Expert Review of Gastroenterology & Hepatology
ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: http://www.tandfonline.com/loi/ierh20
Alleviating mucositis: are we on track for a novel therapeutic? Rajesh V Lalla To cite this article: Rajesh V Lalla (2015) Alleviating mucositis: are we on track for a novel therapeutic?, Expert Review of Gastroenterology & Hepatology, 9:2, 127-128 To link to this article: http://dx.doi.org/10.1586/17474124.2015.965146
Published online: 01 Oct 2014.
Submit your article to this journal
Article views: 202
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierh20 Download by: [45.64.96.9]
Date: 19 October 2015, At: 07:08
Editorial
Alleviating mucositis: are we on track for a novel therapeutic? Expert Rev. Gastroenterol. Hepatol. 9(2), 127–128 (2015)
Rajesh V Lalla
Downloaded by [45.64.96.9] at 07:08 19 October 2015
Section of Oral Medicine, University of Connecticut Health Center, 263, Farmington Avenue, Farmington, CT 06030-1605, USA Tel.: +1 860 679 2952 Fax: +1 860 679 4760 [email protected]
Oral and gastrointestinal mucositis has emerged as an important toxicity of cancer therapy. In addition to supportive care measures, agents for the prevention or treatment of mucositis in specific patient populations are described in the evidence-based clinical practice guidelines published by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. However, there still remains an unmet clinical need for preventive and therapeutic agents in several patient populations. The successful development of such agents will rely on our improved understanding of the pathogenic mechanisms underlying mucositis. Studies are also underway on novel delivery mechanisms and risk prediction models that can facilitate the selective use of interventions for mucositis in a targeted and cost–effective manner. A large number of agents are at various stages in the clinical development pipeline. Enhanced management of this dose-limiting toxicity will allow the delivery of optimal cancer therapy and improve patient prognosis.
Oral and gastrointestinal mucositis has emerged as an important toxicity of cancer therapy, including conventional chemotherapy, targeted agents and radiation therapy. Oropharyngeal mucositis presents as mouth and throat erythema and ulcerations that are extremely painful and negatively impact oral intake [1]. Gastrointestinal mucositis may present as diarrhea, abdominal pain or nausea [2]. Mucositis necessitates the use of symptomatic supportive therapy, decreases quality of life, increases cost of care and may lead to undesirable dose reductions or treatment breaks, negatively impacting cancer prognosis [3,4]. The traditional management of mucositis has heavily relied on supportive care aimed at managing symptoms and complications of mucositis. This includes pain control, nutritional support, management of diarrhea and treatment of secondary infections [5]. Although these elements continue to be of great importance, recent research has also identified some specific strategies to prevent or reduce the severity of mucositis. These strategies are delineated in the evidence-
based clinical practice guidelines for oral and gastrointestinal mucositis prepared by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology [6]. For oral mucositis, interventions recommended or suggested for use (depending on the level of supporting evidence) in specific patient populations include oral care protocols, cryotherapy, keratinocyte growth factor-1, low-level laser therapy, benzydamine mouthwash and zinc. For gastrointestinal mucositis, interventions recommended or suggested for use (depending on the level of supporting evidence) in specific patient populations include octreotide, intravenous amifostine, sucralfate enemas, sulfasalazine, probiotics and hyperbaric oxygen. A summary of the Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology mucositis guidelines and free full text access to publications related to the guidelines is available at [7]. However, there continue to be several patient populations for which no effective or feasible intervention has been identified. Therefore, there is still an
KEYWORDS: cancer • chemotherapy • gastrointestinal • mucositis • oral • radiation therapy
informahealthcare.com
10.1586/17474124.2015.965146
Ó 2015 Informa UK Ltd
ISSN 1747-4124
127
Downloaded by [45.64.96.9] at 07:08 19 October 2015
Editorial
Lalla
unmet clinical need for additional preventive and therapeutic agents for mucositis. The successful development of such agents will rely on our improved understanding of the pathogenic mechanisms underlying mucositis. Previously, mucositis was thought to be simply due to cell death of mucosal cells due to the direct effects of chemotherapy or radiation therapy. It is now appreciated that the pathogenesis is much more complex, involving various cell types, cellular and extracellular pathways and direct and indirect effects of cancer therapy [8,9]. This greater understanding provides the opportunity to develop preventive or therapeutic agents directed at various steps along the subclinical and clinical course of mucositis. For example, in an animal model of radiation mucositis, antrum mucosal protein peptide reduced the occurrence of ulceration and accelerated healing. In vitro studies suggested this effect was mediated, at least in part, by its anti-apoptotic activity [10]. A recently published Phase Ib study, in head and neck cancer patients receiving induction chemotherapy, examined the use of AG013, an oral rinse containing recombinant Lactococcus lactis secreting the mucosal protectant human trefoil factor 1. The efficacy analyses showed a 35% reduction in the percentage of days with ulcerative oral mucositis in AG013 subjects, compared to placebo [11]. Thus, not only new agents, but also novel delivery mechanisms are under investigation. Research is also ongoing on methodologies to accurately predict the development of clinically significant mucositis. For example, a cluster of single nucleotide polymorphisms derived from salivary DNA was demonstrated to have a predictive accuracy of 81% for severe oral mucositis in a cohort of 16 patients who received highdose chemotherapy for a stem cell transplant [12]. The further development of such risk prediction models can facilitate the References
5.
selective use of interventions for mucositis in a targeted and cost–effective manner. The pace of research in this clinical space has increased significantly in recent years [13]. A large number of agents are at various stages in the clinical development pipeline. A recent search on clinicaltrials.gov identified more than 30 mucositis trials in the active stage. The interventions being tested in these trials include acetylcysteine rinse, acupuncture, botanical extracts, clonidine mucoadhesive tablet, cryotherapy, glutamine rinse and swallow, grape extract, honey mouthwash, immunomodulatory dietary supplement, leucovorin, low-level laser therapy, neem mouthrinse, probiotic lozenges containing Lactobacillus brevis, rebamipide liquid, supersaturated calcium phosphate rinse, synthetic peptide targeting the innate immune system and topical nanopolymer. The diverse nature and large number of interventions being clinically tested offers the hope that one or more of these agents will prove to be effective in prevention or treatment of mucositis. In turn, enhanced management of this dose-limiting toxicity will allow the delivery of optimal cancer therapy and improve patient prognosis. Financial & competing interests disclosure
RV Lalla serves as Chair of the Mucositis Study Group of MASCC/ISOO and as Chair of the Mucositis Guidelines Panel. He has received research funding from BioAlliance Pharma and has served as a consultant for Sucampo AG, iNova Pharmaceuticals, Fera Pharmaceuticals and Phillips Gilmore Oncology Communications. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am 2008;52(1):61-77; viii
Lalla RV, Saunders DP, Peterson DE. Chemotherapy or radiation-induced oral mucositis. Dent Clin North Am 2014; 58(2):341-9
6.
2.
Lalla RV, Keefe DM. Mucositis (oral and gastrointestinal). In: Olver IN, editor. The MASCC textbook of cancer supportive care and survivorship. Springer; New York, NY, USA: 2011. p. 241-8
Lalla RV, Bowen J, Barasch A, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 2014;120(10): 1453-61
7.
3.
Elting LS, Cooksley CD, Chambers MS, Garden AS. Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys 2007;68(4): 1110-20
MASCC/ISOO Mucositis Guidelines. Available from: www.mascc.org/mucositisguidelines
8.
Sonis ST. New thoughts on the initiation of mucositis. Oral Dis 2010;16(7):597-600
9.
Al-Dasooqi N, Sonis ST, Bowen JM, et al. Emerging evidence on the pathobiology of mucositis. Support Care Cancer 2013;21(7): 2075-83
1.
4.
Elting LS, Cooksley C, Chambers M, et al. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 2003;98(7):1531-9
128
10.
Wu X, Chen P, Sonis ST, et al. A novel peptide to treat oral mucositis blocks endothelial and epithelial cell apoptosis. Int
J Radiat Oncol Biol Phys 2012;83(3): e409-15 11.
Limaye SA, Haddad RI, Cilli F, et al. Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy. Cancer 2013;119(24): 4268-76
12.
Sonis S, Antin J, Tedaldi M, Alterovitz G. SNP-based Bayesian networks can predict oral mucositis risk in autologous stem cell transplant recipients. Oral Dis 2013;19(7): 721-7
13.
Peterson D, Srivastava R, Lalla R. Oral mucosal injury in oncology patients: perspectives on maturation of a field. Oral Dis 2013; doi; 10.1111/odi.12167. [Epub ahead of print]
Expert Rev. Gastroenterol. Hepatol. 9(2), (2015)
ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: http://www.tandfonline.com/loi/ierh20
Alleviating mucositis: are we on track for a novel therapeutic? Rajesh V Lalla To cite this article: Rajesh V Lalla (2015) Alleviating mucositis: are we on track for a novel therapeutic?, Expert Review of Gastroenterology & Hepatology, 9:2, 127-128 To link to this article: http://dx.doi.org/10.1586/17474124.2015.965146
Published online: 01 Oct 2014.
Submit your article to this journal
Article views: 202
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierh20 Download by: [45.64.96.9]
Date: 19 October 2015, At: 07:08
Editorial
Alleviating mucositis: are we on track for a novel therapeutic? Expert Rev. Gastroenterol. Hepatol. 9(2), 127–128 (2015)
Rajesh V Lalla
Downloaded by [45.64.96.9] at 07:08 19 October 2015
Section of Oral Medicine, University of Connecticut Health Center, 263, Farmington Avenue, Farmington, CT 06030-1605, USA Tel.: +1 860 679 2952 Fax: +1 860 679 4760 [email protected]
Oral and gastrointestinal mucositis has emerged as an important toxicity of cancer therapy. In addition to supportive care measures, agents for the prevention or treatment of mucositis in specific patient populations are described in the evidence-based clinical practice guidelines published by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. However, there still remains an unmet clinical need for preventive and therapeutic agents in several patient populations. The successful development of such agents will rely on our improved understanding of the pathogenic mechanisms underlying mucositis. Studies are also underway on novel delivery mechanisms and risk prediction models that can facilitate the selective use of interventions for mucositis in a targeted and cost–effective manner. A large number of agents are at various stages in the clinical development pipeline. Enhanced management of this dose-limiting toxicity will allow the delivery of optimal cancer therapy and improve patient prognosis.
Oral and gastrointestinal mucositis has emerged as an important toxicity of cancer therapy, including conventional chemotherapy, targeted agents and radiation therapy. Oropharyngeal mucositis presents as mouth and throat erythema and ulcerations that are extremely painful and negatively impact oral intake [1]. Gastrointestinal mucositis may present as diarrhea, abdominal pain or nausea [2]. Mucositis necessitates the use of symptomatic supportive therapy, decreases quality of life, increases cost of care and may lead to undesirable dose reductions or treatment breaks, negatively impacting cancer prognosis [3,4]. The traditional management of mucositis has heavily relied on supportive care aimed at managing symptoms and complications of mucositis. This includes pain control, nutritional support, management of diarrhea and treatment of secondary infections [5]. Although these elements continue to be of great importance, recent research has also identified some specific strategies to prevent or reduce the severity of mucositis. These strategies are delineated in the evidence-
based clinical practice guidelines for oral and gastrointestinal mucositis prepared by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology [6]. For oral mucositis, interventions recommended or suggested for use (depending on the level of supporting evidence) in specific patient populations include oral care protocols, cryotherapy, keratinocyte growth factor-1, low-level laser therapy, benzydamine mouthwash and zinc. For gastrointestinal mucositis, interventions recommended or suggested for use (depending on the level of supporting evidence) in specific patient populations include octreotide, intravenous amifostine, sucralfate enemas, sulfasalazine, probiotics and hyperbaric oxygen. A summary of the Multinational Association of Supportive Care in Cancer/ International Society of Oral Oncology mucositis guidelines and free full text access to publications related to the guidelines is available at [7]. However, there continue to be several patient populations for which no effective or feasible intervention has been identified. Therefore, there is still an
KEYWORDS: cancer • chemotherapy • gastrointestinal • mucositis • oral • radiation therapy
informahealthcare.com
10.1586/17474124.2015.965146
Ó 2015 Informa UK Ltd
ISSN 1747-4124
127
Downloaded by [45.64.96.9] at 07:08 19 October 2015
Editorial
Lalla
unmet clinical need for additional preventive and therapeutic agents for mucositis. The successful development of such agents will rely on our improved understanding of the pathogenic mechanisms underlying mucositis. Previously, mucositis was thought to be simply due to cell death of mucosal cells due to the direct effects of chemotherapy or radiation therapy. It is now appreciated that the pathogenesis is much more complex, involving various cell types, cellular and extracellular pathways and direct and indirect effects of cancer therapy [8,9]. This greater understanding provides the opportunity to develop preventive or therapeutic agents directed at various steps along the subclinical and clinical course of mucositis. For example, in an animal model of radiation mucositis, antrum mucosal protein peptide reduced the occurrence of ulceration and accelerated healing. In vitro studies suggested this effect was mediated, at least in part, by its anti-apoptotic activity [10]. A recently published Phase Ib study, in head and neck cancer patients receiving induction chemotherapy, examined the use of AG013, an oral rinse containing recombinant Lactococcus lactis secreting the mucosal protectant human trefoil factor 1. The efficacy analyses showed a 35% reduction in the percentage of days with ulcerative oral mucositis in AG013 subjects, compared to placebo [11]. Thus, not only new agents, but also novel delivery mechanisms are under investigation. Research is also ongoing on methodologies to accurately predict the development of clinically significant mucositis. For example, a cluster of single nucleotide polymorphisms derived from salivary DNA was demonstrated to have a predictive accuracy of 81% for severe oral mucositis in a cohort of 16 patients who received highdose chemotherapy for a stem cell transplant [12]. The further development of such risk prediction models can facilitate the References
5.
selective use of interventions for mucositis in a targeted and cost–effective manner. The pace of research in this clinical space has increased significantly in recent years [13]. A large number of agents are at various stages in the clinical development pipeline. A recent search on clinicaltrials.gov identified more than 30 mucositis trials in the active stage. The interventions being tested in these trials include acetylcysteine rinse, acupuncture, botanical extracts, clonidine mucoadhesive tablet, cryotherapy, glutamine rinse and swallow, grape extract, honey mouthwash, immunomodulatory dietary supplement, leucovorin, low-level laser therapy, neem mouthrinse, probiotic lozenges containing Lactobacillus brevis, rebamipide liquid, supersaturated calcium phosphate rinse, synthetic peptide targeting the innate immune system and topical nanopolymer. The diverse nature and large number of interventions being clinically tested offers the hope that one or more of these agents will prove to be effective in prevention or treatment of mucositis. In turn, enhanced management of this dose-limiting toxicity will allow the delivery of optimal cancer therapy and improve patient prognosis. Financial & competing interests disclosure
RV Lalla serves as Chair of the Mucositis Study Group of MASCC/ISOO and as Chair of the Mucositis Guidelines Panel. He has received research funding from BioAlliance Pharma and has served as a consultant for Sucampo AG, iNova Pharmaceuticals, Fera Pharmaceuticals and Phillips Gilmore Oncology Communications. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am 2008;52(1):61-77; viii
Lalla RV, Saunders DP, Peterson DE. Chemotherapy or radiation-induced oral mucositis. Dent Clin North Am 2014; 58(2):341-9
6.
2.
Lalla RV, Keefe DM. Mucositis (oral and gastrointestinal). In: Olver IN, editor. The MASCC textbook of cancer supportive care and survivorship. Springer; New York, NY, USA: 2011. p. 241-8
Lalla RV, Bowen J, Barasch A, et al. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 2014;120(10): 1453-61
7.
3.
Elting LS, Cooksley CD, Chambers MS, Garden AS. Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys 2007;68(4): 1110-20
MASCC/ISOO Mucositis Guidelines. Available from: www.mascc.org/mucositisguidelines
8.
Sonis ST. New thoughts on the initiation of mucositis. Oral Dis 2010;16(7):597-600
9.
Al-Dasooqi N, Sonis ST, Bowen JM, et al. Emerging evidence on the pathobiology of mucositis. Support Care Cancer 2013;21(7): 2075-83
1.
4.
Elting LS, Cooksley C, Chambers M, et al. The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 2003;98(7):1531-9
128
10.
Wu X, Chen P, Sonis ST, et al. A novel peptide to treat oral mucositis blocks endothelial and epithelial cell apoptosis. Int
J Radiat Oncol Biol Phys 2012;83(3): e409-15 11.
Limaye SA, Haddad RI, Cilli F, et al. Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy. Cancer 2013;119(24): 4268-76
12.
Sonis S, Antin J, Tedaldi M, Alterovitz G. SNP-based Bayesian networks can predict oral mucositis risk in autologous stem cell transplant recipients. Oral Dis 2013;19(7): 721-7
13.
Peterson D, Srivastava R, Lalla R. Oral mucosal injury in oncology patients: perspectives on maturation of a field. Oral Dis 2013; doi; 10.1111/odi.12167. [Epub ahead of print]
Expert Rev. Gastroenterol. Hepatol. 9(2), (2015)
