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The effects of rikkunshito on body weight loss after esophagectomy
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The effects of rikkunshito on body weight loss after esophagectomy Masaki Nakamura, MD, Mikihito Nakamori, MD, Toshiyasu Ojima, MD, Masahiro Katsuda, MD, Keiji Hayata, MD, Makoto Iwahashi, MD, and Hiroki Yamaue, MD* Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama, Japan
article info
abstract
Article history:
Background: After esophagectomy, esophageal cancer patients suffer from malnutrition,
Received 3 December 2015
anorexia, and dysfunction of digestion and absorption. Rikkunshito, a traditional Japanese
Received in revised form
herbal medicine, reportedly attenuates gastrointestinal symptoms and appetite loss after
4 March 2016
gastrointestinal surgery. We evaluated the clinical effect of rikkunshito and its relationship
Accepted 5 April 2016
with ghrelin in esophageal cancer patients after esophagectomy.
Available online 13 April 2016
Methods: This prospective nonrandomized study included 40 patients with esophageal cancer who underwent esophagectomy at Wakayama Medical University Hospital. They
Keywords:
were assigned to either the control group (n ¼ 20, April 2011-January 2012) or the rikkun-
Rikkunshito
shito group (n ¼ 20, January 2012-August 2012). Patients in the rikkunshito group received
Japanese herbal medicine
2.5 g of rikkunshito before every meal for 48 wk beginning 4 wk after surgery. During the
Ghrelin
48-week treatment, we assessed body weight loss, nutritional parameters, and quality of
Esophagectomy
life (Functional Assessment of Cancer Therapy-Esophageal scale). The primary end point
Esophageal cancer
was the rate of body weight loss in two groups after the 48-week treatments. Results: The rate of body weight loss was significantly less in the rikkunshito group than in the control group (P ¼ 0.016). The acyl ghrelin level after the 48-week treatments was significantly higher in the rikkunshito group (131.7% 74.5%) than in the control group (75.6% 47.5%, P ¼ 0.039). For the Functional Assessment of Cancer Therapy-Esophageal symptom scale, satisfaction of food consumption in the rikkunshito group was significantly better than in the control group at 52 wk postoperatively (P ¼ 0.031). Conclusions: For esophageal cancer patients after esophagectomy, rikkunshito is useful for improving body weight loss in connection with an increase in plasma acyl ghrelin levels. ª 2016 Elsevier Inc. All rights reserved.
Introduction As the prognosis of patients with esophageal cancer has improved in recent years because of advances in treatment, including perioperative chemotherapy, it is necessary to improve the quality of life (QOL) for these patients. In a recent
population-based study of esophageal cancer surgery, twothirds of patients had lost more 10% of their preoperative body weight within 6 mo of surgery, and one in five had lost more than 20%.1 Body weight loss and malnutrition are a considerable problem after esophagectomy and has been linked to appetite loss, eating difficulties, odynophagia, a
* Corresponding author. Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8510, Japan. Tel.: þ81 73 441 0613; fax: þ81 73 446 6566. E-mail address: [email protected] (H. Yamaue). 0022-4804/$ e see front matter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2016.04.004
nakamura et al effects of rikkunshito after esophagectomy
decrease in oral intake due to early satiety, a decrease in gastric acid production, neoadjuvant therapy, and female gender.1,2 Rikkunshito, a traditional Japanese herbal medicine, was reported to improve gastric emptying in patients with functional dyspepsia3,4 and in patients who underwent proximal gastrectomy.5 Recently, rikkunshito was reported to increase food intake and body weight in a rat anorexia model induced by administration of cisplatin.6 Administration of rikkunshito has been shown to enhance the secretion of acyl ghrelin (i.e., the activated form of ghrelin) in rats,6 and it was also reported to improve symptoms in patients with functional dyspepsia, accompanied by an increase in the plasma ghrelin levels.7 However, there have been no studies investigating the clinical effect of rikkunshito and its relationship with ghrelin levels for esophageal cancer patients after esophagectomy. Ghrelin is a 28-amino-acid peptide that is mainly secreted from the X/A-like cells in the gastric fundus, and several other tissues including the brain, duodenum, jejunum, and lung.8 It acts as a natural ligand for the growth hormone secretagogue receptor and plays a role not only in growth hormone secretion8 but also in initiating feeding as an appetite stimulant.9 Ghrelin has two major molecular forms: acyl ghrelin and des-acyl ghrelin. Acyl ghrelin is thought to be an active form that specifically stimulates the release of growth hormone from the pituitary, as well as gastric motor activity and food intake.8 Des-acyl ghrelin has opposing effects, decreasing food intake, and delaying gastric emptying.10 Therefore, an increase in acyl ghrelin level and a decrease in des-acyl ghrelin level may be a favorable response that improves nutritional status and QOL in patients after gastrointestinal surgery. The plasma ghrelin level decreases immediately after gastrectomy and recovers gradually thereafter. However, recovery is poor after both total gastrectomy and proximal gastrectomy11 because ghrelin-secreting X/A-like cells are abundant in the gastric fundus.12 The aim of the present study was to investigate the safety and efficacy of rikkunshito for esophageal cancer patients after esophagectomy. Moreover, we evaluated the clinical effects of rikkunshito on body weight loss, QOL, and plasma ghrelin levels for these patients.
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Study design This trial was designed as a prospective nonrandomized study. This trial was approved by the Ethical Committee on Clinical Investigation of WMUH and registered at UMIN-CTR ID #000006966 (www.umin.ac.jp/ctr/). Informed consent was obtained from all participating patients preoperatively, and they also agreed to follow-up for at least 52 wk after surgery. Inclusion criteria were: (1) thoracic esophageal cancer patient who would undergo radical transthoracic esophagectomy with gastric tube reconstruction; (2) aged 20-85 years; (3) performance status 0-2 according to Eastern Cooperative Oncology Group criteria13; and (4) appropriate informed consent obtained. Exclusion criteria were: (1) severe comorbidity, such as myocardial infarction, respiratory disorder requiring oxygen inhalation, liver cirrhosis, or chronic renal failure requiring hemodialysis; (2) the presence of other organ malignancies; (3) inability of oral intake; (4) patients who took Japanese herbal medicine within 2 wk before rikkunshito treatments; (5) a history of hypersensitivity to any Japanese herbal medicine preparation; (6) female patients who were pregnant, desiring pregnancy, or breastfeeding; and (7) patients who were diagnosed as inappropriate for this study by a physician. During the 48-week rikkunshito treatment, the following parameters were assessed: body weight loss, nutritional parameters (albumin, prealbumin, transferrin, acyl ghrelin, and des-acyl ghrelin), and QOL based on the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scale.
Rikkunshito Rikkunshito (Tsumura & Co, Tokyo, Japan) is a granular preparation of a mixture of eight crude drugs, Glycyrrhizae Radix (4.7%), Zingiberis Rhizoma (2.3%), Atractylodis Lanceae Rhizoma (18.6%), Zizyphi Fructus (9.3%), Aurantii Nobilis Pericarpium (9.3%), Ginseng Radix (18.6%), Pinelliae Tuber (18.6%), and Hoelen (18.6%), that is extracted with hot water. It has been approved for medicinal use by the Japanese Ministry of Health and Welfare, and its quality has been controlled by the Japanese Pharmacopoeia and the Japanese Herbal Medicine Codex (JHMC, non-Japanese Pharmacopoeia crude drug standards).
Surgical procedures
Patients and methods Patients Forty consecutive patients with thoracic esophageal cancer who underwent an esophagectomy from April 2011 to August 2012 at Wakayama Medical University Hospital (WMUH) in Japan were enrolled preoperatively in this study. The consecutive patients in the first half of the study registration period were assigned to the control group (n ¼ 20, April 2011-January 2012), and they in the latter half were assigned to the rikkunshito group (n ¼ 20, January 2012-August 2012). In the control group, patients were managed without rikkunshito or a placebo postoperatively. In the rikkunshito group, patients received 2.5 g of rikkunshito before every meal for 48 wk beginning 4 wk after the surgery. Patients were not blinded for their postoperative treatment.
All patients underwent radical esophagectomy with a twoor three-field lymph node dissection via a cervicothoracoabdominal approach. A right transthoracic procedure was performed via thoracotomy or thoracoscopy. All patients underwent esophageal reconstruction using stomach to replace the esophagus. In all patients, a gastric conduit through the retrosternal route or the posterior mediastinum was used to reconstruct the anastomosis with the cervical esophagus.
Neoadjuvant therapy and adjuvant therapy Beginning in 2005, our institution administered neoadjuvant chemotherapy for patients with clinical lymph node metastases and neoadjuvant chemoradiotherapy for patients with clinical T4 lesions. Nine patients in each group received neoadjuvant therapy. Among them, eight patients in each group
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Table 1 e Characteristics of enrolled patients. Rikkunshito (n ¼ 20) Sex (male/female) Age (y) Performance status (0/1) Body weight (kg)
Control (n ¼ 20)
P value
15/5
18/2
0.212
65 (50-83)
68 (42-80)
0.690
20/0
20/0
d
60.6 10.5
61.0 11.1
0.923
6/14
9/11
0.327
Transthoracic approach Thoracotomy/ thoracoscopy Route of reconstruction Retrosternum/posterior mediastinum
11/9
12/8
0.749
8/7/5/0
4/8/6/2
0.322
6/14
10/10
0.197
9
6
0.327
6/2/1
6/0/0
d d
Advanced stage I/II/III/IVA Lymph node dissection 2 fields/3 fields Concomitant disease HT/DM/COPD Neoadjuvant therapy
Chronic Illness Therapy measurement system. The general core questionnaire (FACT-General [FACT-G]) is comprised of four general subscales: physical well being (PWB), social well being (SWB), emotional well being (EWB), and functional well being (FWB). The FACT-E questionnaire combines the 27 items of FACT-G and the 17 newly validated items of the esophagus cancer subscale (ECS), which assesses esophageal cancerspecific domains of eating and/or swallowing, speaking, pain, coughing, and weight loss. QOL assessment using FACT-E questionnaire were assessed preoperatively and at 4, 13, 26, and 52 wk after surgery. Blood samples were collected before breakfast after an overnight fast before surgery and postoperatively at 4, 13, 26, and 52 wk. The samples were immediately separated for plasma sampling and stored at 80 C until the time of the assay.
Subgroup analysis
9
9
Chemotherapy/CRT
8/1
8/1
d
Adjuvant chemotherapy
1
9
0.003
Recurrence
1
3
0.292
Data are given as the mean standard deviation. HT ¼ hypertension; DM ¼ diabetes mellitus; COPD ¼ chronic obstructive pulmonary disease; CRT ¼ chemoradiotherapy.
received chemotherapy consisting of 5-fluorouracil/cisplatin or 5-fluorouracil/cisplatin/docetaxel, and one patient received radiotherapy with chemotherapy (Table 1). One patient in the rikkunshito group and nine patients in the control group received postoperative adjuvant chemotherapy consisting of 5-fluorouracil/cisplatin or 5-fluorouracil/cisplatin/docetaxel. There were no patients who received radiotherapy with chemotherapy after esophagectomy.
Histopathologic assessment The pathologic classification of the primary tumor, degree of lymph node involvement, and the presence of organ metastasis were determined according to the Tumor-Node-Metastasis classification system of the American Joint Committee on Cancer.14
Patient follow-up
Because adjuvant therapy may affect the postoperative QOL, a subgroup analysis was performed on 30 patients (rikkunshito group: n ¼ 19, control group: n ¼ 11) who did not receive adjuvant chemotherapy.
Study end points The primary end point was body weight loss in the two groups after the 48-week treatments. Secondary end points were the feasibility and safety of administering rikkunshito after esophagectomy on our protocol, nutritional parameters and QOL assessment (FACT-E scale) after the 48-week treatments.
Statistical analysis Data for body weight are expressed as a percentage of preoperative data. Follow-up data for QOL are expressed as adjusted mean changes from preoperative data in the FACT-E scores. The laboratory findings are expressed as a percentage of the preoperative level. All values are expressed as the mean standard deviation with comparisons between the two groups made using the c2 test and Student’s t-test. Values of P < 0.05 were considered to be statistically significant. The statistical analysis was performed with the SPSS version 21.0 software program (SPSS Inc, Chicago, IL).
Results Clinicopathologic characteristics
The patients were routinely followed up at the WMUH outpatient clinic in the first month after surgery and then every 3 months thereafter. The median follow-up time for all patients was 412 days (range, 372-449 days). No patient was lost to follow-up.
QOL instruments and data collection QOL was recorded using the FACT-E questionnaire, version 4.15-17 The FACT-E is part of the Functional Assessment of
The characteristics of the 40 patients are listed in Table 1. No significant differences were observed in the gender, median age, performance status, preoperative weight, transthoracic approach, route of reconstruction, stage, field of lymph node dissection, the presence of concomitant disease, the presence of neoadjuvant therapy, or recurrence between the two groups. Significantly fewer patients in the rikkunshito group received adjuvant chemotherapy than in the control group (P ¼ 0.003).
nakamura et al effects of rikkunshito after esophagectomy
Table 2 e Postoperative complications according to the ClavieneDindo classification.
Morbidity
Rikkunshito (n ¼ 20)
Control (n ¼ 20)
P value
6
5
0.723
2
1
d
0
2
d
Grade I Recurrent nerve paralysis (transient) Grade II Pneumonia
0
1
d
Asthma
1
0
d
Cholecystitis
1
0
d
Angina pectoris
1
0
d
Collection of pericardial effusion
1
0
d
0
1
d
0
0
d
Grade IIIa
Mortality
associated with the administration of rikkunshito (n ¼ 0 for grades 1, 2, 3, and 4). In the rikkunshito group, 80% of patients (n ¼ 16) were able to take full doses of rikkunshito, 10% (n ¼ 2) could take more than two-thirds of the full dose, and 10% (n ¼ 2) took less than two-thirds of the full dose during the 48-week treatment. However, no patients withdrew treatment of rikkunshito, and all patients were able to continue the 48-week treatment.
Nutritional status
Atrial fibrillation
Leakage of lymph in the neck
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Morbidity and mortality Postoperative complications were analyzed using the ClavienDindo classification system in each group.18 No significant differences were found between the two groups regarding the total postoperative complications, and there was no mortality in the two groups (Table 2).
Compliance of rikkunshito According to the Common Terminology Criteria for Adverse Events version 4, during the 48-week treatment none of the patients in the rikkunshito group reported adverse side effects
The rate of body weight loss was significantly less in the rikkunshito group than in the control groups at 52 wk postoperatively (rikkunshito group, 11.8% 8.2%; control group, 18.0% 6.9%, P ¼ 0.016; Fig. 1A). Similarly, the rate of body weight loss in the subgroup of patients who did not receive adjuvant chemotherapy was significantly less in the rikkunshito group than in the control group at 52 wk postoperatively (rikkunshito group, 10.9% 7.3%; control group, 18.0% 7.0%, P ¼ 0.022; Fig. 1B). The acyl ghrelin level was significantly higher in the rikkunshito group than in the control group at 52 wk postoperatively (P ¼ 0.039; Fig. 2A). On the other hand, the des-acyl ghrelin levels were lower in the rikkunshito group than in the control group at 13 (P ¼ 0.007), 26 (P ¼ 0.033), and 52 wk postoperatively (P ¼ 0.027; Fig. 2B). Similarly, in the subgroup of patients without adjuvant chemotherapy the acyl ghrelin level was significantly higher in the rikkunshito group at 52 wk postoperatively (P ¼ 0.011; Fig. 2C), and the des-acyl ghrelin levels were lower in the rikkunshito group than in the control group (13 wk, P ¼ 0.001; 26 wk, P ¼ 0.003; 52 wk, P ¼ 0.002; Fig. 2D). The serum albumin, prealbumin, transferrin, and retinolbinding protein levels of all patients and those who did not receive adjuvant chemotherapy were similar between the two groups at 4, 13, 26, and 52 wk postoperatively.
Fig. 1 e Change of body weight in all patients (A) and those who did not receive adjuvant chemotherapy (B) in the rikkunshito group and control group at 4, 13, 26, and 52 wk postoperatively. The rate of body weight loss of those patients was significantly less in the rikkunshito group than in the control groups at 52 weeks postoperatively (*P [ 0.016, **P [ 0.022).
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Fig. 2 e Change of the acyl ghrelin levels in the rikkunshito group and control group at 4, 13, 26, and 52 weeks postoperatively (A). The level was significantly higher in the rikkunshito group than in the control group at 52 weeks postoperatively (*P [ 0.039). Change of the des-acyl ghrelin levels in the rikkunshito group and control group at 4, 13, 26, and 52 weeks postoperatively (B). The levels were lower in the rikkunshito group than in the control group at 13, 26, and 52 wk postoperatively (*P [ 0.007, **P [ 0.033, #P [ 0.027). Change of the acyl ghrelin levels of patients who did not receive adjuvant chemotherapy in the rikkunshito and control groups (C). The level of those patients was significantly higher in the rikkunshito group than in the control group at 52 wk postoperatively (*P [ 0.011). Change of the des-acyl ghrelin levels of patients who did not receive adjuvant chemotherapy in the rikkunshito and control groups (D). The levels of those patients were lower in the rikkunshito group than in the control group at 13, 26, and 52 wk postoperatively (*P [ 0.001, **P [ 0.003, # P [ 0.002).
These results were similar to those of the statistical analyses using log scales.
Assessment of QOL Patient QOL was examined preoperatively and at 4, 13, 26, and 52 wk postoperatively. The scores of PWB, SWB, EWB, FWB, ECS, FACT-E Trial Outcome Index, FACT-G, and FACT-E were similar between the two groups (Fig. 3). For the symptom scale, satisfaction of food consumption in the rikkunshito group was significantly better than in the control group at 52 wk postoperatively (P ¼ 0.031; Fig. 4). Likewise, the scores of PWB, SWB, EWB, FWB, ECS, FACT-E Trial Outcome Index, FACT-G, and FACT-E of patients without the adjuvant chemotherapy were similar between the two groups (Fig. 5). For the symptom scale, satisfaction of food consumption at postoperative wk 52 in the rikkunshito group was significantly better than in the control group (P ¼ 0.037; Fig. 6).
Discussion The present pilot study is the first clinical trial showing that rikkunshito is useful for improving body weight loss in
connection with increased plasma acyl ghrelin levels for esophageal cancer patients after esophagectomy. Our data clearly showed that the rate of body weight loss was significantly less in the rikkunshito group than in the control group at 52 wk postoperatively. Moreover, the acyl ghrelin level was significantly higher, and the des-acyl ghrelin level was significantly lower in the rikkunshito group than in the control group at the same period. Body weight loss after esophagectomy might be linked to neoadjuvant or adjuvant therapy.2 In our study, there were significantly fewer patients who received adjuvant chemotherapy in the rikkunshito group than in the control group. Therefore, we analyzed subgroups of patients who did not receive adjuvant chemotherapy to exclude this influence. Even in the subgroups, the rate of body weight loss was lower, and the acyl ghrelin level was higher in the rikkunshito group. Thus, our findings indicate that recovery of body weight was related to an increase in acyl ghrelin levels after the administration of rikkunshito. Previous studies reported that patients who underwent total gastrectomy showed a very large decrease in serum ghrelin at postoperative day 7 to 12% of the preoperative level, and those who underwent distal gastrectomy and esophagectomy with gastric tube reconstruction showed
nakamura et al effects of rikkunshito after esophagectomy
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Fig. 3 e Adjusted mean changes in function scales from preoperative scores based on FACT-E, version 4 questionnaire over a 52-week period in PWB, SWB, EWB, FWB, esophagus cancer subscale (ECS), Trial Outcome Index, FACT-G, and FACT-E scores in the rikkunshito group (solid line) and control group (dashed line). Changes >0 reflect an improved QOL relative to the preoperative status, whereas scores <0 reflect a worse QOL relative to the preoperative status. All scores were similar between the two groups.
an approximately 50% reduction in serum ghrelin.19-22 Several flavonoids in rikkunshito have serotonin 2B/2C receptor antagonist activity and accelerate active ghrelin release.6,23 Two active components of rikkunshito, hesperidin and atractylodin, stimulate ghrelin and/or ghrelin receptor-binding activity, and potentiate ghrelin secretion, and receptor signaling, respectively.24 Moreover, it has been reported that rikkunshito might enhance plasma acyl ghrelin by inhibition of ghrelin deacylating enzymes.25 Rikkunshito stimulates the secretion of ghrelin and enhances ghrelin’s orexigenic effect by these mechanisms. Our study also showed that the acyl ghrelin levels significantly increased postoperatively in the rikkunshito group compared with the preoperative level. During the surgery, our team usually made a narrow greater curvature gastric tube (about 4 cm in width), so some of the gastric endocrine cells that secrete ghrelin may remain after esophagectomy. We believe that as those cells are stimulated by rikkunshito, production of ghrelin would increase. Doki et al.19 showed that ghrelin levels were eventually restored after esophagectomy and that they were significantly higher after 3 y than at 1-3 y postoperatively. Another study found that patients who underwent esophagectomy showed weight loss during the first 6 mo after surgery and that this
continued for 3 y.26 Together with the present results, these findings suggest that administration of rikkunshito during the early phase after esophagectomy would be effective for improving malnutrition in the early postoperative period with the increase in the acyl ghrelin levels. The present study also showed that rikkunshito significantly improved patients’ satisfaction of food consumption at 52 wk postoperatively, both in the total patient sample and in the subgroup that did not receive adjuvant chemotherapy. Regarding the relationship to the postoperative complications, one patient in the control group developed leakage of lymph in the neck and required percutaneous intracervical drainage. All grade II morbidities were treated conservatively. As these morbidities occurred temporarily in the hospital, we considered that they would not have an effect on the postoperative QOL. On the other hand, in addition to the enhancement of ghrelin secretion by rikkunshito, there are several other mechanisms responsible for the effects of rikkunshito on gastrointestinal function, such as enhancement of gastric emptying, motility, and adaptive relaxation.3,4,27 The improvement in satisfaction of food consumption by rikkunshito in this study seemed to be mediated by these pathways as well as ghrelin signaling, and these multiple
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Fig. 4 e Adjusted mean changes in symptom scales from preoperative scores based on the FACT-E, version 4 questionnaire over a 52-week period in satisfaction of food consumption, appetite, nausea, and epigastralgia scores in the rikkunshito group (solid line) and control group (dashed line). Changes >0 reflect an improved QOL relative to the preoperative status, whereas scores <0 reflect a worse QOL relative to the preoperative status. Satisfaction of food consumption in the rikkunshito group was significantly better than in the control group at 52 wk postoperatively (*P [ 0.031).
Fig. 5 e Adjusted mean changes in function scales from preoperative scores based on FACT-E, version 4 questionnaire over a 52-week period in the patients who did not receive adjuvant chemotherapy in the rikkunshito group (solid line) and control group (dashed line). See Figure 3 for more details. All scores were similar between the two groups.
nakamura et al effects of rikkunshito after esophagectomy
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Fig. 6 e Adjusted mean changes in symptom scales from preoperative scores based on the FACT-E, version 4 questionnaire over a 52-week period in satisfaction of food consumption, appetite, nausea, and epigastralgia scores of patients who did not receive adjuvant chemotherapy in the rikkunshito group (solid line) and control group (dashed line). See Figure 4 for more details. Satisfaction of food consumption in the rikkunshito group was significantly better than in the control group at 52 wk postoperatively (*P [ 0.037).
actions might lead to recovery of body weight loss after esophagectomy.
Conclusions Our findings indicate that rikkunshito can help to improve body weight loss in connection with increased plasma acyl ghrelin levels for esophageal cancer patients after esophagectomy. However, this study was small and nonrandomized. Therefore, a multicenter, randomized, placebocontrolled study is needed to validate these findings.
Acknowledgment Author’s contribution: Conceiving and designing the study, collecting the data, analyzing and interpreting the data were carried out by M.N., M.N., T.O., M.K., K.H., M.I., and H.Y. Writing the manuscript, providing critical revisions that are important for the intellectual content was done by M.N. and H.Y. Approving the final version of the manuscript was done with the help of M.N., M.N., T.O., M.K., K.H., M.I., and H.Y.
Disclosure This study received the research funding from Tsumura & Co. (Tokyo, Japan).
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10. Asakawa A, Inui A, Fujimiya M, et al. Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut. 2005;54:18e24. 11. Jeon TY, Lee S, Kim HH, et al. Changes in plasma ghrelin concentration immediately after gastrectomy in patients with early gastric cancer. J Clin Endocrinol Metab. 2004;89:5392e5396. 12. Date Y, Kojima M, Hosoda H, et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology. 2000;141:4255e4261. 13. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology group. Am J Clin Oncol. 1982;5:649e655. 14. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. New York: Springer; 2010. 15. Darling G, Eton DT, Sulman J, Casson AG, Celia D. Validation of the functional assessment of cancer therapy esophageal cancer subscale. Cancer. 2006;107:854e863. 16. Ronellenfitsch U, Najmeh S, Andalib A, et al. Functional outcomes and quality of life after proximal gastrectomy with esophagogastrostomy using a narrow gastric conduit. Ann Surg Oncol. 2015;22:772e779. 17. Yamashita H, Omori M, Okuma K, Kobayashi R, Igaki H, Nakagawa K. Longitudinal assessments of quality of life and late toxicities before and after definitive chemoradiation for esophageal cancer. Jpn J Clin Oncol. 2014;44:78e84. 18. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205e213.
19. Doki Y, Takachi K, Ishikawa O, et al. Ghrelin reduction after esophageal substitution and its correlation to postoperative body weight loss in esophageal cancer patients. Surgery. 2006;139:797e805. 20. Yamamoto K, Takiguchi S, Miyata H, et al. Randomized phase II study of clinical effects of ghrelin after esophagectomy with gastric tube reconstruction. Surgery. 2010;148:31e38. 21. Takachi K, Doki Y, Ishikawa O, et al. Postoperative ghrelin levels and delayed recovery from body weight loss after distal or total gastrectomy. J Surg Res. 2006;130:1e7. 22. Miyazaki T, Tanaka N, Hirai H, et al. Ghrelin level and body weight loss after esophagectomy for esophageal cancer. J Surg Res. 2012;176:74e78. 23. Yakabi K, Sadakane C, Noguchi M, et al. Reduced ghrelin secretion in the hypothalamus of rats due to cisplatininduced anorexia. Endocrinology. 2010;151:3773e3782. 24. Fujitsuka N, Asakawa A, Uezono Y, et al. Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival. Transl Psychiatry. 2011;1:e23. 25. Sadakane C, Muto S, Nakagawa K, et al. 10-Gingerol, a component of rikkunshito, improves cisplatin-induced anorexia by inhibiting acylated ghrelin degradation. Biochem Biophys Res Commun. 2011;412:506e511. 26. Martin L, Lagergren P. Long-term weight change after oesophageal cancer surgery. Br J Surg. 2009;96: 1308e1314. 27. Kido T, Nakai Y, Kase Y, et al. Effects of rikkunshi-to, a traditional Japanese medicine, on the delay of gastric emptying induced by N(G)-nitro-L-arginine. J Pharmacol Sci. 2005;98:161e167.
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The effects of rikkunshito on body weight loss after esophagectomy Masaki Nakamura, MD, Mikihito Nakamori, MD, Toshiyasu Ojima, MD, Masahiro Katsuda, MD, Keiji Hayata, MD, Makoto Iwahashi, MD, and Hiroki Yamaue, MD* Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama, Japan
article info
abstract
Article history:
Background: After esophagectomy, esophageal cancer patients suffer from malnutrition,
Received 3 December 2015
anorexia, and dysfunction of digestion and absorption. Rikkunshito, a traditional Japanese
Received in revised form
herbal medicine, reportedly attenuates gastrointestinal symptoms and appetite loss after
4 March 2016
gastrointestinal surgery. We evaluated the clinical effect of rikkunshito and its relationship
Accepted 5 April 2016
with ghrelin in esophageal cancer patients after esophagectomy.
Available online 13 April 2016
Methods: This prospective nonrandomized study included 40 patients with esophageal cancer who underwent esophagectomy at Wakayama Medical University Hospital. They
Keywords:
were assigned to either the control group (n ¼ 20, April 2011-January 2012) or the rikkun-
Rikkunshito
shito group (n ¼ 20, January 2012-August 2012). Patients in the rikkunshito group received
Japanese herbal medicine
2.5 g of rikkunshito before every meal for 48 wk beginning 4 wk after surgery. During the
Ghrelin
48-week treatment, we assessed body weight loss, nutritional parameters, and quality of
Esophagectomy
life (Functional Assessment of Cancer Therapy-Esophageal scale). The primary end point
Esophageal cancer
was the rate of body weight loss in two groups after the 48-week treatments. Results: The rate of body weight loss was significantly less in the rikkunshito group than in the control group (P ¼ 0.016). The acyl ghrelin level after the 48-week treatments was significantly higher in the rikkunshito group (131.7% 74.5%) than in the control group (75.6% 47.5%, P ¼ 0.039). For the Functional Assessment of Cancer Therapy-Esophageal symptom scale, satisfaction of food consumption in the rikkunshito group was significantly better than in the control group at 52 wk postoperatively (P ¼ 0.031). Conclusions: For esophageal cancer patients after esophagectomy, rikkunshito is useful for improving body weight loss in connection with an increase in plasma acyl ghrelin levels. ª 2016 Elsevier Inc. All rights reserved.
Introduction As the prognosis of patients with esophageal cancer has improved in recent years because of advances in treatment, including perioperative chemotherapy, it is necessary to improve the quality of life (QOL) for these patients. In a recent
population-based study of esophageal cancer surgery, twothirds of patients had lost more 10% of their preoperative body weight within 6 mo of surgery, and one in five had lost more than 20%.1 Body weight loss and malnutrition are a considerable problem after esophagectomy and has been linked to appetite loss, eating difficulties, odynophagia, a
* Corresponding author. Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8510, Japan. Tel.: þ81 73 441 0613; fax: þ81 73 446 6566. E-mail address: [email protected] (H. Yamaue). 0022-4804/$ e see front matter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2016.04.004
nakamura et al effects of rikkunshito after esophagectomy
decrease in oral intake due to early satiety, a decrease in gastric acid production, neoadjuvant therapy, and female gender.1,2 Rikkunshito, a traditional Japanese herbal medicine, was reported to improve gastric emptying in patients with functional dyspepsia3,4 and in patients who underwent proximal gastrectomy.5 Recently, rikkunshito was reported to increase food intake and body weight in a rat anorexia model induced by administration of cisplatin.6 Administration of rikkunshito has been shown to enhance the secretion of acyl ghrelin (i.e., the activated form of ghrelin) in rats,6 and it was also reported to improve symptoms in patients with functional dyspepsia, accompanied by an increase in the plasma ghrelin levels.7 However, there have been no studies investigating the clinical effect of rikkunshito and its relationship with ghrelin levels for esophageal cancer patients after esophagectomy. Ghrelin is a 28-amino-acid peptide that is mainly secreted from the X/A-like cells in the gastric fundus, and several other tissues including the brain, duodenum, jejunum, and lung.8 It acts as a natural ligand for the growth hormone secretagogue receptor and plays a role not only in growth hormone secretion8 but also in initiating feeding as an appetite stimulant.9 Ghrelin has two major molecular forms: acyl ghrelin and des-acyl ghrelin. Acyl ghrelin is thought to be an active form that specifically stimulates the release of growth hormone from the pituitary, as well as gastric motor activity and food intake.8 Des-acyl ghrelin has opposing effects, decreasing food intake, and delaying gastric emptying.10 Therefore, an increase in acyl ghrelin level and a decrease in des-acyl ghrelin level may be a favorable response that improves nutritional status and QOL in patients after gastrointestinal surgery. The plasma ghrelin level decreases immediately after gastrectomy and recovers gradually thereafter. However, recovery is poor after both total gastrectomy and proximal gastrectomy11 because ghrelin-secreting X/A-like cells are abundant in the gastric fundus.12 The aim of the present study was to investigate the safety and efficacy of rikkunshito for esophageal cancer patients after esophagectomy. Moreover, we evaluated the clinical effects of rikkunshito on body weight loss, QOL, and plasma ghrelin levels for these patients.
131
Study design This trial was designed as a prospective nonrandomized study. This trial was approved by the Ethical Committee on Clinical Investigation of WMUH and registered at UMIN-CTR ID #000006966 (www.umin.ac.jp/ctr/). Informed consent was obtained from all participating patients preoperatively, and they also agreed to follow-up for at least 52 wk after surgery. Inclusion criteria were: (1) thoracic esophageal cancer patient who would undergo radical transthoracic esophagectomy with gastric tube reconstruction; (2) aged 20-85 years; (3) performance status 0-2 according to Eastern Cooperative Oncology Group criteria13; and (4) appropriate informed consent obtained. Exclusion criteria were: (1) severe comorbidity, such as myocardial infarction, respiratory disorder requiring oxygen inhalation, liver cirrhosis, or chronic renal failure requiring hemodialysis; (2) the presence of other organ malignancies; (3) inability of oral intake; (4) patients who took Japanese herbal medicine within 2 wk before rikkunshito treatments; (5) a history of hypersensitivity to any Japanese herbal medicine preparation; (6) female patients who were pregnant, desiring pregnancy, or breastfeeding; and (7) patients who were diagnosed as inappropriate for this study by a physician. During the 48-week rikkunshito treatment, the following parameters were assessed: body weight loss, nutritional parameters (albumin, prealbumin, transferrin, acyl ghrelin, and des-acyl ghrelin), and QOL based on the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scale.
Rikkunshito Rikkunshito (Tsumura & Co, Tokyo, Japan) is a granular preparation of a mixture of eight crude drugs, Glycyrrhizae Radix (4.7%), Zingiberis Rhizoma (2.3%), Atractylodis Lanceae Rhizoma (18.6%), Zizyphi Fructus (9.3%), Aurantii Nobilis Pericarpium (9.3%), Ginseng Radix (18.6%), Pinelliae Tuber (18.6%), and Hoelen (18.6%), that is extracted with hot water. It has been approved for medicinal use by the Japanese Ministry of Health and Welfare, and its quality has been controlled by the Japanese Pharmacopoeia and the Japanese Herbal Medicine Codex (JHMC, non-Japanese Pharmacopoeia crude drug standards).
Surgical procedures
Patients and methods Patients Forty consecutive patients with thoracic esophageal cancer who underwent an esophagectomy from April 2011 to August 2012 at Wakayama Medical University Hospital (WMUH) in Japan were enrolled preoperatively in this study. The consecutive patients in the first half of the study registration period were assigned to the control group (n ¼ 20, April 2011-January 2012), and they in the latter half were assigned to the rikkunshito group (n ¼ 20, January 2012-August 2012). In the control group, patients were managed without rikkunshito or a placebo postoperatively. In the rikkunshito group, patients received 2.5 g of rikkunshito before every meal for 48 wk beginning 4 wk after the surgery. Patients were not blinded for their postoperative treatment.
All patients underwent radical esophagectomy with a twoor three-field lymph node dissection via a cervicothoracoabdominal approach. A right transthoracic procedure was performed via thoracotomy or thoracoscopy. All patients underwent esophageal reconstruction using stomach to replace the esophagus. In all patients, a gastric conduit through the retrosternal route or the posterior mediastinum was used to reconstruct the anastomosis with the cervical esophagus.
Neoadjuvant therapy and adjuvant therapy Beginning in 2005, our institution administered neoadjuvant chemotherapy for patients with clinical lymph node metastases and neoadjuvant chemoradiotherapy for patients with clinical T4 lesions. Nine patients in each group received neoadjuvant therapy. Among them, eight patients in each group
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Table 1 e Characteristics of enrolled patients. Rikkunshito (n ¼ 20) Sex (male/female) Age (y) Performance status (0/1) Body weight (kg)
Control (n ¼ 20)
P value
15/5
18/2
0.212
65 (50-83)
68 (42-80)
0.690
20/0
20/0
d
60.6 10.5
61.0 11.1
0.923
6/14
9/11
0.327
Transthoracic approach Thoracotomy/ thoracoscopy Route of reconstruction Retrosternum/posterior mediastinum
11/9
12/8
0.749
8/7/5/0
4/8/6/2
0.322
6/14
10/10
0.197
9
6
0.327
6/2/1
6/0/0
d d
Advanced stage I/II/III/IVA Lymph node dissection 2 fields/3 fields Concomitant disease HT/DM/COPD Neoadjuvant therapy
Chronic Illness Therapy measurement system. The general core questionnaire (FACT-General [FACT-G]) is comprised of four general subscales: physical well being (PWB), social well being (SWB), emotional well being (EWB), and functional well being (FWB). The FACT-E questionnaire combines the 27 items of FACT-G and the 17 newly validated items of the esophagus cancer subscale (ECS), which assesses esophageal cancerspecific domains of eating and/or swallowing, speaking, pain, coughing, and weight loss. QOL assessment using FACT-E questionnaire were assessed preoperatively and at 4, 13, 26, and 52 wk after surgery. Blood samples were collected before breakfast after an overnight fast before surgery and postoperatively at 4, 13, 26, and 52 wk. The samples were immediately separated for plasma sampling and stored at 80 C until the time of the assay.
Subgroup analysis
9
9
Chemotherapy/CRT
8/1
8/1
d
Adjuvant chemotherapy
1
9
0.003
Recurrence
1
3
0.292
Data are given as the mean standard deviation. HT ¼ hypertension; DM ¼ diabetes mellitus; COPD ¼ chronic obstructive pulmonary disease; CRT ¼ chemoradiotherapy.
received chemotherapy consisting of 5-fluorouracil/cisplatin or 5-fluorouracil/cisplatin/docetaxel, and one patient received radiotherapy with chemotherapy (Table 1). One patient in the rikkunshito group and nine patients in the control group received postoperative adjuvant chemotherapy consisting of 5-fluorouracil/cisplatin or 5-fluorouracil/cisplatin/docetaxel. There were no patients who received radiotherapy with chemotherapy after esophagectomy.
Histopathologic assessment The pathologic classification of the primary tumor, degree of lymph node involvement, and the presence of organ metastasis were determined according to the Tumor-Node-Metastasis classification system of the American Joint Committee on Cancer.14
Patient follow-up
Because adjuvant therapy may affect the postoperative QOL, a subgroup analysis was performed on 30 patients (rikkunshito group: n ¼ 19, control group: n ¼ 11) who did not receive adjuvant chemotherapy.
Study end points The primary end point was body weight loss in the two groups after the 48-week treatments. Secondary end points were the feasibility and safety of administering rikkunshito after esophagectomy on our protocol, nutritional parameters and QOL assessment (FACT-E scale) after the 48-week treatments.
Statistical analysis Data for body weight are expressed as a percentage of preoperative data. Follow-up data for QOL are expressed as adjusted mean changes from preoperative data in the FACT-E scores. The laboratory findings are expressed as a percentage of the preoperative level. All values are expressed as the mean standard deviation with comparisons between the two groups made using the c2 test and Student’s t-test. Values of P < 0.05 were considered to be statistically significant. The statistical analysis was performed with the SPSS version 21.0 software program (SPSS Inc, Chicago, IL).
Results Clinicopathologic characteristics
The patients were routinely followed up at the WMUH outpatient clinic in the first month after surgery and then every 3 months thereafter. The median follow-up time for all patients was 412 days (range, 372-449 days). No patient was lost to follow-up.
QOL instruments and data collection QOL was recorded using the FACT-E questionnaire, version 4.15-17 The FACT-E is part of the Functional Assessment of
The characteristics of the 40 patients are listed in Table 1. No significant differences were observed in the gender, median age, performance status, preoperative weight, transthoracic approach, route of reconstruction, stage, field of lymph node dissection, the presence of concomitant disease, the presence of neoadjuvant therapy, or recurrence between the two groups. Significantly fewer patients in the rikkunshito group received adjuvant chemotherapy than in the control group (P ¼ 0.003).
nakamura et al effects of rikkunshito after esophagectomy
Table 2 e Postoperative complications according to the ClavieneDindo classification.
Morbidity
Rikkunshito (n ¼ 20)
Control (n ¼ 20)
P value
6
5
0.723
2
1
d
0
2
d
Grade I Recurrent nerve paralysis (transient) Grade II Pneumonia
0
1
d
Asthma
1
0
d
Cholecystitis
1
0
d
Angina pectoris
1
0
d
Collection of pericardial effusion
1
0
d
0
1
d
0
0
d
Grade IIIa
Mortality
associated with the administration of rikkunshito (n ¼ 0 for grades 1, 2, 3, and 4). In the rikkunshito group, 80% of patients (n ¼ 16) were able to take full doses of rikkunshito, 10% (n ¼ 2) could take more than two-thirds of the full dose, and 10% (n ¼ 2) took less than two-thirds of the full dose during the 48-week treatment. However, no patients withdrew treatment of rikkunshito, and all patients were able to continue the 48-week treatment.
Nutritional status
Atrial fibrillation
Leakage of lymph in the neck
133
Morbidity and mortality Postoperative complications were analyzed using the ClavienDindo classification system in each group.18 No significant differences were found between the two groups regarding the total postoperative complications, and there was no mortality in the two groups (Table 2).
Compliance of rikkunshito According to the Common Terminology Criteria for Adverse Events version 4, during the 48-week treatment none of the patients in the rikkunshito group reported adverse side effects
The rate of body weight loss was significantly less in the rikkunshito group than in the control groups at 52 wk postoperatively (rikkunshito group, 11.8% 8.2%; control group, 18.0% 6.9%, P ¼ 0.016; Fig. 1A). Similarly, the rate of body weight loss in the subgroup of patients who did not receive adjuvant chemotherapy was significantly less in the rikkunshito group than in the control group at 52 wk postoperatively (rikkunshito group, 10.9% 7.3%; control group, 18.0% 7.0%, P ¼ 0.022; Fig. 1B). The acyl ghrelin level was significantly higher in the rikkunshito group than in the control group at 52 wk postoperatively (P ¼ 0.039; Fig. 2A). On the other hand, the des-acyl ghrelin levels were lower in the rikkunshito group than in the control group at 13 (P ¼ 0.007), 26 (P ¼ 0.033), and 52 wk postoperatively (P ¼ 0.027; Fig. 2B). Similarly, in the subgroup of patients without adjuvant chemotherapy the acyl ghrelin level was significantly higher in the rikkunshito group at 52 wk postoperatively (P ¼ 0.011; Fig. 2C), and the des-acyl ghrelin levels were lower in the rikkunshito group than in the control group (13 wk, P ¼ 0.001; 26 wk, P ¼ 0.003; 52 wk, P ¼ 0.002; Fig. 2D). The serum albumin, prealbumin, transferrin, and retinolbinding protein levels of all patients and those who did not receive adjuvant chemotherapy were similar between the two groups at 4, 13, 26, and 52 wk postoperatively.
Fig. 1 e Change of body weight in all patients (A) and those who did not receive adjuvant chemotherapy (B) in the rikkunshito group and control group at 4, 13, 26, and 52 wk postoperatively. The rate of body weight loss of those patients was significantly less in the rikkunshito group than in the control groups at 52 weeks postoperatively (*P [ 0.016, **P [ 0.022).
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Fig. 2 e Change of the acyl ghrelin levels in the rikkunshito group and control group at 4, 13, 26, and 52 weeks postoperatively (A). The level was significantly higher in the rikkunshito group than in the control group at 52 weeks postoperatively (*P [ 0.039). Change of the des-acyl ghrelin levels in the rikkunshito group and control group at 4, 13, 26, and 52 weeks postoperatively (B). The levels were lower in the rikkunshito group than in the control group at 13, 26, and 52 wk postoperatively (*P [ 0.007, **P [ 0.033, #P [ 0.027). Change of the acyl ghrelin levels of patients who did not receive adjuvant chemotherapy in the rikkunshito and control groups (C). The level of those patients was significantly higher in the rikkunshito group than in the control group at 52 wk postoperatively (*P [ 0.011). Change of the des-acyl ghrelin levels of patients who did not receive adjuvant chemotherapy in the rikkunshito and control groups (D). The levels of those patients were lower in the rikkunshito group than in the control group at 13, 26, and 52 wk postoperatively (*P [ 0.001, **P [ 0.003, # P [ 0.002).
These results were similar to those of the statistical analyses using log scales.
Assessment of QOL Patient QOL was examined preoperatively and at 4, 13, 26, and 52 wk postoperatively. The scores of PWB, SWB, EWB, FWB, ECS, FACT-E Trial Outcome Index, FACT-G, and FACT-E were similar between the two groups (Fig. 3). For the symptom scale, satisfaction of food consumption in the rikkunshito group was significantly better than in the control group at 52 wk postoperatively (P ¼ 0.031; Fig. 4). Likewise, the scores of PWB, SWB, EWB, FWB, ECS, FACT-E Trial Outcome Index, FACT-G, and FACT-E of patients without the adjuvant chemotherapy were similar between the two groups (Fig. 5). For the symptom scale, satisfaction of food consumption at postoperative wk 52 in the rikkunshito group was significantly better than in the control group (P ¼ 0.037; Fig. 6).
Discussion The present pilot study is the first clinical trial showing that rikkunshito is useful for improving body weight loss in
connection with increased plasma acyl ghrelin levels for esophageal cancer patients after esophagectomy. Our data clearly showed that the rate of body weight loss was significantly less in the rikkunshito group than in the control group at 52 wk postoperatively. Moreover, the acyl ghrelin level was significantly higher, and the des-acyl ghrelin level was significantly lower in the rikkunshito group than in the control group at the same period. Body weight loss after esophagectomy might be linked to neoadjuvant or adjuvant therapy.2 In our study, there were significantly fewer patients who received adjuvant chemotherapy in the rikkunshito group than in the control group. Therefore, we analyzed subgroups of patients who did not receive adjuvant chemotherapy to exclude this influence. Even in the subgroups, the rate of body weight loss was lower, and the acyl ghrelin level was higher in the rikkunshito group. Thus, our findings indicate that recovery of body weight was related to an increase in acyl ghrelin levels after the administration of rikkunshito. Previous studies reported that patients who underwent total gastrectomy showed a very large decrease in serum ghrelin at postoperative day 7 to 12% of the preoperative level, and those who underwent distal gastrectomy and esophagectomy with gastric tube reconstruction showed
nakamura et al effects of rikkunshito after esophagectomy
135
Fig. 3 e Adjusted mean changes in function scales from preoperative scores based on FACT-E, version 4 questionnaire over a 52-week period in PWB, SWB, EWB, FWB, esophagus cancer subscale (ECS), Trial Outcome Index, FACT-G, and FACT-E scores in the rikkunshito group (solid line) and control group (dashed line). Changes >0 reflect an improved QOL relative to the preoperative status, whereas scores <0 reflect a worse QOL relative to the preoperative status. All scores were similar between the two groups.
an approximately 50% reduction in serum ghrelin.19-22 Several flavonoids in rikkunshito have serotonin 2B/2C receptor antagonist activity and accelerate active ghrelin release.6,23 Two active components of rikkunshito, hesperidin and atractylodin, stimulate ghrelin and/or ghrelin receptor-binding activity, and potentiate ghrelin secretion, and receptor signaling, respectively.24 Moreover, it has been reported that rikkunshito might enhance plasma acyl ghrelin by inhibition of ghrelin deacylating enzymes.25 Rikkunshito stimulates the secretion of ghrelin and enhances ghrelin’s orexigenic effect by these mechanisms. Our study also showed that the acyl ghrelin levels significantly increased postoperatively in the rikkunshito group compared with the preoperative level. During the surgery, our team usually made a narrow greater curvature gastric tube (about 4 cm in width), so some of the gastric endocrine cells that secrete ghrelin may remain after esophagectomy. We believe that as those cells are stimulated by rikkunshito, production of ghrelin would increase. Doki et al.19 showed that ghrelin levels were eventually restored after esophagectomy and that they were significantly higher after 3 y than at 1-3 y postoperatively. Another study found that patients who underwent esophagectomy showed weight loss during the first 6 mo after surgery and that this
continued for 3 y.26 Together with the present results, these findings suggest that administration of rikkunshito during the early phase after esophagectomy would be effective for improving malnutrition in the early postoperative period with the increase in the acyl ghrelin levels. The present study also showed that rikkunshito significantly improved patients’ satisfaction of food consumption at 52 wk postoperatively, both in the total patient sample and in the subgroup that did not receive adjuvant chemotherapy. Regarding the relationship to the postoperative complications, one patient in the control group developed leakage of lymph in the neck and required percutaneous intracervical drainage. All grade II morbidities were treated conservatively. As these morbidities occurred temporarily in the hospital, we considered that they would not have an effect on the postoperative QOL. On the other hand, in addition to the enhancement of ghrelin secretion by rikkunshito, there are several other mechanisms responsible for the effects of rikkunshito on gastrointestinal function, such as enhancement of gastric emptying, motility, and adaptive relaxation.3,4,27 The improvement in satisfaction of food consumption by rikkunshito in this study seemed to be mediated by these pathways as well as ghrelin signaling, and these multiple
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Fig. 4 e Adjusted mean changes in symptom scales from preoperative scores based on the FACT-E, version 4 questionnaire over a 52-week period in satisfaction of food consumption, appetite, nausea, and epigastralgia scores in the rikkunshito group (solid line) and control group (dashed line). Changes >0 reflect an improved QOL relative to the preoperative status, whereas scores <0 reflect a worse QOL relative to the preoperative status. Satisfaction of food consumption in the rikkunshito group was significantly better than in the control group at 52 wk postoperatively (*P [ 0.031).
Fig. 5 e Adjusted mean changes in function scales from preoperative scores based on FACT-E, version 4 questionnaire over a 52-week period in the patients who did not receive adjuvant chemotherapy in the rikkunshito group (solid line) and control group (dashed line). See Figure 3 for more details. All scores were similar between the two groups.
nakamura et al effects of rikkunshito after esophagectomy
137
Fig. 6 e Adjusted mean changes in symptom scales from preoperative scores based on the FACT-E, version 4 questionnaire over a 52-week period in satisfaction of food consumption, appetite, nausea, and epigastralgia scores of patients who did not receive adjuvant chemotherapy in the rikkunshito group (solid line) and control group (dashed line). See Figure 4 for more details. Satisfaction of food consumption in the rikkunshito group was significantly better than in the control group at 52 wk postoperatively (*P [ 0.037).
actions might lead to recovery of body weight loss after esophagectomy.
Conclusions Our findings indicate that rikkunshito can help to improve body weight loss in connection with increased plasma acyl ghrelin levels for esophageal cancer patients after esophagectomy. However, this study was small and nonrandomized. Therefore, a multicenter, randomized, placebocontrolled study is needed to validate these findings.
Acknowledgment Author’s contribution: Conceiving and designing the study, collecting the data, analyzing and interpreting the data were carried out by M.N., M.N., T.O., M.K., K.H., M.I., and H.Y. Writing the manuscript, providing critical revisions that are important for the intellectual content was done by M.N. and H.Y. Approving the final version of the manuscript was done with the help of M.N., M.N., T.O., M.K., K.H., M.I., and H.Y.
Disclosure This study received the research funding from Tsumura & Co. (Tokyo, Japan).
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