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Keywords:

  • ghrelin;
  • esophageal cancer;
  • food intake;
  • appetite;
  • cisplatin-based chemotherapy

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

BACKGROUND:

Cisplatin reduces plasma ghrelin levels through the 5-hydroxytryptamine (5-HT) receptor. This may cause cisplatin-induced gastrointestinal disorders and hinders the continuation of chemotherapy. The authors of this report conducted a prospective, randomized phase 2 trial to evaluate the effects of exogenous ghrelin during cisplatin-based chemotherapy.

METHODS:

Forty-two patients with esophageal cancer who were receiving cisplatin-based neoadjuvant chemotherapy were assigned to either a ghrelin group (n = 21) or a placebo group (n = 21). They received either intravenous infusions of synthetic human ghrelin (3 μg/kg) or saline twice daily for 1 week with cisplatin administration. The primary endpoint was changes in oral calorie intake, and the secondary endpoints were chemotherapy-related adverse events; appetite visual analog scale (VAS) scores; changes in gastrointestinal hormones and nutritional status, including rapid turnover proteins, and quality of life (QoL) estimated with the European Organization for Research and Treatment of Cancer QoL core questionnaire (QLQ-C30).

RESULTS:

Two patients were excluded from the final analysis: One patient suspended ghrelin administration because of excessive diaphoresis, and another patient in the placebo group failed to monitor the self-questionnaire. Food intake and appetite VAS scores were significantly higher in the ghrelin group than in the placebo group (18.2 ± 5.2 kcal/kg/day vs 12.7 ± 3.4 kcal/kg/day [P = .001] and 6.2 ± 0.9 vs 4.1 ± 0.9 [P < .0001], respectively). Patients in the ghrelin group had fewer adverse events during chemotherapy related to anorexia and nausea than patients in the control group. Significant deterioration was noted after chemotherapy in the placebo group in QoL scores, appetite, nausea and vomiting, and global health status.

CONCLUSIONS:

Short-term administration of exogenous ghrelin at the start of cisplatin-based chemotherapy stimulated food intake and minimized adverse events. Cancer 2012. © 2012 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

Neoadjuvant and/or adjuvant chemotherapy using multiple antitumor agents is an important component of any therapeutic regimen for advance-stage solid tumors.1 Cisplatin plays a central role in the success of such multidrug chemotherapy regimens for various cancers2; however, it is also associated with an assortment of adverse effects, including nephrotoxicity, myelosuppression, and gastrointestinal disorders like nausea, vomiting, and appetite loss. These gastrointestinal symptoms generally are nonlethal and reversible; however, their high frequency and strength can strongly impair the patient's quality of life (QoL) and, in general, may preclude the completion of chemotherapy.

The acute phase of cisplatin-induced gastrointestinal disorders involve increased serotonin (5-hydroxytryptamine [5-HT]) secretion from enterochromaffin cells.3 Consequently, a 5-HT3-receptor antagonist was developed and is widely used for patients with cancer who are receiving cisplatin-based chemotherapy.4 Despite this advance, many patients still suffer from gastrointestinal disorders because of cisplatin, especially in the later phases of treatment.

Ghrelin is an endogenous ligand for the growth hormone (GH) secretagogue receptor and is secreted predominantly by gastric endocrine cells.5 It induces dose-dependent, GH-releasing activity5, 6; stimulates appetite and food intake; and triggers a positive energy balance through a central mechanism involving hypothalamic neuropeptides.5-9 In rodents, ghrelin increases GH secretion, feeding, and body weight when administered centrally or peripherally.7-9 We also reported previously that intravenous administration of ghrelin enhanced oral feeding and diminished weight loss in patients who underwent total gastrectomy10 and esophagectomy.11

In rodents, cisplatin markedly decreased plasma ghrelin concentrations, whereas the administration of exogenous ghrelin improved cisplatin-induced decreases in food intake.12, 13 These observations suggested that ghrelin also may be effective in minimizing the gastrointestinal disorders induced by cisplatin in humans, although there are huge differences in feeding activity between the 2 species. Accordingly, we undertook a randomized clinical trial to elucidate the effect of exogenous ghrelin on patients with esophageal cancer who were receiving cisplatin-based neoadjuvant chemotherapy.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

Patients

This prospective, randomized, placebo-controlled phase 2 study enrolled 42 patients with advanced esophageal cancer who received cisplatin-based neoadjuvant chemotherapy. The Human Ethics Review Committee of Osaka University School of Medicine approved the study protocol, and a signed consent form was obtained from each enrolled patient before study entry in accordance with the Declaration of Helsinki. This study was registered on the University Hospital Medical Information Network (R000005924). It began in February 2010, and enrollment of patients ended in January 2011. The eligibility criteria for the study were as follows: 1) histopathologically confirmed squamous cell carcinoma of the esophagus; 2) stage II or III disease according to criteria of the International Union Against Cancer (UICC), sixth edition14; 3) ages 20 to 80 years; 4) no esophageal obstruction by tumor and capacity for oral intake of soft solid foods; 5) adequate function of major organs; 6) no other active malignancy; 7) an Eastern Cooperative Oncology Group performance status (PS) of 0 or 1; and, 8) provision of written informed consent. The exclusion criteria for the study were as follows: 1) pregnant or potentially (willingly) pregnant women; 2) a past history of other chemotherapy or radiotherapy; and, 3) patients judged to be ineligible by the investigator.

A coordinating center (a section of the Department of Gastroenterological Surgery, Osaka University Medical School) was responsible for creating the treatment allocation code using a computer-generated randomization table with a statistician. Patients were randomized at a 1:1 ratio to receive intravenous infusion of either synthetic human ghrelin (3 μg/kg) or placebo (saline). Treatment allocation was arranged before the beginning of chemotherapy. The study was performed in a single-blind manner, ie, without knowledge of allocation to the patients.

Calculation of Sample Size

We estimated that oral intake of food calories during the study period in the placebo group would be 1600 ± 300 kcal/day. The power calculation was based on a 20% improvement by ghrelin administration in oral food intake calories, with a power of 85% and an α value of 5%, requiring at least 17 patients per study group. Assuming that approximately 20% of patients in each group would not complete the study, the initial proposal aimed to recruit 20 patients in each group.

Neoadjuvant Chemotherapy Regimen

The enrolled patients received cisplatin-based chemotherapy. This was a regimen consisting of either 5-fluorouracil, cisplatin, and doxorubicin (ACF)3, 15 or 5-fluorouracil, cisplatin, and docetaxel (DCF).16 Both regimens entailed 2 treatments every 4 weeks. Specifically, the ACF regimen comprised cisplatin (70 mg) and doxorubicin (35 mg) on day 1 and a continuous infusion of 5-fluorouracil (700 mg/day) for 7 days, whereas the DCF regimen comprised cisplatin (70 mg) and docetaxel (70 mg) on day 1 and then a continuous infusion of 5-fluorouracil (700 mg/day) for 5 days. Supportive therapy and prophylaxis against expected side effects was provided. All patients were premedicated with intravenous ramosetron hydrochloride (0.3 mg), a representative 5-HT3 receptor antagonist. This was infused 1 hour before the administration of cisplatin on day 1 and every morning thereafter on days 2 through 7 (ACF regimen) or days 2 through 5 (DCF regimen). Hypersensitivity reactions were treated prophylactically with intravenous dexamethasone (8 mg), which was infused 1 hour before the administration of cisplatin. Adequate hydration was ensured before and after cisplatin infusion. Additional antiemetics or steroid preparations were recommended in case of grade 3 or greater anorexia, nausea, and vomiting according to toxicity grading criteria from the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE).17 After completion of the second cycle of neoadjuvant chemotherapy, the patient underwent curative resection, ie, subtotal esophagectomy with reconstruction by gastric tube, together with 2-field or 3-field lymphadenectomy.18

Evaluation of Adverse Events and Criteria for Dose Modifications

Adverse events were evaluated each day of chemotherapy and were scored by the most severe event in the first cycle (days 1-28) based on the toxicity grading criteria from the CTCAE by each primary physician. Before starting the second cycle of chemotherapy, patients were required to have grade <2 hematologic toxicity. When patients did not recover within a 2-week delay or had grade 4 nonhematologic toxicity in the first cycle, the chemotherapy was discontinued, and surgical resection was considered.

Dose modifications in the second cycle were based on treatment-related adverse events recorded in the first cycle. In the ACF regimen, the doses of cisplatin and doxorubicin were reduced by 20% for grade 4 neutropenia that lasted >5 days, febrile neutropenia grade ≥3, and thrombocytopenia grade ≥3. In the DCF regimen, the doses of cisplatin and docetaxel were reduced by 20% for the same hematogenic toxicity. The dose of cisplatin was reduced by 20% in the second cycle in both regimens after a rise in serum creatinine level above 1.5 mg/dL during the first cycle. The dose of 5-fluorouracil was reduced by 20% for grade ≥3 diarrhea and mucositis. After completing 2 cycles of neoadjuvant chemotherapy, all patients were restaged by endoscopy and computed tomography to evaluate the clinical response to chemotherapy 2 weeks after the completion of chemotherapy. Clinical responses were categorized according to criteria based on the World Health Organization response criteria for measurable disease and the Japanese Society for Esophageal Diseases.19

Study Protocol

The study protocol is summarized in Figure 1A. Patients who were assigned to the ghrelin group received ghrelin treatment at a dose of 3 μg/kg body weight diluted in 50 mL saline given over 30 minutes twice daily (before breakfast and before dinner) for 7 consecutive days (days 1-7), as in our previous studies.10, 11 Synthetic ghrelin was prepared and supplied as described previously.10, 11 Patients in the placebo group received a corresponding placebo (pure saline) infusion in the same fashion. All participants received the same protocol of intravenous infusion in both groups, ie, 3000 mL/day from days 1 to 3 and 2000 mL/day from days 4 to 7 of chemotherapy, including 43 g glucose, 35 millequivalents (mEq) sodium, 20 mEq potassium, 35 mEq chloride, and 20 mEq lactate in 1000 mL.

thumbnail image

Figure 1. (A) This is a flow diagram of process through the trial. (B) The study protocol is illustrated. IVD indicates intravenous drip; FAP, combined 5-fluorouracil, doxorubicin (Adriamycin), and cisplatin; DCF, combined docetaxel, cisplatin, and 5-fluororuacil; VAS; visual analog scale; EORTC QLQ C-30, European Organization for Research and Treatment of Cancer Core-30 Quality-of-Life Questionnaire; QOL, quality of life.

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Endpoints

The primary endpoint of this study was alteration in oral calorie intake from day 1 to day 7 of chemotherapy. Patients in this study were served standard meals and were allowed to receive extra food if desired. All dietary intake calories were calculated by a national registered dietitian at Osaka University Hospital by measuring the weight of each dish diet before and after every meal.10, 11 The secondary endpoints included changes in appetite, adverse events, QoL, body weight, nutritional status, hormonal assays, and blood tests. Appetite profiles were measured using a 100-mm visual analog scale (VAS), with the questions “How hungry are you?” and “How full do you feel?,” which were anchored with “0 not at all” and “100-extremely.” Patients were instructed to rate themselves by selecting the scale before each meal that was most appropriate to their feeling at that time. The mean VAS score was calculated each day. Questionnaires included the European Organization for Research and Treatment of Cancer core QoL questionnaire (QLQ-C30) before and after chemotherapy (day 8).20 The QLQ-C30 contains 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), a global health/QoL scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All scale scores and single items scores range from 0 to 100. A high score for a functional scale represents a higher (“better”) level of functioning, whereas a high score for a symptom scale or item represents a higher (“worse”) level of symptoms.

Blood samples were collected before breakfast after an overnight fast before chemotherapy and on Days 3 and 8 of chemotherapy. The samples were transferred immediately into chilled tubes containing disodium ethylenediamine tetra-acetic acid and aprotinin, centrifuged at 4°C, separated for serum sampling, and stored at −50°C. The plasma samples were mixed with a 10% volume of 1 M hydrochloric acid before storing at −50°C. Plasma acyl-ghrelin and desacyl-ghrelin concentrations were measured with a sandwich-type enzyme immunoassay kit according to the protocol supplied by the manufacturer (Mitsubishi Kagaku Iatron, Inc., Tokyo, Japan).21 Total plasma ghrelin concentration was calculated as acyl-ghrelin plus desacyl-ghrelin concentration. Serum GH, insulin, and leptin concentrations were measured using a GH “Daiichi” kit (TFB, Inc., Tokyo, Japan), a chemiluminescent enzyme immunoassay (Fujirebio, Inc., Tokyo, Japan), and a human leptin radioimmunoassay (RIA) kit (Linco Research Inc., St. Charles, Mo), respectively. Serum insulin-like growth factor-1 (IGF-1) levels were measured by RIA (SRL Company Ltd., Tokyo, Japan).

Statistical Analysis

Continuous variables are expressed as the mean ± standard deviation unless stated otherwise. Statistical differences between groups were calculated by using the Student t test, the Fisher exact test, the Mann-Whitney test, or the chi-square test, as appropriate. Comparisons of the time course of food intake calories and appetite score were tested by using a 2-way repeated-measures analysis of variance (ANOVA). Statistical significance was set at P < .05. All calculations were performed using the JMP (version 9.0) software program (SAS Institute Inc, Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

Patient Characteristics

In total, 42 enrolled patients were randomized into either the ghrelin group (21 patients) or the placebo group (21 patients). One patient (4.8%) in the ghrelin group who developed excessive diaphoresis during ghrelin infusion, equivalent to grade 2 according to CTCAE, and another patient (4.8%) in the placebo group who was unable to monitor the self-questionnaire because of general fatigue were excluded from the analysis (Fig. 1B). Table 1 lists the demographic and clinical characteristics of all patients. There were no significant differences in the background characteristics, including age, sex, body mass index, localization of cancer, clinical cancer staging, or chemotherapy regimen.

Table 1. Patient Characteristics
 No. of Patients 
ParameterGhrelin GroupPlacebo GroupP
  1. Abbreviations: ACF: doxorubicin, cisplatin, and 5-fluorouracil; BMI, body mass index; DCF: docetaxel, cisplatin and 5-fluorouracil; SD, standard deviation; UICC, International Union Against Cancer.

No. of patients2020 
Age: Mean±SD, y65.8±5.261.8±10.9.14
Sex  .28
 Men1917 
 Women13 
BMI: Mean±SD, kg/m221.6±.321.0±2.7.44
Tumor localization  .27
 Upper thoracic41 
 Middle thoracic99 
 Lower thoracic710 
Clinical UICC TNM stage   
 Tumor classification  .45
  T100 
  T264 
  T3812 
  T464 
 Lymph node status  .51
  N086 
  N11214 
 Metastasis classification  .43
  M01715 
  M135 
 Disease stage  .38
  I00 
  II97 
  III88 
  IV35 
Chemotherapy regimen  .74
 ACF1312 
 DCF78 

Effect of Ghrelin on Dietary Intake and Appetite Scoring

The mean dietary intake gradually decreased after cisplatin administration to reach the lowest level on days 5 through 7. After completing chemotherapy, it took another 4 to 7 days for oral intake to recover and to allow hospital discharge. Although patients in the ghrelin and placebo groups reflected this trend, the decline in dietary intake with chemotherapy was significantly less in the ghrelin group compared with the placebo group (18.1 kcal/kg/day vs 12.7 kcal/kg/day overall), especially at day 1 (26.7 kcal/kg/day vs 23.1 kcal/kg/day) compared with day 7 (15.0 kcal/kg/day vs 8.5 kcal/kg/day) (Fig. 2A). In other words, the improved oral food intake because of ghrelin administration was more significant in the later phase of chemotherapy (repeated-measures ANOVA: ghrelin group vs placebo group, P = .0027). Changes in the VAS score reflected the changes in dietary intake between the 2 groups with a significant difference among them (repeated-measures ANOVA: ghrelin group vs placebo group, P < .0001, Fig. 2B). Notably, the appetite scores recovered more quickly after day 4 of chemotherapy in the ghrelin group than in the placebo group.

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Figure 2. (A) Serial changes in dietary calorie intake are illustrated before and during chemotherapy in the ghrelin group (solid squares) and the placebo group (solid circles). (B) The visual analog scale score for appetite was similar in the 2 groups before chemotherapy. Data shown are means ± standard deviations. ANOVA indicate analysis of variance.

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Effect of Ghrelin on Nutritional and Hormone Status

Table 2 details the blood test results before and after chemotherapy (day 8) in the ghrelin and placebo groups. There were no significant differences in nutritional parameters before chemotherapy, including hemoglobin, albumin, lymphocyte numbers, cholinesterase, total cholesterol, and the rapid turnover proteins (RTP) (prealbumin, retinol-binding protein, and transferrin). In the placebo group, significant declines after chemotherapy were observed for hemoglobin, prealbumin, and transferrin, but not for the other nutritional parameters tested. This RTP finding is consistent with ghrelin preventing nutritional deterioration because of chemotherapy compared with the placebo group (prealbumin: 26.4 ± 4.6 mg/dL vs 21.7 ± 2.8 mg/dL [P = .042]; transferrin: 205 ± 18 mg/dL vs 162 ± 32 mg/dL [P = .037]).

Table 2. Results of Laboratory Tests, Nutritional Status, and Hormone Assays
 Mean±SD Value 
VariableaGhrelin GroupPlacebo GroupP
  • Abbreviations: SD, standard deviation.

  • a

    P < .05 for before versus after.

  • bBefore indicates before chemotherapy; After: after chemotherapy (day 8).

Hemoglobin, g/dL   
 Before11.2±0.811.5±1.3.35
 After10.4±0.710.2±1.1a.41
Albumin, g/dL   
 Before3.6±0.33.4±0.4.78
 After3.2±0.53.3±0.6.67
Lymphocytes, /μL   
 Before1590±3501620±400.56
 After1450±3201540±350.58
Cholinesterase, IU/L   
 Before225±65212±48.21
 After205±45190±38.25
Total cholesterol, mg/dL   
 Before138±45148±42.46
 After144±42142±48.36
Rapid turnover protein   
 Prealbumin, mg/dL   
  Before24.6±6.626.2±5.8.65
  After26.4±4.621.7±2.8a.042
 Retinol binding protein, mg/dL   
  Before3.5±0.83.8±0.6.31
  After3.8±0.83.6±0.9.37
 Transferrin, mg/dL   
  Before210±38235±23.45
  After205±18162±32a.037
Hormones   
 Total ghrelin, fmol/mL   
  Before144±65135±58.34
  After94±48a82±32a.42
 Growth hormone, ng/mL   
  Before1.8±1.51.7±0.8.81
  After1.5±0.91.4±0.8.26
 Insulin-like growth factor-1, ng/mL   
  Before144±52152±45.58
  After134±47141±42.47
 Insulin, μIU/mL   
  Before6.4±3.28.2±4.1.54
  After5.3±2.46.3±3.8.42
Leptin, ng/mL   
 Before3.2±1.82.9±1.7.76
 After2.1±0.42.5±0.5.32

With respect to ghrelin and associated hormones, plasma total ghrelin levels (acyl-ghrelin plus desacyl-ghrelin) significantly decreased after chemotherapy, accounting for 61% of the baseline values (before chemotherapy) in the placebo group. GH, a target hormone for ghrelin, and IGF-1, a mediator of GH, consistently tended to decrease after chemotherapy. However, despite the poor dietary intake during chemotherapy, leptin tended to decrease rather than increase after chemotherapy. There were no significant differences in plasma ghrelin levels between the groups before and after chemotherapy because of its rapid turnover. Likewise, the levels of GH, IGF-1, insulin, and leptin did not differ between the ghrelin and placebo groups.

Adverse Events

Table 3 lists the hematologic and nonhematologic adverse events during the first cycle of chemotherapy. Diaphoresis is a known physiologic effect of ghrelin. One patient with grade 2 diaphoresis was excluded, whereas another with grade 1 diaphoresis completed the study protocol and was included in the analysis. Anorexia and nausea are the most common toxicities reported with cisplatin-based chemotherapy. In our study, grade ≥3 symptoms were noted in 55% (anorexia) and 60% (nausea) of patients in the placebo group. Ghrelin administration significantly reduced these adverse effects to 15% and 20%, respectively (anorexia: ghrelin group vs placebo group, P = .016; nausea: ghrelin group vs placebo group, P = .012). Other adverse effects, including myelosuppression, renal toxicity, and stomatitis, did not differ significantly between the 2 groups.

Table 3. Adverse Events Encountered During Chemotherapy
 No. of Events 
Adverse EventsaGhrelin GroupPlacebo GroupP
  • a

    Adverse events were evaluated according to toxicity grading criteria from version 4.0 of the Common Terminology Criteria for Adverse Events.

Neutropenia  .49
 Grade 044 
 Grade 1-296 
 Grade 3-4710 
Lymphopenia  .75
 Grade 01211 
 Grade 1-289 
 Grade 3-400 
Anemia  .75
 Grade 01413 
 Grade 1-256 
 Grade 3-411 
Thrombocytopenia  .59
 Grade 01617 
 Grade 1-223 
 Grade 3-420 
Renal toxicity  .91
 Grade 01313 
 Grade 1-276 
 Grade 3-401 
Diaphoresis  .32
 Grade 01920 
 Grade 1-210 
 Grade 3-400 
Anorexia  .016
 Grade 042 
 Grade 1-2137 
 Grade 3-4311 
Nausea  .012
 Grade 031 
 Grade 1-2137 
 Grade 3-4412 
Vomiting  .35
 Grade 054 
 Grade 1-21210 
 Grade 3-436 
Diarrhea  .77
 Grade 0910 
 Grade 1-2109 
 Grade 3-411 
Stomatitis  .77
 Grade 033 
 Grade 1-21514 
 Grade 3-423 

Treatment Outcome

Dose modifications were necessary in the second cycle of chemotherapy for 6 patients (30%) in the ghrelin group and for 10 patients (50%) in the placebo group according to the criteria for dose modifications. Thus, patients in the ghrelin group displayed less toxicity from chemotherapy than those in the placebo group during the second cycle, although the difference did not reach statistical significance (P = .17). Ghrelin administration tended to reduce the length of hospital stay in the ghrelin group compared with the placebo group (18.4 days vs 23.5 days; P = .12). The objective tumor response rate after the second cycle of chemotherapy was not different between the 2 groups: In the ghrelin group, 13 patients achieved a partial response, 6 patients had no change, and 1 patient had progressive disease (PD); whereas, in the placebo group, 13 patients had a partial response, 4 patients had no change, and 3 patients had progressive disease. After 2 cycles of chemotherapy, 16 patients in the ghrelin group and 15 patients in the placebo group underwent curative resection. There were no significant differences in major surgical complications between the 2 groups.

Quality-of-Life Evaluation

Patients in the ghrelin group reported significantly better overall global health status scores after chemotherapy than patients in the placebo group (52 ± 18 vs 26 ± 13, respectively; P < .0001), although there were no significant differences in the functional scale parameters. With respect to the symptom scale scores and items, patients in the ghrelin group scored better after chemotherapy than patients in the placebo group on nausea/vomiting (ghrelin group vs placebo group: 16 ± 14 vs 36 ± 29; P < .0001) and appetite loss (26 ± 14 vs 54 ± 22; P < .0001). Although the differences were not statistically significant, patients in the ghrelin group scored better after chemotherapy than patients in the placebo group on fatigue (P = .082). There were no significant differences in other symptom scales or items (Table 4).

Table 4. Quality-of-Life Scores
 Mean±SD Score 
QLQ-C30aGhrelin GroupPlacebo GroupP
  • Abbreviations: SD, standard deviation.

  • a

    Before indicates before chemotherapy; After: after chemotherapy (day 8).

Global health status score
 Before78±3074±22.51
 After52±1826±13< .0001
Functional scales   
 Physical functioning   
  Before86±892±10.62
  After78±2072±18.42
 Role functioning   
  Before80±1288±8.43
  After68±1670±15.29
 Emotional functioning   
  Before78±1482±12.26
  After70±1868±14.44
 Cognitive functioning   
  Before88±1190±10.72
  After86±1488±18.67
 Social functioning   
  Before84±2082±22.54
  After82±1678±14.52
Symptom scales/items   
 Fatigue   
  Before12±614±8.37
  After22±1134±16.082
 Nausea/vomiting   
  Before5±64±7.62
  After16±1436±29< .0001
 Pain   
  Before8±67±9.47
  After10±1112±14.59
 Dyspnea   
  Before8±147±13.68
  After8±127±14.66
 Insomnia   
  Before12±814±12.75
  After20±1219±14.37
 Loss of appetite   
  Before8±147±13.43
  After26±1454±22< .0001
 Constipation   
  Before7±138±12.29
  After12±1814±20.21
 Diarrhea   
  Before12±1412±18.69
  After22±1826±22.32
 Financial difficulties   
  Before16±2218±17.58
  After18±2416±21.72

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

In this prospective, randomized trial, we demonstrated that the administration of synthetic ghrelin during cisplatin-based neoadjuvant chemotherapy successfully increased food intake and appetite and decreased the adverse effects of chemotherapy. To our knowledge, this is the first report on the usefulness of ghrelin administration during cisplatin-based chemotherapy in humans.

It has been reported that acute gastrointestinal disorders caused by cisplatin involve 5-HT secretion from the enterochromaffin cells in association with 5-HT3 receptors.3, 4 Therefore, the administration of a 5-HT3 receptor antagonist is effective in the suppression of cisplatin-induced nausea and vomiting that occur within 24 hours after administration.4 However, late-phase chemotherapy-induced anorexia, nausea, and vomiting still are difficult to adequately control. In the current study, the mean oral intake of calories decreased significantly to about 25% of the baseline level at day 8 after chemotherapy despite the use of a 5-HT3 antagonist.

Several observations suggest that ghrelin may play an important role in the delayed cisplatin-induced gastrointestinal effects. In rodents, a single cisplatin administration caused a transient decrease in plasma ghrelin concentration and prolonged suppression of both food intake and body weight loss.22 Cotreatment with a 5-HT3 antagonist did not result in the recovery of ghrelin levels or dietary activity in that experiment. In our clinical study, we observed that chemotherapy that included cisplatin reduced plasma ghrelin levels to 67% and 57% of the baseline levels on days 3 and 8, respectively. In addition, there was a close relation between the extent of decline in plasma ghrelin, nutritional status, and adverse events of chemotherapy.23 In the current trial, we demonstrated that the administration of synthetic ghrelin during chemotherapy successfully increased food intake and appetite. This effect may be explained by the effect on the GH/IGF-1 axis. The growth-promoting effect of GH is mediated, at least in part, by IGF-1.24 However, serum GH and IGF-1 levels were stable in both groups, probably because of the rapid turnover of GH. Although this phenomenon was reported previous in earlier studies,14, 24 we should have measured GH and IGF-1 in a brief period.

5-HT3 antagonist also was administered in the current clinical study. Taken together, the acute and delayed effects of cisplatin on gastrointestinal functions may involve different mechanisms, and the delayed effects, which seemingly are not mediated through the 5-HT3 receptor, affect nutrition status in cancer patients more strongly than the acute effects.

Conversely, recent reports indicate that both the 5-HT2C receptor and the 5-HT2B receptor, but not the 5-HT3 receptor, mediate cisplatin-induced ghrelin suppression in rodents.13, 22 The 5-HT2B receptor is distributed mainly in gastrointestinal smooth muscle,25 and the 5-HT2C receptor is localized in the central nerve system.26 Vagal nerve function may regulate afferent and efferent signaling, which controls ghrelin secretion through these 5-HT2B and 5-HT2C receptors. However, in our previous study, ghrelin was administered to patients who had undergone gastrectomy and esophagectomy, which also included truncal vagotomy, and we observed significant effects on appetite and body weight increase.10, 11 Therefore, the association between ghrelin signaling and the vagal nerve remains unresolved.27 In the literature, urinary 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, increased rapidly and subsequently returned to baseline within the first 24 hours after cisplatin administration, and it was associated strongly with chemotherapy-induced emesis.3, 4, 12, 28 In the current study, serum 5-HT and 5-HIAA levels on days 3 and 8 of chemotherapy did not increase significantly compared with baseline values (data not shown). Thus, because plasma ghrelin undergoes rapid turnover, our observation regarding 5-HIAA suggests that 5-HT does not directly control ghrelin secretion.

In other studies, substance P and neurokinin-1 (NK-1) receptor contributed to the delayed emetic symptoms associated with chemotherapy.29 Accordingly, an NK-1 receptor antagonist could inhibit the binding of substance P to the NK1 receptor in the vomiting center.29 Several studies have established that administration of such antagonists, such as aprepitant, together with the 5-HT3 receptor antagonist, lessens chemotherapy-induced nausea and vomiting in patients who are receiving emetogenic chemotherapy during the first 120 hours after initiation of chemotherapy.30 Although aprepitant was not used commonly during the study period in our country, it is now used widely in clinical practice. Although the exact functional association between ghrelin and NK-1 receptor still is under investigation, their synergistic effect would be novel, and it would be interesting to resolve this issue in a clinical setting in the near future.

Exogenous ghrelin, as expected, successfully increased oral intake and nutritional status and also maintained QoL during chemotherapy. However, our ultimate objective is to ease the completion of chemotherapy and to enhance the overall antitumor effect. In this study, the required dose modifications in the second cycle of chemotherapy tended to be fewer in the ghrelin group (6 patients; 30%) than in the placebo group (10 patients; 50%). Specifically, modifications in the ghrelin group were because of 3 episodes of neutropenia, 2 episodes of thrombocytopenia, and 1 episode of nephrotoxicity; whereas the reasons for modifications in the placebo group included 6 episodes of neutropenia, 3 episodes of nephrotoxicity, and 1 episode of diarrhea. This suggests that ghrelin can prevent some adverse events directly in addition to its indirect effects through improvement of nutritional status. A larger cohort study is needed to verify this aspect of ghrelin administration.

Another clinical question to be answered is whether nutritional support during chemotherapy should be provided orally or intravenously.31 Recently, we conducted a randomized trial to address this issue in patients with esophageal cancer who were receiving cisplatin-based chemotherapy. Various adverse effects of the chemotherapy, including hematologic toxicity, were observed less frequently in patients who received forced enteral nutrition than in those who received parenteral nutrition, although their total calorie intake was identical (unpublished data). This observation encourages the clinical application of ghrelin administration, which can physiologically increase oral food intake.

In terms of chemotherapy regimens, for this study, both the ACF regimen and the DCF regimen were used. Recently, intensive chemotherapy protocols involving multiple drugs are in fashion; however, to use such regimens, the adverse effects of the regimen components must be adequately managed. An appropriate nutrition supplement through oral food intake will be more important in the future.

In conclusion, the current study demonstrated that short-term administration of exogenous ghrelin at the start of cisplatin-based chemotherapy stimulated food intake and minimized adverse events. We believe that ghrelin administration could increase the efficiency of chemotherapy, and we recommend the use of ghrelin in clinical practice.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

We thank Tomoyuki Sugimoto from the Department of Biomedical Statistics, Osaka University, for the advice on statistical analysis. We also thank the national registered dietitians of Osaka University Hospital for calculating food intake calories in this study.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES

This study was supported by a Health and Labor Sciences Research Grant from the Ministry of Health, Labor, and Welfare of Japan.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. FUNDING SOURCES
  9. REFERENCES
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