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Editorial

Knowledge of gastrointestinal toxicity mechanisms is paving the way for improved assessment and management of patient supportive care

Stringer, Andrea M.a,b; Blijlevens, Nicolec

Current Opinion in Supportive and Palliative Care: June 2019 - Volume 13 - Issue 2 - p 111–113
doi: 10.1097/SPC.0000000000000424
GASTROINTESTINAL SYMPTOMS: Edited by Nicole Blijlevens and Andrea M. Stringer
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aSchool of Pharmacy and Medical Sciences, University of South Australia

bAdelaide Medical School, The University of Adelaide, Adelaide, Australia

cDepartment of Hematology, Radboud University Medical Centre, Nijmegen, The Netherlands

Correspondence to Andrea M. Stringer, PhD, Senior Research Fellow, School of Pharmacy and Medical Sciences, University of South Australia, North Terrace, Adelaide, SA 5000, Australia. Tel: +61 8 8302 7388; e-mail: andrea.stringer@unisa.edu.au

Cancer treatments are often recognized as causing severe and debilitating gastrointestinal toxicities. Treatments are constantly evolving, and as a result, so are the side effects. Often, these gastrointestinal toxicities are under-recognized by healthcare professionals, and under-reported by patients, meaning that patients receiving cancer treatments do not receive the supportive care required to manage the associated gastrointestinal effects. Both healthcare professionals and patients often prioritize the curative action of the cancer treatment over the treatment of any toxic effects.

One of the most challenging toxicities is pelvic radiation disease (PRD). A key characteristic of this condition can be a permanent change in bowel habits and gastrointestinal function, which almost always leads to a permanent diminished quality of life [1]. There are often disjointed communication channels between oncology and radiation oncology departments, and gastroenterology departments, further complicating management options for gastrointestinal toxicities. Adequately assessing alterations to bowel habits and gastrointestinal function following radiotherapy treatments is, therefore, vital in the process of both developing restorative gastrointestinal treatments and using them during, following, or sometimes decades after radiotherapy treatments.

The awareness of gastrointestinal toxicities following cancer treatments, and knowledge related to mechanisms promoting poor gastrointestinal outcomes following cancer treatments has vastly improved over the last 10–20 years. Over this time, some of the most impactful findings related to gastrointestinal effects following cancer treatments include the activity of apoptotic pathways [2], involvement of inflammatory mediators and immune modulation [3] and involvement of the gut microbiome and importance of the host–microbe interactions in the gut that regulate these outcomes [4]. These findings have all contributed evidence to support the five-phase model of mucositis hypothesised by Sonis [5] in 2004, confirm that similar pathways and phases occur in both the mouth and intestine, and contribute additional pathways to the originally proposed model.

The need for knowledge is also growing. Therapies are often combined to enhance the antineoplastic effects and improve the survival of cancer patients. The combination of therapies can lead to a combination of toxicities, not least being gastrointestinal effects. With the addition of targeted therapies and immunotherapies to the list of cancer treatments and possible combinations of treatments, our knowledge and understanding in how these toxicities occur also needs to increase, as the mechanisms promoting detrimental gastrointestinal effects from these therapies are often different to those from traditional chemotherapy and radiotherapy.

It is also imperative to break down the ‘toxicity silos’ often built by clinicians. Cancer treatments (traditional and new) tend to work systemically, creating a myriad of detrimental effects for patients. Studies have shown that many toxicities occur together and can predict future occurrences and severity of toxicities [6].

Over the years, researchers have shown that the gut is not a standalone organ or system, and the pathways initiated in normal cells and tissues by cancer treatments are also not standalone. Many studies have confirmed involvement of the gut microbiome in cancer treatment-induced gastrointestinal toxicities, so this is not just an interaction of pathways, but also an interaction of organisms. When kept in check, this interaction has very positive outcomes, and provides protection against gastrointestinal damage and damage to other body systems. However, compositional changes to the gut microbiota have been implicated in conjunction with gastrointestinal effects associated not only with cancer treatments but also inflammatory bowel disorders, gastrointestinal cancers and many other aspects of human health overall.

An interesting finding emerged in 2016, when Vanlancker et al. discovered that changes to the gut microbiome following chemotherapy (5-fluorouracil, and irinotecan metabolite SN-38) did not occur in vitro in the simulator of human intestinal microbial ecosystem (SHIME) [7]. This suggests there is a host response to the chemotherapy required for these microbial changes reported in animal and human studies to occur, which adds a further level of complexity to the gastrointestinal toxicity issue for cancer treatment recipients. When you take this knowledge and combine it with the effects that a modified microbiome, and the associated changes in metabolic products produced by said microbiome have in return on the host, it is plausible that the toxic effects come about through a tornado-like process, where additional pathways, reactions, and interactions are swept into the process along the way.

Refinement of the way we administer cancer treatments has been paramount in the overall efforts to reduce not only gastrointestinal toxicities associated with cancer treatments but also other systemic toxicities as well. Targeted radiotherapy techniques are aiming to reduce the amount of normal noncancerous tissue that gets irradiated, which in turn reduces the amount of normal tissue susceptible to the direct effects of the irradiation. Many intervention agents have been trialled to either protect normal tissue from the effects of radiotherapy, and/or chemotherapy, and/or targeted therapies or to target specific pathways associated with the development of gastrointestinal toxicities associated with these cancer treatment modalities [8]. Some recent key advances in preventing or treating gastrointestinal toxicities include guidelines suggesting the use of hyperbaric oxygen, sucralfate and sulfsalazine for PRD, and probiotics to reduce diarrhoea in patients receiving radiotherapy or chemotherapy to treat pelvic malignancies [8].

Whilst in-vitro experimentation has an important place in the determination of specific mechanisms at a cellular level, in-vivo animal models are required to observe and analyse the systemic and organismal effects of cancer treatments. Animal models of gastrointestinal toxicities tend to be homologous with the clinical presentation of gastrointestinal toxicities. However, caution is still required when attempting to translate between in-vivo and clinical investigations, because of the difficulty in interpreting symptoms associated with gastrointestinal toxicities, such as pain, which requires verbal communication to gauge the severity. Techniques, such as the judgement bias test to assess affective state have been developed to assess rodent behaviour [9], but introduces a level of subjectivity and interpretation of rodent behaviour and the cause of it. As many animal models for gastrointestinal toxicities are rodent-based, this poses difficulty in observing common human gastrointestinal symptoms, such as nausea and vomiting because of the lack of emetogenic reflexes in rodents.

The benefits of animal models in furthering our knowledge and understanding of gastrointestinal toxicities in response to cancer treatments far outweigh the limitations. Many of the pathobiological advances in underpinning the mechanisms behind gastrointestinal toxicities associated with cancer treatments have been made in animal models. Animal models allow multiple mechanisms to be investigated in one model, often with one experiment, which is paramount in attempts to elucidate these individual mechanisms and how they coerce to create such devastating gastrointestinal effects.

The intestine is protected by a thick layer of mucus, contributing largely to innate immunity and host defence against intestinal microbes, and damaging agents present in the intestinal lumen. Mucins are recognized as glycoproteins produced by goblet cells, which contribute to the composition of the mucus layer, particularly in the intestine. Cancer treatments are known to result in a rapid exocytosis of mucin stores from goblet cells, likely because of the actions of pro-inflammatory cytokines, including interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-α [10].

Developing ways to help maintain the integrity of mucin stores, and the mucus layer protecting the intestine may be advantageous, reminiscent of an early intervention type of strategy. Recent studies have demonstrated that dietary interventions may help to preserve mucins and the integrity of the mucus layer [11], and that H2-receptor antagonists may be promising in maintaining the levels of mucins present [12]. Although these studies are quite preliminary in nature, mucins and the mucus layer are worthwhile targets to investigate for gastrointestinal toxicity intervention to maintain the protective mucus barrier. Muc4 (a transmembrane mucin) is involved in signalling pathways affecting cell proliferation, motility and apoptosis. Moreover, mucins (including Muc4) are present on the mucus layer, with the ability to interact with microbiota and their metabolic products, including enzymes capable of mucin degradation, again highlighting the importance of maintaining the composition of the gut microbiome.

In summary, clinicians and scientists need to continue to improve our knowledge of the pathobiology underpinning gastrointestinal toxicities, and continue to think outside the box when we encounter patients with these toxicities. The future is promising in the field of supportive care, with the next generation of research filtering through, confirming initial hypotheses and building on those to deliver new and meaningful targets for intervention of gastrointestinal toxicities.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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