How can we prevent diarrhea induced by systemic treatments in oncological patients? An evaluation of phase II trials

KEYWORDS:

• Diarrhea
• chemotherapy
• target therapy
• immune-check point inhibitors
• oncology

1. Introduction

Several oncology drugs can cause diarrhea, which is a serious, debilitating, and potentially fatal complication for patients with cancer. Among these agents, there are conventional cytotoxic agents (irinotecan, 5-fluorouracil, capecitabine, taxanes), targeted therapies (such as EGFR inhibitors, anti-HER2, multi-tyrosine kinase inhibitors TKI, anti-VEGFR, ALK-inhibitors, anti-Trop2, cyclin-dependent kinase inhibitors, anti-PI3KCA), and immune check-point inhibitors (such as anti-CTLA4, anti-PDL1, and anti-PD1). Between 50% and 80% of patients receiving a systemic treatment can experience diarrhea, depending on the type of regimens and combinations [1,2].

Various antidiarrheal agents are available; however, none directly targets the underlying mechanism of diarrhea. Cancer drug-induced diarrhea may be secretory, osmotic, related to altered motility, inflammatory, or multimodal [3]. General measures for chemotherapy-induced diarrhea (ciD) and targeted-agent diarrhea include dietary modifications, oral or intravenous hydration, and loperamide as a first-line pharmacological treatment. For immune-checkpoint inhibitors-induced diarrhea (irD), oral or intravenous steroids are the first choice, and their doses may be modulated according to the severity of the diarrhea [4].

In patient with persistent ciD who do not respond to loperamide, data support the administration of octreotide, tincture of opium and other opioids (i.e. codeine), or budesonide [4]. Uridine triacetate can be orally given for the management of early-onset and severe diarrhea within 96 h following the end of 5-fluorouracil (5-FU) or capecitabine administration [4]. For irD which does not respond to intravenous steroids, infliximab and vedolizumab are usually administered [4].

In this regard, several agents have been studied, without being included in international guidelines due to the small size of the trial, negative or inconsistent results, or lack of confirmatory results.

Activated charcoal has been shown to possibly mitigate irinotecan-induced diarrhea in colorectal cancer studies [5]. In irinotecan-induced diarrhea, other substances have been evaluated in small studies: chrysin (positive trial) [6], encephalinase inhibitor (negative trial) [7], thalidomide (positive trial) [8], amifostine (negative trial) [9], Kampo medicine (TJ-14) (negative trial) [10], calcium aluminosilicate clay [11] (negative trial), KD018 (four traditional Chinese herbs; results not available) [12].

Lafutidine, a histamine H2 receptor antagonist, has been evaluated in a small, randomized trial in gastric cancer patients treated with adjuvant tegafur/gimeracil/oteracil (S-1). Patients who received lafutidine experienced a lower incidence of diarrhea, but low numbers prevent any type of recommendation [13].

The role of glutamine in preventing ciD is controversial. In three studies, glutamine did not reduce the incidence of severe diarrhea [14–16]. However, in another study, a modest benefit of prophylactic oral glutamine has been reported in decreasing the duration of diarrhea (but not of the severity) in patients treated with 5FU for colorectal cancer [17]. Similarly, it is not possible to adopt a strong recommendation in favor of palifermin, a human recombinant keratinocyte growth factor (KGF), due to contrasting results on its activity and efficacy [18,19].

The last adjournment of the Multinational Association of Supportive Care in Cancer (MASCC) systematic review and clinical practice guidelines for the management of cancer treatment-induced diarrhea did not introduce any substantial change [20], reflecting the rigor of the methodology that underpins these guidelines and the heterogeneity in emerging trials.

Among new compounds, there is a wide variety of bacteria-composed products, like probiotics, prebiotics, synbiotics, postbiotics, and paraprobiotic [21]. Some studies reveal that the incorporation of probiotics as a therapeutic alternative to prevent or improve ciD is an approach that shows favorable outcomes. For example, a probiotic complex (composed of different species of Bifidobacterium, Lactobacillus, and Streptococcus) reduced irinotecan-induced diarrhea severity and use of loperamide in colorectal cancer [22]. In another study, 150 patients treated with 5-FU using a Lactobacillus rhamnosus GG probiotic showed reduced diarrhea frequency and less abdominal discomfort, contributing to sustaining the chemotherapeutic dose intensity [23]. However, other studies [24] showed no efficacy in limiting ciD, and a caution in the use of probiotics in immunocompromised patients should be adopted due to the risk of infections [25,26]. More studies on this topic are now recruiting patients in different countries.

Data on specific management of targeted-agents-induced diarrhea are poor. A recent Italian study evaluated the role of fecal manipulated microbiota transplantation in metastatic renal cancer patients receiving sunitinib or pazopanib [27]. Authors found out that therapeutic manipulation of gut microbiota may become a treatment option to manage TKI-dependent diarrhea. Different trials are investigating fecal transplantation also in treating irD [28].

Crofelemer is purified from Croton lechleri tree sap [29] and it is FDA-approved for HIV adult patients with diarrhea receiving antiretroviral therapy, and it regulates luminal chloride efflux and fluid secretion [30]. The phase II HALT-D study (NCT02910219) evaluated diarrhea prophylaxis with crofelemer 125 mg orally twice daily during the first and second cycles of therapy containing trastuzumab, pertuzumab, and taxane in patients with breast cancer (BC) [31]. Results show that the incidence of grade ≥2 diarrhea was reduced with crofelemer, and less frequent watery diarrhea was observed [32]. The phase III OnTARGET study is evaluating crofelemer for the prophylaxis of diarrhea in adult patients with different solid tumors receiving targeted agents with or without chemotherapy [33].

The phase II study CONTROL evaluated the importance of a proactive approach for the control of diarrhea induced by pan-HER tyrosine kinase inhibitor neratinib in breast cancer, with mandatory prophylaxis with loperamide and then additional budesonide and colestipol [34]. A similar trial, the DIANER study, is currently studying the role of prophylaxis with loperamide and colesevelam in BC patients receiving neratinib [35]. Another study on this topic is evaluating loperamide, golden bifid, and montmorillonite powder in preventing pyrotinib (an irreversible dual pan-ErbB receptor TKI) induced-diarrhea in HER2-positive BC [36].

Alternative non-pharmacological interventions are also under investigation. A Chinese trial is evaluating the role of Chinese traditional medicine in the management of pyrotinib-induced diarrhea [37]. Acupuncture is under evaluation in irinotecan-induced diarrhea in pediatric patients [38].

2. Expert opinion

Diarrhea is a common adverse event in a large number of systemic treatments in cancer, caused by complex, interacting mechanisms. Physicians and patients often have different points of view while evaluating diarrhea, due to the fact that diarrhea can be defined by increased stool frequency, liquidity, or volume. The different possible ways of defining diarrhea can create discrepancies in thinking between physician (who tends to define diarrhea as increased frequency) and patient (who tends to define diarrhea as passage of soft stools). A number of promising agents for oncological treatment-induced diarrhea are in development, but because of the multifactorial pathogenesis of the condition and of the inconsistent results in different trials, a few drugs are approved. In general, most cases of chemotherapy-induced diarrhea recognize one of these different pathophysiologic mechanisms: increased secretion of electrolytes with reduced absorptive capacity/disruption of intestinal mucosa (secretory diarrhea); increased intraluminal osmotic substances (osmotic diarrhea); or altered gastrointestinal motility. On the other side, diarrhea induced by targeted agents is often multimodal. Immune-checkpoint inhibitors-induced diarrhea is immune mediated and mechanisms involving CD8+ T cells, CD4+ Th1 cells, IFN gamma overproduction, and inflammatory TNF-alpha producing macrophages have been proposed. In addition, alterations in the gut microbiome have been observed. A physician has to determine the severity, the volume, the type, and duration of diarrhea, and has to analyze other possible causes or contributory factors (such as infections, other drugs, malabsorption, overflow diarrhea). Due to the complexity of pathophysiologic mechanisms and the interaction with other factors, it is difficult to develop new antidiarrheal drugs, and a much more robust holistic assessment is required when evaluating an oncological patient with diarrhea.

It is likely that we need to focus on the prevention of diarrhea and the patients’ education programs. Different trials are now testing therapies in order to prevent or delay the development of diarrhea and, therefore, improve quality of life for patients with cancer. In this regards, different agents are on studying in particular in the prophylaxis of TKI-induced diarrhea.

Due to the multifactorial nature of systemic agent-induced diarrhea and the limited efficacy of single therapies, a multi-targeted approach or targeting a mechanism that is known to contribute to multiple drivers of diarrhea may be the most effective treatments. In addition, validated patient education programs could be essential to encourage patients to understand the purpose of diarrhea management strategies.

Despite all these strands of research, the evidence of research in prevention and treatment of oncologic treatment-induced diarrhea is still limited. We should advocate for more quality research in this field: well-designed clinical trials, with homogeneous population in terms of type of disease, treatment, and comorbidities; an adequate sample size; and with the sufficient requirements to be replied in the real-world setting.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.