Abstract
Background
Chemotherapeutic agents, especially cisplatin, cause severe gastrointestinal disorders, including nausea, vomiting, and anorexia, which markedly impair quality of life and encourage discontinuation of chemotherapy. Since cisplatin was recently reported to decrease plasma ghrelin and food intake in rodents, we monitored the plasma ghrelin level and its association with nutritional status and adverse events during chemotherapy in patients with esophageal cancer.
Patients and methods
Twenty patients with advanced esophageal cancer who underwent cisplatin-based neoadjuvant chemotherapy were enrolled in a prospective observational study. Changes in gastrointestinal hormones including ghrelin were measured and correlated with feeding activity, including appetite and dietary intake, nutritional status including rapid turnover proteins, and adverse events from chemotherapy.
Results
Plasma total ghrelin significantly decreased at days 3 and 8 of chemotherapy but recovered at day 28 (baseline: 140 ± 54; day 3: 107 ± 46; day 8: 82 ± 32; day 28: 126 ± 43 fmol/ml; p = 0.023 for day 3 and p = 0.034 for day 8). No changes were noted in plasma leptin (baseline: 3.2 ± 1.8; day 8: 2.5 ± 1.5 ng/ml; p = 0.18). Among blood nutritional parameters, transferrin was the only parameter that decreased significantly and its decline, as well as loss of oral intake and appetite, correlated significantly with plasma ghrelin levels (p = 0.0013, p = 0.0063, and p = 0.013, respectively). Neutropenia and anorexia were more frequent in patients with low plasma ghrelin than in those with high plasma ghrelin (p = 0.015 and p = 0.011, respectively).
Conclusion
Cisplatin-based chemotherapy significantly reduced plasma ghrelin and feeding activity. Ghrelin is a potentially useful novel therapy for minimizing the adverse effects of chemotherapy.
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References
Kranzfelder M, Buchler P, Lange K et al (2010) Treatment options for squamous cell cancer of the esophagus: a systematic review of the literature. J Am Coll Surg 210:351–359
Bedenne L, Michel P, Bouche’ O et al (2007) Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 25:1160–1168
Ajani JA, Barthel JS, Bekaii-Saab T et al (2008) Esophageal cancer. J Natl Compr Canc Netw 6:818–849
Akita H, Doki Y, Yano M et al (2009) Effects of neoadjuvant chemotherapy on primary tumor and lymph node metastasis in esophageal squamous cell carcinoma: additive association with prognosis. Dis Esophagus 22:291–297
Medical Research Council Oesophageal Cancer Working Group (2002) Surgical resection with and without chemotherapy in oesophageal cancer. Lancet 359:1727–1733
Yano M, Takachi K, Doki Y et al (2006) Preoperative chemotherapy for clinically node-positive patients with squamous cell carcinoma of the esophagus. Dis Esophagus 19:158–163
Matsuyama J, Doki Y, Yasuda T et al (2007) The effect of neoadjuvant chemotherapy on lymph node micrometastases in squamous cell carcinomas of the thoracic esophagus. Surgery 141:570–580
Hesketh PJ, Van Belle S, Aapro M et al (2003) Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 39:1074–1080
Cubeddu LX, Hoffmann IS (1993) Participation of serotonin on early and delayed emesis induced by initial and subsequent cycles of cisplatinum-based chemotherapy: effects of antiemetics. J Clin Pharmacol 33:691–697
Butcher ME (1993) Global experience with ondansetron and future potential. Oncology 50:191–197
Kojima M, Hosoda H, Date Y et al (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660
Nakazato M, Murakami N, Date Y et al (2001) A role for ghrelin in the central regulation of feeding. Nature 409:194–198
Van der Lely AJ, Tschop M, Heiman ML et al (2004) Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 25:426–457
Korbonits M, Goldstone AP, Gueorguiev M et al (2004) Ghrelin—a hormone with multiple functions. Front Neuroendocrinol 25:27–68
Akamizu T, Kangawa K (2006) Translation research on the clinical applications of ghrelin. Endocr J 53:585–591
Ariyasu H, Iwakura H, Yamada G et al (2008) Efficacy of ghrelin as a therapeutic approach for age related physiological changes. Endocrinology 149:3722–3728
Shintani M, Ogawa Y, Ebihara K et al (2001) Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 50:227–232
Adachi S, Takiguchi S, Okada K et al (2010) Effects of ghrelin administration after total gastrectomy: a prospective, randomized, placebo-controlled phase II study. Gastroenterology 138:1312–1320
Yamamoto K, Takiguchi S, Miyata H et al (2010) Randomized phase II study of clinical effects of ghrelin after esophagectomy with gastric tube reconstruction. Surgery 141:31–38
Liu Y-L, Malik NM, Sanger GJ et al (2006) Ghrelin alleviates cancer chemotherapy-associated dyspepsia in rodents. Cancer Chemother Pharmacol 58:326–333
Takeda H, Sadakane C, Hattori T et al (2008) Rikkunshito, an herbal medicine, suppresses cisplatin-induced anorexia in rats via 5-HT2 receptor antagonism. Gastroenterology 134:2004–2013
Shimakawa T, Naritaka Y, Asaka S et al (2008) Neoadjuvant chemotherapy (FAP) for advanced esophageal cancer. Anticancer Res 28:2321–2326
Tanaka Y, Yoshida K, Sanada Y et al (2010) Biweekly docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy for advanced esophageal squamous cell carcinoma: a phase I dose-escalation study. Cancer Chemother Pharmacol 66:1159–1165
Takahashi H, Arimura Y, Yamashita K et al (2010) Phase I/II study of docetaxel/cisplatin/fluorouracil combination chemotherapy against metastatic esophageal squamous cell carcinoma. J Thorac Oncol 1:122–128
CTCAE v4.0. https://cabig-kc.nci.nih.gov/Vocab/KC/index.php/CTCAE
Japanese Society for Esophageal Diseases (2001) Guidelines for clinical and pathologic studies on carcinoma in the esophagus, 9th edn. Kanehara & Co., Ltd, Tokyo
Akamizu T, Shinomiya T, Irako T et al (2005) Separate measurement of plasma levels of acylated and desacyl ghrelin in healthy subjects using a new direct ELISA assay. J Clin Endocrinol Metab 90:6–9
Nonogaki K, Nozue K, Oka Y (2006) Hyperphagia alters expression of hypothalamic 5-HT2C and 5-HT1B receptor genes and plasma des-acyl ghrelin levels in Ay mice. Endocrinology 147:5893–5900
Castejon AM, Paez X, Hernandez L et al (1999) Use of intravenous microdialysis to monitor changes in serotonin release and metabolism induced by cisplatin in cancer patients: comparative effects of granisetron and ondansetron. J Pharmacol Exp Ther 291:960–966
Cubeddu LX, Hoffmann IS, Fuenmayor NT et al (1992) Changes in serotonin metabolism in cancer patients: Its relationship to nausea and vomiting induced by chemotherapeutic drugs. Br J Cancer 66:198–203
Barnes NM, Ge J, Jones WG et al (1990) Cisplatin-induced emesis: preliminary results indicative of changes in plasma levels of 5-hydroxytryptamine. Br J Cancer 62:862–864
Du Bois A, Vach W, Siebert C et al (1997) The relationship between parameters of serotonin metabolism and emetogenic potential of platinum-based chemotherapy regimens. Support Care Cancer 5:212–218
Wilder-Smith OHG, Borgeat A, Chappuis P et al (1993) Urinary serotonin metabolite excretion during cisplatin chemotherapy. Cancer 72:2239–2241
Latreille J, Pater J, Johnston D et al (1998) Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy. J Clin Oncol 16:1174–1178
Olver I, Paska W, Depierre A et al (1996) A multicentre, double-blind study comparing placebo, ondansetron and ondansetron plus dexamethasone for the control of cisplatin-induced delayed emesis. Ann Oncol 9:945–952
Cocquyt V, Van Belle S, Reinhardt RR et al (2001) Comparison of L-758,298, a prodrug for the selective neurokinin-1 antagonist, L-754,030, with ondansetron for the prevention of cisplatin-induced emesis. Eur J Cancer 37:835–842
Diemunsch P, Grelot L (2000) Potential of substance P antagonists as antiemetics. Drugs 60:535–546
Gerald MH, Miklos LA, Ramin A et al (2006) 5-Hydroxyindoleacetic acid and substance P profiles in patients receiving emetogenic chemotherapy. J Oncol Pharm Practice 12:201–209
Campos D, Pereira JR, Reinhardt RR et al (2001) Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone. J Clin Oncol 19:1759–1767
Hesketh PJ, Grunberg SM, Gralla RJ et al (2003) The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A multinational, randomized, double-blind, placebo-controlled trial in patients receiving high dose cisplatin—The Aprepitant Protocol 052 Study Group. J Clin Oncol 21:4112–4119
Herrstedt J, Muss HB, Warr DG et al (2005) Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer 104:1548–1555
Takahashi T, Hoshi E, Takagi M et al (2010) Multicenter, phase II, placebo-controlled, double-blind, randomized study of aprepitant in Japanese patients receiving high-dose cisplatin. Cancer Sci. 101:2455–2461
Arrieta O, Michel Ortega RM et al (2010) Association of nutritional status and serum albumin levels with development of toxicity in patients with advanced non-small cell lung cancer treated with paclitaxel-cisplatin chemotherapy: a prospective study. BMC Cancer 10:50
Alexandre J, Gross-Goupil M, Falissard B et al (2003) Evaluation of the nutritional and inflammatory status in cancer patients for the risk assessment of severe hematological toxicity following chemotherapy. Ann Oncol 14:36–41
Klastersky J, Paesmans M, Rubenstein EB et al (2000) The Multinational Association for Supportive Care in Cancer Risk Index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 18:3038–3051
Andreyev HJ, Norman AR, Oates J et al (1998) Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur J Cancer 34:503–509
Blay JY, Chauvin F, Le Cesne A et al (1996) Early lymphopenia after cytotoxic chemotherapy as a risk factor for febrile neutropenia. J Clin Oncol 14:636–643
Kalra SP, Kalra PS (2003) Neuropeptide Y: a physiological orexigen modulated by the feedback action of ghrelin and leptin. Endocrine 22:49–56
Acknowledgments
The authors thank Tomoyuki Sugimoto from the Department of Biomedical Statistics, Osaka University for advice on statistical analysis. The authors also thank the National Registered Dietitians of Osaka University Hospital for calculating food intake calories in this study.
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The authors declare no conflict of interest.
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Hiura, Y., Takiguchi, S., Yamamoto, K. et al. Fall in plasma ghrelin concentrations after cisplatin-based chemotherapy in esophageal cancer patients. Int J Clin Oncol 17, 316–323 (2012). https://doi.org/10.1007/s10147-011-0289-0
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DOI: https://doi.org/10.1007/s10147-011-0289-0