted nutrition in patients with advanced cancer edited by the MASCC concluded that although ANH are not indicated for the management of cachexia-related symptoms, every patient requires individualized management and patient-centered care [
      • Alderman B.
      • Allan L.
      • Amano K.
      • Bouleuc C.
      • Davis M.
      • Lister-Flynn S.
      • et al.
      Multinational Association of Supportive Care in Cancer (MASCC) expert opinion/guidance on the use of clinically assisted nutrition in patients with advanced cancer.
      ].
      The present results showed that the majority of patients were severely malnourished because the mean body mass index was approximately 18.0 kg/m2, percent body weight loss in 1 month was more than 80.0%, and the mean serum level of albumin was approximately 2.6 g/dL, and these findings were collectively interpreted as protein energy malnutrition. Since some of these patients may benefit from ANH, particularly ETF or supplemental PNH, they need to be provided with the opportunity to receive optimal nutrition support even in palliative care settings. The initiation and use of ANH need to be considered based on the deterioration of the nutritional status due to prolonged starvation rather than on tumor spread in this population. Patients with head and neck cancer or esophageal cancer need to be screened for malnutrition at admission to palliative care units and referred to a nutritional support team, as needed, in a timely manner.
      Only 7.0% of all patients included in the original study had head and neck cancer or esophageal cancer and the prevalence of dysphagia in the original cohort and the present study were 26.6 and 61.8%, respectively. Among the 669 patients with advanced cancer examined in an observational study conducted in palliative care settings, 3.1% had head and neck cancer and 15.3% had dysphagia [
      • Mercadante S.
      • Aielli F.
      • Adile C.
      • Ferrera P.
      • Valle A.
      • Fusco F.
      • et al.
      Prevalence of oral mucositis, dry mouth, and dysphagia in advanced cancer patients.
      ]. This study also showed that dysphagia limited oral intake in 88.3% of dysphagic patients [
      • Mercadante S.
      • Aielli F.
      • Adile C.
      • Ferrera P.
      • Valle A.
      • Fusco F.
      • et al.
      Prevalence of oral mucositis, dry mouth, and dysphagia in advanced cancer patients.
      ]. Another cross-sectional, observational study investigating dysphagia in cancers in the upper gastrointestinal tract and outside the head and neck revealed that the prevalence of dysphagia was 30% in palliative care and 32% in hospice care [
      • Kenny C.
      • Regan J.
      • Balding L.
      • Higgins S.
      • O'Leary N.
      • Kelleher F.
      • et al.
      Dysphagia Prevalence and Predictors in Cancers Outside the Head, Neck, and Upper Gastrointestinal Tract.
      ]. These findings suggest that the incidence of dysphagia in head and neck cancer and esophageal cancer is very high and that swallowing disorders may result in the development of malnutrition.
      The initiation and use of ANH for patients with advanced cancer in palliative care settings remains controversial because evidence to support its use for these patients is currently very limited. Detailed comparisons of survival between patients receiving and not receiving ANH has not yet been performed [
      • Arends J.
      • Bachmann P.
      • Baracos V.
      • Barthelemy N.
      • Bertz H.
      • Bozzetti F.
      • et al.
      ESPEN guidelines on nutrition in cancer patients.
      ,
      • Arends J.
      • Baracos V.
      • Bertz H.
      • Bozzetti F.
      • Calder P.C.
      • Deutz N.E.P.
      • et al.
      ESPEN expert group recommendations for action against cancer-related malnutrition.
      ,
      • Alderman B.
      • Allan L.
      • Amano K.
      • Bouleuc C.
      • Davis M.
      • Lister-Flynn S.
      • et al.
      Multinational Association of Supportive Care in Cancer (MASCC) expert opinion/guidance on the use of clinically assisted nutrition in patients with advanced cancer.
      ,
      • Tobberup R.
      • Thoresen L.
      • Falkmer U.G.
      • Yilmaz M.K.
      • Solheim T.S.
      • Balstad T.R.
      Effects of current parenteral nutrition treatment on health-related quality of life, physical function, nutritional status, survival and adverse events exclusively in patients with advanced cancer: A systematic literature review.
      ,
      • Roeland E.J.
      • Bohlke K.
      • Baracos V.E.
      • Bruera E.
      • Del Fabbro E.
      • Dixon S.
      • et al.
      Management of Cancer Cachexia: ASCO Guideline.
      ,
      • Arends J.
      • Strasser F.
      • Gonella S.
      • Solheim T.S.
      • Madeddu C.
      • Ravasco P.
      • et al.
      Cancer cachexia in adult patients: ESMO Clinical Practice Guidelines. ESMO Guidelines Committee.
      ]. Randomized controlled trials are ideally required to assess the effects of ANH in this population; however, it is very difficult to recruit subjects from patients who become unable to take sufficient nourishment orally because a study arm of starving patients is not ethically acceptable [
      • Bozzetti F.
      Is there a place for nutrition in palliative care?.
      ]. Therefore, we recently conducted a prospective multicenter cohort study to assess the beneficial effects of ANH on survival in palliative care patients. The findings obtained indicated the beneficial effects of ANH and the superiority of enteral nutrition (oral intake and ETF) over PNH in various cancers [
      • Amano K.
      • Maeda I.
      • Ishiki H.
      • Miura T.
      • Hatano Y.
      • Tsukuura H.
      • et al.
      Effects of enteral nutrition and parenteral nutrition on survival in patients with advanced cancer cachexia: Analysis of a multicenter prospective cohort study.
      ]. Furthermore, another study suggested the beneficial effects of PNH for prolonging survival in advanced cancer patients with malignant bowel obstruction [
      • Arakawa S.
      • Amano K.
      • Oyamada S.
      • Maeda I.
      • Ishiki H.
      • Miura T.
      • et al.
      Effects of parenteral nutrition and hydration on survival in advanced cancer patients with malignant bowel obstruction: Secondary analysis of a multicenter prospective cohort study.
      ]. However, as described above, patients with head and neck cancer and esophageal cancer have unique reasons for malnutrition due to an obstruction in the digestive tract and/or swallowing disorders. Therefore, we performed a secondary analysis of the cohort study using stratified data.
      The present study has several limitations that need to be considered. Since head and neck cancer (tumors of the oropharynx, hypopharynx, and larynx) and esophageal cancer (tumors of the cervical, thoracic, and abdominal esophagus) were included together, tumor heterogeneity was neglected. However, it is common that dysphagia frequently limits oral intake in both head and neck cancer and esophageal cancer [
      • Arends J.
      • Bachmann P.
      • Baracos V.
      • Barthelemy N.
      • Bertz H.
      • Bozzetti F.
      • et al.
      ESPEN guidelines on nutrition in cancer patients.
      ,
      • Arends J.
      • Baracos V.
      • Bertz H.
      • Bozzetti F.
      • Calder P.C.
      • Deutz N.E.P.
      • et al.
      ESPEN expert group recommendations for action against cancer-related malnutrition.
      ,
      • Einarsson S.
      • Laurell G.
      • Tiblom Ehrsson Y.
      Mapping the frequency of malnutrition in patients with head and neck cancer using the GLIM Criteria for the Diagnosis of Malnutrition.
      ,
      • Curtin P.
      • Akbar A.
      • Kramer H.
      • Iqbal A.
      • Markossian T.
      The Status of Nutritional Management Guidelines for Head and Neck Cancer Patients.
      ,
      • Findlay M.
      • Purvis M.
      • Venman R.
      • Luong R.
      • Carey S.
      Nutritional management of patients with oesophageal cancer throughout the treatment trajectory: benchmarking against best practice.
      ]. Moreover, there may have been potential confounders in the present study due to the nature of a prospective cohort study, although some variables were included in the multivariate model. Furthermore, since patients were grouped using data on the primary route of ANH and averaged calorie intake per day during the first week after admission to palliative care units, data on switching in ANH and decreases in calories after categorization on the 7th day were not considered. In addition, the beneficial effects of ANH on the performance status, symptoms, and quality of life were not assessed, and the negative impact of ANH, including adverse effects, discomfort, and reduced quality of life, in the last several days of life were not evaluated; therefore, these parameters caused by the use of ANH need to be investigated in the future. The present results suggest that ETF was superior to PNH, although most patients with advanced cancer generally prefer PNH to ETF when they become unable to take sufficient nourishment orally [
      • Amano K.
      • Morita T.
      • Miyamoto J.
      • Uno T.
      • Katayama H.
      • Tatara R.
      Perception of need for nutritional support in advanced cancer patients with cachexia: a survey in palliative care settings.
      ]. Therefore, further research is warranted.

      Conclusion

      The present results indicated the beneficial effects of ETF for prolonging survival in patients with head and neck cancer and esophageal cancer in palliative care units. However, decisions on ANH need to be made in consideration of the preferences of patients and family members.

      Funding

      The present study was supported in part by a Grant-in-Aid from the Japan Hospice Palliative Care Foundation .

      Ethics approval

      The present study was approved by the local Institutional Review Boards of all participating institutions.

      Consent to participate

      Since Japanese law does not require individual informed consent from participants in a non-invasive observational trial, we used an opt-out method rather than acquiring written or oral informed consent.

      Consent for publication

      All authors agree to this submission.

      Availability of data and materials

      The datasets generated and/or analyzed during the present study were not publicly available because sharing is not explicitly covered by patient consent.

      Code availability

      Not applicable.

      Author contributions

      Study concept and design: Koji Amano, Hiroto Ishiki, Isseki Maeda, Yutaka Hatano, Masanori Mori, Tatsuya Morita.
      Collection and/or assembly of data: All authors.
      Statistical analysis: Sayuri Yokota, Koji Amano, Shunsuke Oyamada.
      Data analysis and interpretation: Sayuri Yokota, Koji Amano, Shunsuke Oyamada, Hiroto Ishiki, Masanori Mori, Tatsuya Morita.
      Drafting of the manuscript: Sayuri Yokota, Koji Amano, Shunsuke Oyamada, Hiroto Ishiki.
      Final approval of the manuscript: All authors.

      Declaration of competing interest

      The authors have read and understood the journal's policy on the declaration of interest and declare that there is no conflict of interest.

      Acknowledgments

      The present study was performed in the East-Asian collaborative cross-cultural Study to Elucidate the Dying process (EASED). The participating study sites and site investigators in Japan were as follows: Satoshi Inoue, M.D. (Seirei Hospice, Seirei Mikatahara General Hospital), Naosuke Yokomichi, M.D., Ph.D. (Department of Palliative and Supportive Care, Seirei Mikatahara General Hospital), Kengo Imai, M.D. (Seirei Hospice, Seirei Mikatahara General Hospital), Hiroaki Tsukuura, M.D., Ph.D. (Department of Palliative Care, TUMS Urayasu Hospital), Toshihiro Yamauchi, M.D. (Seirei Hospice, Seirei Mikatahara General Hospital), Akemi Shirado Naito, M.D. (Department of palliative care Miyazaki Medical Association Hospital), Akira Yoshioka, M.D., Ph.D. (Department of Oncology and Palliative Medicine, Mitsubishi Kyoto Hospital), Shuji Hiramoto, M.D. (Department of Oncology and Palliative Medicine, Mitsubishi Kyoto Hospital), Ayako Kikuchi, M.D. (Department of Oncology and Palliative Medicine, Mitsubishi Kyoto Hospital), Keiko Tanaka, M.D., Ph.D. (Department of Palliative Care Tokyo Metropolitan Cancer & Infectious Diseases Center Komagome Hospital), Tina Kamei, M.D. (Department of Palliative Care, NTT Medical Center Tokyo), Yukari Azuma, M.D. (Home Care Clinic Aozora Shin-Matsudo), Teruaki Uno, M.D. (Department of Palliative Medicine, Osaka City General Hospital), Jiro Miyamoto, M.D. (Department of Palliative Medicine, Osaka City General Hospital), Hirofumi Katayama, M.D. (Department of Palliative Medicine, Osaka City General Hospital), Hideyuki Kashiwagi, M.D., MBA. (Aso Iizuka Hospital/Transitional and Palliative Care), Eri Matsumoto, M.D. (Aso Iizuka Hospital/Transitional and Palliative Care), Kiyofumi Oya, M.D. (Aso Iizuka Hospital/Transitional and Palliative Care), Takeya Yamaguchi, M.D. (Japan Community Health care Organization Kyushu Hospital/Palliative Care), Tomonao Okamura, M.D., MBA. (Aso Iizuka Hospital/Transitional and Palliative Care), Hoshu Hashimoto, M.D., MBA. (Inoue Hospital/Internal Medicine), Shunsuke Kosugi, M.D. (Department of General Internal Medicine, Aso Iizuka Hospital), Nao Ikuta, M.D. (Department of Emergency Medicine, Osaka Red Cross Hospital), Yaichiro Matsumoto, M.D. (Department of Transitional and Palliative Care, Aso Iizuka Hospital), Takashi Ohmori, M.D. (Department of Transitional and Palliative Care, Aso Iizuka Hospital), Takehiro Nakai, M.D. (Immuno-Rheumatology Center, St Luke's International Hospital), Takashi Ikee, M.D. (Department of Cardiology, Aso Iizuka Hospital), Yuto Unoki, M.D. (Department of General Internal Medicine, Aso Iizuka Hospital), Kazuki Kitade, M.D. (Department of Orthopedic Surgery, Saga-Ken Medical Centre Koseikan), Shu Koito, M.D. (Department of General Internal Medicine, Aso Iizuka Hospital), Nanao Ishibashi, M.D. (Environmental Health and Safety Division, Environmental Health Department, Ministry of the Environment), Masaya Ehara, M.D. (TOSHIBA), Kosuke Kuwahara, M.D. (Department of General Internal Medicine, Aso Iizuka Hospital), Shohei Ueno, M.D. (Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital), Shunsuke Nakashima, M.D. (Oshima Clinic), Yuta Ishiyama, M.D. (Department of Transitional and Palliative Care, Aso Iizuka Hospital), Akihiro Sakashita, M.D., Ph.D. (Department of Palliative Medicine, Kobe University School of Medicine), Ryo Matsunuma, M.D. (Department of Palliative Medicine, Kobe University Graduate School of Medicine), Hana Takatsu, M.D. (Division of Palliative Care, Konan Medical Center), Takashi Yamaguchi, M.D., Ph.D. (Division of Palliative Care, Konan Medical Center), Satoko Ito, M.D. (Hospice, The Japan Baptist Hospital), Toru Terabayashi, M.D. (Hospice, The Japan Baptist Hospital), Jun Nakagawa, M.D. (Hospice, The Japan Baptist Hospital), Tetsuya Yamagiwa, M.D., Ph.D. (Hospice, The Japan Baptist Hospital), Akira Inoue, M.D., Ph.D. (Department of Palliative Medicine Tohoku University School of Medicine), Takuhiro Yamaguchi, Ph.D. (Professor of Biostatistics, Tohoku University Graduate School of Medicine), Mitsunori Miyashita, R.N., Ph.D. (Department of Palliative Nursing, Health Sciences, Tohoku University Graduate School of Medicine), Saran Yoshida, Ph.D. (Graduate School of Education, Tohoku University), Yusuke Hiratsuka, M.D., Ph.D. (Department of Palliative Medicine Tohoku University School of Medicine), Keita Tagami, M.D., Ph.D. (Department of Palliative Medicine Tohoku University School of Medicine), Hiroaki Watanabe, M.D. (Department of Palliative Care, Komaki City Hospital), Takuya Odagiri, M.D. (Department of Palliative Care, Komaki City Hospital), Tetsuya Ito, M.D., Ph.D. (Department of Palliative Care, Japanese Red Cross Medical Center), Masayuki Ikenaga, M.D. (Hospice, Yodogawa Christian Hospital), Keiji Shimizu, M.D., Ph.D. (Department of Palliative Care Internal Medicine, Osaka General Hospital of West Japan Railway Company), Akira Hayakawa, M.D., Ph.D. (Hospice, Yodogawa Christian Hospital), Rena Kamura, M.D. (Hospice, Yodogawa Christian Hospital), Takeru Okoshi, M.D., Ph.D. (Okoshi Nagominomori Clinic), Tomohiro Nishi, M.D. (Kawasaki Municipal Ida Hospital, Kawasaki Comprehensive Care Center), Kazuhiro Kosugi, M.D. (Department of Palliative Medicine, National Cancer Center Hospital East), Yasuhiro Shibata, M.D. (Kawasaki Municipal Ida Hospital, Kawasaki Comprehensive Care Center), Takayuki Hisanaga, M.D. (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Takahiro Higashibata, M.D., Ph.D. (Department of General Medicine and Primary Care, Palliative Care Team, University of Tsukuba Hospital), Ritsuko Yabuki, M.D. (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Shingo Hagiwara, M.D., Ph.D. (Department of Palliative Medicine, Yuai Memorial Hospital), Miho Shimokawa, M.D. (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Satoshi Miyake, M.D., Ph.D. (Professor, Department of Clinical Oncology Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University (TMDU)), Junko Nozato, M.D. (Specially Appointed Assistant Professor, Department of Internal Medicine, Palliative Care, Medical Hospital, Tokyo Medical and Dental University), Tetsuji Iriyama, M.D. (Specially Appointed Assistant Professor, Department of Internal Medicine, Palliative Care, Medical Hospital, Tokyo Medical and Dental University), Keisuke Kaneishi, M.D., Ph.D. (Department of Palliative Care Unit, JCHO Tokyo Shinjuku Medical Center), Mika Baba, M.D., Ph.D. (Department of Palliative medicine Suita Tokushukai Hospital), Yoshihisa Matsumoto, M.D., Ph.D. (Department of Palliative Medicine, National Cancer Center Hospital East), Ayumi Okizaki, Ph.D. (Department of Palliative Medicine, National Cancer Center Hospital East), Yuki Sumazaki Watanabe, M.D. (Department of Palliative Medicine, National Cancer Center Hospital East), Yuko Uehara, M.D. (Department of Palliative Medicine, National Cancer Center Hospital East), Eriko Satomi, M.D. (Department of palliative medicine, National Cancer Center Hospital), Kaoru Nishijima, M.D. (Department of Palliative Medicine, Kobe University Graduate School of Medicine), Junichi Shimoinaba, M.D. (Department of Hospice Palliative Care, Eikoh Hospital), Ryoichi Nakahori, M.D. (Department of Palliative Care, Fukuoka Minato Home Medical Care Clinic), Takeshi Hirohashi, M.D. (Eiju General Hospital), Jun Hamano, M.D., Ph.D. (Assistant Professor, Faculty of Medicine, University of Tsukuba), Natsuki Kawashima, M.D. (Department of Palliative Medicine, Tsukuba Medical Center Hospital), Takashi Kawaguchi, Ph.D. (Tokyo University of Pharmacy and Life Sciences Department of Practical Pharmacy), Megumi Uchida, M.D., Ph.D. (Dept. of Psychiatry and Cognitive-Behavioral Medicine, Nagoya City University Graduate School of Medical Sciences), Ko Sato, M.D., Ph.D. (Hospice, Ise Municipal General Hospital), Yoichi Matsuda, M.D., Ph.D. (Department of Anesthesiology & Intensive Care Medicine/Osaka University Graduate School of Medicine), Satoru Tsuneto, M.D., Ph.D. (Professor, Department of Human Health Sciences, Graduate School of Medicine, Kyoto University Department of Palliative Medicine, Kyoto University Hospital), Sayaka Maeda, M.D. (Department of Palliative Medicine, Kyoto University Hospital), Yoshiyuki Kizawa M.D., Ph.D., FJSIM, DSBPMJ. (Designated Professor and Chair, Department of Palliative Medicine, Kobe University School of Medicine), Hiroyuki Otani, M.D. (Palliative Care Team, and Palliative and Supportive Care, National Kyushu Cancer Center).

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