Abstract
Purpose
The aim of this study was to update the clinical practice guidelines for the use of agents for the prevention and/or treatment of gastrointestinal mucositis (GIM).
Methods
A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, and No Guideline Possible.
Results
A total of 78 papers across 13 interventions were examined of which 25 were included in the final review. No new guidelines were possible for any agent due to inadequate and/or conflicting evidence. Existing guidelines for probiotics and hyperbaric oxygen were unchanged.
Conclusions
Of the agents studied for the prevention and treatment of GIM, the evidence continues to support use of probiotics containing Lactobacillus spp. for prevention of chemoradiotherapy and radiotherapy-induced diarrhea in patients with pelvic malignancy, and hyperbaric oxygen therapy to treat radiation-induced proctitis. Additional well-designed research is encouraged to enable a decision regarding palifermin, glutamine, sodium butyrate, and dietary interventions, for the prevention or treatment of GIM.
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References
Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB, Mucositis Study Section of the MASCC and the ISOO (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100(9 Suppl):1995–2025
Carlotto A, Hogsett VL, Mairorini EM, Razulis JG, Sonis ST (2013) The economic burden of toxicities associated with cancer treatment: review of the literature and analysis of nausea and vomiting, diarrhoea, oral mucositis and fatigue. Pharmacoeconomics 31:753–766
Gibson RJ, Cummins AG, Bowen JM, Logan RM, Healey T, Keefe DMK (2006) Apoptosis occurs early in the basal layer of the oral mucosa following cancer chemotherapy. Asia Pac J Clin Oncol 2:39–49
Blijlevens NM, Donnelly JP, De Pauw BE (2000) Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplant 25:1269–1278
Stringer AM, Al-Dasooqi N, Bowen JM, Tan TH, Radazum M, Logan RM, Mayo B, Keefe DMK, Gibson RJ (2013) Biomarkers of chemotherapy-induced diarrhea: a clinical study of intestinal microbiome alterations, intestinal inflammation and circulating matrix metalloproteinases. Support Care Cancer 21:1843–1852
Gibson RJ, Keefe DM, Lalla RV, Bateman E, Blijlevens N, Fijlstra M, King EE, Stringer AM, van der Velden WJ, Yazbeck R, Elad S, Bowen JM, For The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer International Society of Oral Oncology (MASCC/ISOO) (2013) Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Support Care Cancer 21:313–326
Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, Elting LS, Fox PC, Cooksley C, Sonis ST (2004) Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 100:2026–2046
Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE, Migliorati CA, DB MG, Hutchins RD, Peterson DE, Mucositis Study Section of the MASCC and the ISOO (2007) Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 109:820–831
Lalla R, Bowen J, Barasch A, Elting L, Epstein J, Keefe D, McGuire D, Migliorati C, Nicolatou-Galitis O, Peterson D, Raber-Durlacher J, Sonis S, Elad S, Al-Dasooqi N, Brennan M, Gibson R, Fulton J, Hewson I, Jensen SB, Logan R, Ohrn KEO, Sarri T, Saunders D, von Bultzingslowen I, Yaron N (2014) MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 120:1453–1461
Keefe DM (2004) Gastrointestinal mucositis: a new biological model. Support Care Cancer 12:6–9
Wardill HR, Bowen JM, Gibson RJ (2012) Biomarkers of small intestinal mucosal damage induced by chemotherapy: an emerging role for the (13)C sucrose breath test. J Support Oncol 11:61–67
Ranna V, Cheng K, Castillo D, Porcello L, Vaddi A, Lalla R, Bossi P, Elad S (2019) Development of the MASCC/ISOO clinical practice guidelines for mucositis: an overview of the methods support care. Support Care Cancer. https://doi.org/10.1007/s00520-019-04891-1
Somerfield MR, Padberg JJ, Pfisher DG, Bennett CL, Recht A, Smith TJ, Weeks JC, Winn RJ, Durant JR (2000) ASCO clinical practice guidelines: process, progress, pitfalls, and prospects. Class Pap Curr Comm 4:881–886
Hadorn DC, Baker D, Hodges JS, Hicks N (1996) Rating the quality of evidence for clinical practice guidelines. J Clin Epidemiol 49:749–754
Sahakitrungruang C, Patiwongpaisarn A, Kanjanasilp P, Malakorn S, Atittharnsakul P (2012) A randomized controlled trial comparing colonic irrigation and oral antibiotics administration versus 4% formalin application for treatment of hemorrhagic radiation proctitis. Dis Colon Rectum 55:1053–1058
Sahakitrungruang C, Thum-Umnuaysuk S, Patiwongpaisarn A, Atittharnsakul P, Rojanasakul A (2011) A novel treatment for haemorrhagic radiation proctitis using colonic irrigation and oral antibiotic administration. Color Dis 13:e79–e82
Razzaghdoust A, Mozdarani H, Mofid B, Aghamiri SM, Heidari AH (2014) Reduction in radiation-induced lymphocytopenia by famotidine in patients undergoing radiotherapy for prostate cancer. Prostate 74:41–47
Wedlake LJ, McGough C, Shaw C, Klopper T, Thomas K, Lalji A, Dearnaley DP, Blake P, Tait D, Khoo VS, Andreyev HJ (2012) Clinical trial: efficacy of a low or modified fat diet for the prevention of gastrointestinal toxicity in patients receiving radiotherapy treatment for pelvic malignancies. J Hum Nutr Diet 25:247–259
Scartoni D, Desideri I, Giacomelli I, Di Cataldo V, Di Brina L, Mancuso A, Furfaro I, Bonomo P, Simontacchi G, Livi L (2015) Nutritional supplement based on zinc, prebiotics, probiotics and vitamins to prevent radiation-related gastrointestinal disorders. Anticancer Res 35:5687–5692
Itoh Y, Mizuno M, Ikeda M, Nakahara R, Kubota S, Ito J, Okada T, Kawamura M, Kikkawa F, Naganawa S (2015) A randomized, double-blind pilot trial of hydrolyzed rice bran versus placebo for radioprotective effect on acute gastroenteritis secondary to chemoradiotherapy in patients with cervical cancer. Evid Based Complement Alternat Med 2015:974390
Garcia-Peris P, Velasco C, Hernandez M, Lozano MA, Paron L, de la Cuerda C, Breton I, Camblor M, Guarner F (2016) Effect of inulin and fructo-oligosaccharide on the prevention of acute radiation enteritis in patients with gynecological cancer and impact on quality-of-life: a randomized, double-blind, placebo-controlled trial. Eur J Clin Nutr 70:170–174
Nascimento M, Aguilar-Nascimento JE, Caporossi C, Castro-Barcellos HM, Motta RT (2014) Efficacy of synbiotics to reduce acute radiation proctitis symptoms and improve quality of life: a randomized, double-blind, placebo-controlled pilot trial. Int J Radiat Oncol Biol Phys 90:289–295
Nelamangala Ramakrishnaiah VP, Javali TD, Dharanipragada K, Reddy KS, Krishnamachari S (2012) Formalin dab, the effective way of treating haemorrhagic radiation proctitis: a randomized trial from a tertiary care hospital in South India. Color Dis 14:876–882
Iyama S, Sato T, Tatsumi H, Hashimoto A, Tatekoshi A, Kamihara Y, Horiguchi H, Ibata S, Ono K, Murase K, Takada K, Sato Y, Hayashi T, Miyanishi K, Akizuki E, Nobuoka T, Mizugichi T, Takimoto R, Kobune M, Hirata K, Kato J (2014) Efficacy of enteral supplementation enriched with glutamine, fiber, and oligosaccharide on mucosal injury following hematopoietic stem cell transplantation. Case Rep Oncol 7:692–699
Topkan E, Parlaks C, Topuk S, Pehlivan B (2012) Influence of oral glutamine supplementation on survival outcomes of patients treated with concurrent chemoradiotherapy for locally advanced non-small cell lung cancer. BMC Cancer 12:502
Vidal-Casariego A, Calleja-Fernández A, de Urbina-González JJ, Cano-Rodríguez I, Cordido F, Ballesteros-Pomar MD (2014) Efficacy of glutamine in the prevention of acute radiation enteritis: a randomized controlled trial. JPEN J Parenter Enteral Nutr 38:205–213
Rotovnik Kozjek N, Kompan L, Soeters P, Oblak I, Mlakar Mastnak D, Možina B, Zadnik V, Anderluh F, Velenik V (2011) Oral glutamine supplementation during preoperative radiochemotherapy in patients with rectal cancer: a randomised double blinded, placebo controlled pilot study. Clin Nutr 30:567–570
Kucuktulu E, Guner A, Kahraman I, Topbas M, Kucuktulu U (2013) The protective effects of glutamine on radiation-induced diarrhea. Support Care Cancer 21:1071–1075
Glover M, Smerdon GR, Andreyev HJ, Benton BE, Bothma P, Firth O, Gothard L, Harrison J, Ignatescu M, Laden G, Martin S, Maynard L, McCann D, Penny CEL, Phillips S, Sharp G, Yarnold J (2016) Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double-blind, sham-controlled phase 3 trial. Lancet Oncol 17:224–233
Tahir AR, Westhuyzen J, Dass J, Collins MK, Webb R, Hewitt S, Fon P, McKay M (2015) Hyperbaric oxygen therapy for chronic radiation-induced tissue injuries: Australasia’s largest study. Asia Pac J Clin Oncol 11:68–77
Hoff PM, Saragiotto DF, Barrios CH, del Giglio A, Coutinho AK, Andrade AC, Dutra C, Forones NM, Correa M, Portella Mdo S, Passos VQ, Chinen RN, van Eyll B (2014) Randomized phase III trial exploring the use of long-acting release octreotide in the prevention of chemotherapy-induced diarrhea in patients with colorectal cancer: the LARCID trial. J Clin Oncol 32:1006–1011
Bradstock KF, Link E, Collins M, Di Iulio J, Lewis ID, Schwarer A, Enno A, Marlton P, Hahn U, Szer J, Cull G, Seymour JF, Australasian Leukaemia and Lymphoma Group (2014) A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia. Br J Haematol 167:618–625
Herbers AH, van der Velden WJ, de Haan AF, Donnelly JP, Blijlevens NM (2014) Impact of palifermin on intestinal mucositis of HSCT recipients after BEAM. Bone Marrow Transplant 49:8–10
Campbell P, Friebe A, Foulstone P, Grigg A, Hempton J, Bajel A (2012) Impact of palifermin on mucosal toxicity in autologous stem cell transplants using busulfan-melphalan conditioning chemotherapy for Hodgkin and non-Hodgkin lymphoma. Leuk Lymphoma 53:1415–1416
Mego M, Chovanec J, Vochyanova-Andrezalova I, Konkolovsky P, Mikulova M, Reckova M, Miskovska V, Bystricky B, Beniak J, Medvecova L, Lagin A, Svetlovska D, Spanik S, Zajac V, Mardiak J, Drgona L (2015) Prevention of irinotecan induced diarrhea by probiotics: a randomized double blind, placebo controlled pilot study. Complement Ther Med 23:356–362
Demers M, Dagnault A, Desjardins J (2014) A randomized double-blind controlled trial: impact of probiotics on diarrhea in patients treated with pelvic radiation. Clin Nutr 33:761–767
Maggio A, Magli A, Rancati T, Fiorino C, Valvo F, Fellin G, Ricardi U, Munoz F, Cosentino D, Cazzaniga LF, Valdagni R, Vavassori V (2014) Daily sodium butyrate enema for the prevention of radiation proctitis in prostate cancer patients undergoing radical radiation therapy: results of a multicenter randomized placebo-controlled dose-finding phase 2 study. Int J Radiat Oncol Biol Phys 89:518–524
Fuccio L, Guido A (2012) Topical rectal beclomethasone dipropionate treatment for the prevention of radiation-induced bleeding. Gut 61:1369
Chruscielewska-Kiliszek MR, Regula J, Polkowski M, Rupinski M, Kraszewska E, Pachlewski J, Czaczkowska-Kurek E, Butruk E (2013) Sucralfate or placebo following argon plasma coagulation for chronic radiation proctitis: a randomized double blind trial. Color Dis 15:e48–e55
Gibson GR, Probert HM, Van Loo J, Rastall RA, Roberfroid M (2004) Dietary modulation of the human colonic microbiota: updating the concept of prebiotics. Nutr Res Rev 17:259–275
García-Peris P, Velasco C, Lozano MA, Moreno Y, Paron L, de la Cuerda C, Bretón I, Camblor M, García-Hernández J, Guarner F, Hernández M (2012) Effect of a mixture of inulin and fructo-oligosaccharide on Lactobacillus and Bifidobacterium intestinal microbiota of patients receiving radiotherapy: a randomised, double-blind, placebo-controlled trial. Nutr Hosp 27:1908–1915
Tutanc OD, Aydogan A, Akkucuk S, Sunbul AT, Zincircioglu SB, Alpagat G, Erden ES (2013) The efficacy of oral glutamine in prevention of acute radiotherapy-induced esophagitis in patients with lung cancer. Contemp Oncol (Pozn) 17:520–524
Algara M, Rodríguez N, Viñals P, Lacruz M, Foro P, Reig A, Quera J, Lozano J, Fernández-Velilla E, Membrive I, Dengra J, Sanz X (2007) Prevention of radiochemotherapy-induced esophagitis with glutamine: results of a pilot study. Int J Radiat Oncol Biol Phys 69:342–349
Jazieh AR, Younas A, Safa M, Redmond K, Buncher R, Howington J (2007) Phase I clinical trial of concurrent paclitaxel, carboplatin, and external beam chest irradiation with glutamine in patients with locally advanced non-small cell lung cancer. Cancer Investig 25:294–298
Zachariah B, Gwede CK, James J, Ajani J, Chin LJ, Donath D, Rosenthal SA, Kane BL, Rotman M, Berk L, Kachnic LA (2010) Octreotide acetate in prevention of chemoradiation-induced diarrhea in anorectal cancer: randomized RTOG trial 0315. J Natl Cancer Inst 102:547–556
Martenson JA, Halyard MY, Sloan JA, Proulx GM, Miller RC, Deming RL, Dick SJ, Johnson HA, Tai TH, Zhu AW, Keit J, Stien KJ, Atherton PJ (2008) Phase III, double-blind study of depot octreotide versus placebo in the prevention of acute diarrhea in patients receiving pelvic radiation therapy: results of North Central Cancer Treatment Group N00CA. J Clin Oncol 26:5248–5253
Franzén L, Hellsing U, Henriksson R, Littbrand B (1998) Managing side-effects in radiotherapy with regard to the gastrointestinal tract. Recent Results Cancer Res 108:127–133
Henriksson R, Franzén L, Littbrand B (1991) Prevention of irradiation-induced bowel discomfort by sucralfate: a double-blind, placebo-controlled study when treating localized pelvic cancer. Am J Med 91:151S–157S
Johansson JE, Hasseus B, Johansson P, Eklof C, Ohman D, Stockelberg D (2009) Gut protection by palifermin during autologous haematopoietic SCT. Bone Marrow Transplant 43:807–811
Rosen LS, Abdi E, Davis ID, Gutheil J, Schnell FM, Zalcberg J, Cesano A, Gayko U, Chen MG, Clarke S (2006) Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol 24:5194–5200
Farrell CL, Rex KL, Chen JN, Bready JV, DiPalma CR, Kaufman SA, Rattan A, Scully S, Lacey DL (2002) The effects of keratinocyte growth factor in preclinical models of mucositis. Cell Prolif 35:78–85
Gibson RJ, Bowen JM, Keefe DM (2005) Palifermin reduces diarrhea and increases survival following irinotecan treatment in tumor-bearing DA rats. Int J Cancer 116:464–470
Sahebnasagh A, Ghasemi A, Akbari J, Alipour A, Lashkardoost H, Ala S, Salehifar E (2017) Successful treatment of acute radiation proctitis with aloe vera: a preliminary randomized controlled clinical trial. J Altern Complement Med 23:858–865
Ziętarska M, Krawczyk-Lipiec J, Kraj L, Zaucha R, Małgorzewicz S (2017) Chemotherapy-related toxicity, nutritional status and quality of life in precachectic oncologic patients with, or without, high protein nutritional support. A prospective, randomized study. Nutrients 9:E1108
Morishita T, Tsushita N, Imai K, Sakai T, Miyao K, Sakemura R, Kato T, Niimi K, Ono Y, Sawa M (2016) The efficacy of an oral elemental diet in patients undergoing hematopoietic stem cell transplantation. Intern Med 55:3561–3569
Miyata H, Yano M, Yasuda T, Yamasaki M, Murakami K, Makino T, Nishiki K, Sugimura K, Motoori M, Shiraishi O, Mori M, Doki Y (2017) Randomized study of the clinical effects of ω-3 fatty acid-containing enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer. Nutrition 33:204–210
van Sebille YZA, Gibson RJ, Wardill HR, Bowen JM (2016) Gastrointestinal toxicities of first and second generation small molecule HER TKIs in advanced non small cell lung cancer. Curr Opin Palliat Support Care 10:152–156
Loriot Y, Perlemuter G, Malka D, Penault-Llorca F, Boige V, Deutsch E, Massard C, Armand JP, Soria JC (2008) Drug insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy. Nat Clin Pract Oncol 5:268–278
Acknowledgments
We would like to acknowledge the expert assistance of our research librarians during the development of the database search terms and paper retrieval; Lorraine Porcello (Bibby Dental Library, Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, NY, USA) and Daniel A. Castillo (Edward G. Miner Library, University of Rochester Medical Center, Rochester, NY, USA). On behalf of the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO).
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These authors disclose no relevant conflict of interest: JC, NB, NA, EB, KC, CDM, BM, AS, WT, HW, YVS, VR, AV, KKFC, SE. JB and RG are MASCC board members.
PB has served an advisory role for AstraZeneca, Helsinn, and Kyowa Kyrin and received grants from Merck, Kyowa Kyrin, and Roche. DK is on the advisor board for Zealand Pharma and Helsinn, the speakers bureau for Merck and Mundipharma, and a consultant for Entrinsic Health Solutions.
RVL has served as a consultant for Colgate Oral Pharmaceuticals, Galera Therapeutics, Ingalfarma SA, Monopar Therapeutics, Mundipharma, and Sucampo Pharma; has received research support to his institution from Galera Therapeutics, Novartis, Oragenics, and Sucampo Pharma, and has received stock in Logic Biosciences.
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Bowen, J.M., Gibson, R.J., Coller, J.K. et al. Systematic review of agents for the management of cancer treatment-related gastrointestinal mucositis and clinical practice guidelines. Support Care Cancer 27, 4011–4022 (2019). https://doi.org/10.1007/s00520-019-04892-0
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DOI: https://doi.org/10.1007/s00520-019-04892-0