Introduction
Aggressive cancer therapy including chemo- and chemoradiotherapy can help patients with various malignancies to achieve greater improvement in survival and prognosis. However, these therapies frequently cause some serious adverse events. Of these, oral mucositis is one of the most frequent and clinically significant complications induced by chemotherapy, with or without radiotherapy (1). Serious oral mucositis, which involves both erythema and painful mucosal ulceration, can cause difficulty in swallowing, dehydration, malnutrition and increased risk for infection (2,3). These clinical sequelae can limit the tolerated dose of chemotherapy, leading to poor prognosis, and severely impair the health-related quality of life (3,4). It has been reported that the incidence of oral mucositis induced by conventional chemotherapy for esophageal cancer is relatively high (35–60%) and that the DCF regimen (docetaxel, cisplatin and 5-fluorouracil), which is occasionally used for patients with esophageal cancer in Japan, is one of the high-risk regimens for oral mucositis (3,5–7). Unfortunately, there are few agents that have been confirmed to reveal consistent protective action against chemo (chemoradio) therapy-induced oral mucositis to date.
Involuntary weight loss is considered a hallmark of advanced cancer, and esophageal cancer has been reported to have the highest median percentage weight loss among the primary tumor sites evaluated (8). Cancer cachexia leads to body weight loss by reducing both lean and fat mass, and muscle loss has recently emerged as a more serious concern. Sarcopenia, which was initially defined as the loss of skeletal muscle mass that occurs with aging, has also been recognized as a clinically important phenomenon that is associated with reduced quality of life and poor clinical outcome in malignant conditions (9,10). There is mounting evidence that sarcopenia or sarcopenic obese patients are independently associated with a poor response to cancer therapy in various malignancies, such as melanoma (11), renal cell (12), hepatic carcinoma (13), colorectal (14), pancreatic (15), breast (16) and lung cancer (17). However, there is limited knowledge on the impact of sarcopenia on the prognostic value and response to chemo (chemoradio) therapy for esophageal cancer. A recent study demonstrated that body composition was markedly changed following chemotherapy for esophageal cancer, and a significant reduction of fat free mass (skeletal muscle) was observed during chemotherapy and the incidence of sarcopenia increased from 57% before chemotherapy to 78.7% after completion of chemotherapy (18). Counteraction of sarcopenia progression during chemotherapy in some way (e.g. nutritional supplement) is considered to be important, since it may attenuate the toxicity of anticancer agents and improve the therapeutic efficacy of chemo (chemoradio) therapy. Although supplementation has been suggested as means of attenuating the reduction of fat free mass during chemotherapy (19,20), robust data supporting that supplemental intervention in cancer patients improves sarcopenia progression during chemo (chemoradio) therapy are currently lacking.
Elental® is one of the widely used nutritional supplements and its special formula contains a variety of amino acids, together with easily digestible nutritions, minerals, vitamins and a major energy source, dextrin (Table I). Fat is present in a very small amount, whereas L-glutamine is present at an especially high dose (1.932 mg/package). Several reports have demonstrated that glutamine supplementation decreases the incidence and severity of chemo (chemoradio) therapy-induced mucositis (21–23). Moreover, it has been reported that amino acids, such as leucine, can stimulate muscle protein synthesis (24) and that supplementation of amino acids improves or prevents sarcopenia in several diseases, including cancer (25). These observations led us to examine the preventive effects of Elental on oral mucositis and sarcopenia progression during chemo (chemoradio) therapy for esophageal cancer.
The primary endpoint of this trial was to explore the potential preventive effect of the amino acid-rich elemental diet Elental on chemo (chemoradio) therapy-induced oral mucositis in patients with esophageal cancer. The impact of the anticatabolic properties of Elental was also studied as a secondary endpoint. Herein, we report that Elental nutrition could counteract sarcopenia progression during chemo (chemoradio) therapy for esophageal cancer, but we did not demonstrate efficacy against chemo (chemoradio) therapy-induced oral mucositis.
Results
Patient characteristics
Thirty-six patients were enrolled in the study between February 2012 and April 2015, after signing the written informed consent, and they were randomly assigned to receive oral rinse with azulene (Arm 1, n=18) or to undergo administration of Elental® (Arm 2, n=18). Of them, three patients were excluded from analysis (Arm 1, 1; Arm 2, 2), who did not receive either treatment (i.e., azulene or elental). Consequently, 33 patients were included in the complete analysis (Fig. 1). The average BMI and SMI for the 33 patients was 20.42 and 6.59 kg/m2, respectively. Although sarcopenia was observed in 20 patients (60.6%) prior to treatment, there was no sarcopenic obesity, i.e., sarcopenia combined with BMI ≥25 kg/m2. The baseline patient characteristics were similar between the groups (Table II). As randomization was stratified by treatment (chemotherapy/chemoradiotherapy) and stage, these were well balanced between the treatment groups. However, with respect to the chemotherapy regimen, triplet chemotherapy regimen, which is a more toxic regimen with an increased incidence of stomatitis (31), was more frequently used for patients in Arm 2 (Arm 1=22.2%; Arm 2=50.0%). Although CRP (P=0.24), white blood cell count (P=0.12) and total neutrophil count (P=0.14) tended to be higher in patients in Arm 2, the differences were not statistically significant. BMI and body composition (i.e., body fat mass and LBM) were comparable between the groups.
Incidence and severity of oral mucositis
During the treatment cycle, oral mucositis CTCAE grade ≥2 developed in 6 patients (18.2%). The incidence of oral mucositis grade ≥2 tended to be lower for patients treated with Elental (Arm 1=23.5%; Arm 2=12.5%), but this was not statistically significant (Table III). Analysis of the severity of oral pain is shown in Table IV. Most of the patients (72.7%) did not complain of oral pain and oral pain grade ≥2 was observed in only 5 patients (15.2%). There was no significant difference in the maximum severity of oral pain between Arm 1 (azulene) and Arm 2 (Elental).
Changes of nutrition indicators from baseline
The average BMI, body fat mass and LBM in the 33 patients decreased significantly after chemo (chemoradio) therapy (Fig. 2). Relative changes of nutrition indicators after the treatment from baseline were calculated using the following formula: 100 x (value after-value before)/value before. When the relative changes of nutrition indicators were compared between Arm 1 (azulene) and Arm 2 (Elental) groups (Fig. 3), a different pattern appeared when BMI, body fat mass and LBM were expressed as the percent change from baseline for each group. BMI and body fat mass were reduced after the treatment relative to baseline in both groups. By contrast, LBM was lost in Arm 1, but increased in Arm 2 after the treatment compared with the baseline values. There was a significant difference between the change of LBM in Arm 1 and in Arm 2 (P=0.007). The laboratory values for total protein, albumin and hemoglobin decreased but total cholesterol increased in both groups after treatment. The relative change of total cholesterol increased more in Arm 1 than in Arm 2, but there was no statistically significant difference between the two groups (P=0.33).
Adverse events of chemotherapy
With respect to adverse events other than oral mucositis during the treatment cycle, common grade 3/4 toxicities included leukopenia, neutropenia and lymphocytopenia (Table V). Although the grade 3/4 neutropenia occurred more often in Arm 1 compared with Arm 2 (41.2 and 25.0%, respectively), this was not statistically significant (P=0.46). The incidence of diarrhea was greater in Arm 2 than in Arm 1 (31.3 and 11.8%, respectively), and was grade 2 or less. There were no statistically significant differences in the incidence or severity of hematological and non-hematological adverse effects between the two arms.
Discussion
Profound weight loss and malnutrition subsequent to severe dysphagia and cancer cachexia are cardinal symptoms in esophageal cancer. Recently, it has been reported that ~25–55% of patients with esophageal cancer undergoing neo-adjuvant therapy were sarcopenic at the time of diagnosis (18,32–35). Moreover, two recent studies in esophageal cancer patients have shown that muscle wasting can worsen with cancer chemo- or chemoradiotherapy (18,34). Although the primary endpoint of a preventive effect against oral mucositis was not met, the present study demonstrated several noteworthy findings. First, the overall prevalence of sarcopenia among Japanese esophageal cancer patients was 60.6% in the present study, which is higher than the prevalences described in previous reports for esophageal cancer patients mainly from Europe (18,32–35). On the other hand, sarcopenic obesity was not observed in this study, however, Anandavadivelan et al (32) reported sarcopenic obesity in 14% of esophageal cancer patients in Sweden. Second, in most patients, both body fat mass and LBM were reduced during the treatment cycle, and average values among all participants were decreased significantly after chemo (chemoradio) therapy. Third, the most important finding in this study is that enteral nutrition using Elental could maintain or even increase LBM post chemo (chemoradio) therapy.
Sarcopenia was recently identified as a poor prognostic factor in patients with various malignancies, such as melanoma, hepatic carcinoma, pancreatic and lung cancer, and liver metastasis from colorectal cancer (11,13,15,17,36). Moreover, sarcopenia and sarcopenic obesity are associated independently with a poor response to cancer chemotherapy in melanoma (11), renal-cell (12), hepatic carcinoma (13), colorectal (14), pancreatic (15), breast (16) and lung cancer (17). More recently, sarcopenic obesity has been reported to be a probable risk factor for dose limiting toxicity during chemotherapy for esophageal cancer (32). Thus, it has become apparent that sarcopenia has a clinically significant impact on treatment response and survival in various malignancies, including esophageal cancer.
The rate of malnutrition in patients with esophageal cancer has been estimated to be as high as 78.9% (37) and marked reductions in both body fat mass and skeletal muscle mass occur during chemotherapy for esophageal cancer (18). Nutritional support is important to decrease major postoperative complications in esophageal cancer patients (38,39). However, the significance of nutritional intervention in patients undergoing chemo- or chemoradiotherapy for esophageal cancer is not clear. In the present study, LBM decreased during treatment in the azulene (control) group, but increased in the Elental® group relative to the baseline and there was a significant difference between the two groups. To the best of our knowledge, this is the first report demonstrating that nutritional intervention can counteract skeletal muscle wasting during chemo- or chemoradiotherapy for esophageal cancer. The treatment response to chemo (chemoradio) therapy did not differ between the azulene and Elental groups in the present study (average change in tumor size after 1 cycle treatment; −18.4 vs. −18.1%, respectively; data not shown), however, this may be due to the short observation period. We believe that nutritional intervention during cancer treatment is important, and can contribute to the improvement of both malnutrition as well as the clinical outcome in cancer patients. Further studies over a longer follow-up period of time are needed to confirm these observations.
It has been reported that amino acid supplementation can stimulate muscle protein synthesis (24,40,41), and among the amino acids, leucine has been recognized to play a significant role in muscle protein synthesis (42). Elental, which does not contain a great amount of leucine (6.84%) (Table I), does contain a large amount of amino acids (12.66 g/one pack). In considering the possible explanations for the results of this study, it appears likely that muscle protein synthesis was enhanced by the high amount of amino acids contained in Elental. Another possible explanation is that Elental could help to maintain mucosal integrity in the gastrointestinal tract, thereby resulting in maintained nutrient absorption. Anticancer drugs, such as 5-fluorouracil, can induce small intestinal mucosal injury and plasma diamine oxidase (DAO) has been reported to be a useful indicator of mucosal injury of the gastrointestinal tract (43). Tanaka et al (7) recently reported that plasma DAO activity was decreased after chemotherapy in patients with esophageal cancer, and patients treated with the Elental diet exhibited a significant increase in DAO activity after chemotherapy. While we did not measure plasma DAO activity during chemo (chemoradio) therapy, amino acids, such as glutamine, which is abundant in Elental, could prevent anticancer drug-induced intestinal mucosal injury and maintain nutrient absorption, including the amino acids, thus contributing to stimulate muscle protein synthesis. However, plasma amino acid concentrations were not measured during this study, and doing this in future experiments could help to validate the results presented here. We also believe further experimental studies are needed to confirm the underlying mechanism.
The present study did not provide evidence of the effectiveness of Elental in protecting against the development of oral mucositis during chemo (chemoradio) therapy. The incidence of oral mucositis (≥ grade 2) in this study was 18.2% among all enrolled patients, which was much lower than previously assumed (the incidence for the azulene arm being 50%), which makes it difficult to achieve statistical significance. Despite lacking statistical significance, the incidence of oral mucositis in the Elental arm was lower than that in the azulene arm (12.5 vs. 23.5%, respectively). It is possible that evidence supporting the efficacy for Elental against oral mucositis might be achieved, if the study were to focus on a high-risk population susceptible to oral mucositis, such as patients who have experienced it prior to undergoing chemo (chemoradio) therapy.
In conclusion, this study revealed that Elental could counteract the development of sarcopenia during the treatment cycle, though we could not demonstrate the efficacy of Elental against chemo (chemoradio) therapy-induced oral mucositis in esophageal cancer patients. Further clinical studies with a larger sample size should be conducted to confirm these results and to elucidate whether the preventive effect of Elental against sarcopenia leads to an improvement of the clinical outcome of esophageal cancer patients undergoing treatment with chemo (chemoradio) therapy.