**1. Introduction**

According to the World Health Organization (WHO), cancer is the second leading cause of death, affecting more than 19.3 million people and claiming 10 million lives worldwide, and the number of new cases is expected to double by 2040 [1]. This disease is diagnosed differently in men and women, with one in every five people developing cancer at some point in their lives, resulting in the death of one in every eight men and one in every eleven women diagnosed with cancer. In this sense, breast, colorectal, lung, cervical, and thyroid cancer are the most common cancers in women, while lung and prostate cancer are the most common in men [2].

There are diverse therapeutic strategies to reduce cell proliferation and disease progression, with surgery, chemotherapy, radiotherapy, and, more recently, immunotherapy and hormone therapy being the most commonly used treatments [3,4]. These treatments have significant side effects, particularly chemotherapy and radiotherapy, which is why it is frequently necessary to use combination treatments to increase effectiveness, despite

**Citation:** Rodriguez-Arrastia, M.; Martinez-Ortigosa, A.; Rueda-Ruzafa, L.; Folch Ayora, A.; Ropero-Padilla, C. Probiotic Supplements on Oncology Patients' Treatment-Related Side Effects: A Systematic Review of Randomized Controlled Trials. *Int. J. Environ. Res. Public Health* **2021**, *18*, 4265. https://doi.org/10.3390/ ijerph18084265

Academic Editor: Paul Tchounwou

Received: 26 March 2021 Accepted: 15 April 2021 Published: 17 April 2021

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the fact that this strategy multiplies side effects [5]. As a result, cancer treatments have the greatest impact on cells with the highest rate of cell division, resulting in low cell counts in blood cells, which manifests as anemia, infections, and bleedings. Likewise, gastrointestinal cells are also altered, resulting in nausea, vomiting, diarrhea, taste disturbances, mucositis, and swallowing difficulties [6,7], which cause many patients to postpone or discontinue their treatments [8].

Chemo- and radiotherapy modify the composition of intestinal microbiota in a process known as dysbiosis, which is often associated with biochemistry and immunologic disorders in the gastrointestinal tract [9,10]. Multiple strategies are being developed to modify microbiota with the underlying idea of propelling this dysbiosis toward eubiosis or the hemostasis of the gu<sup>t</sup> microbiota in order to prevent or inhibit cancer progression [11,12]. In this regard, it has been reported that paclitaxel, a mitosis inhibitor, is able to increase matrix metalloproteinase 9 (MMP9) and tumor necrosis factor-alpha (TNFα) levels and alter bacterial diversity in female mice colon [13]. Probiotics, defined as live microorganisms that provide a health benefit to the host when administered in adequate amounts [14], have been shown to be effective in the managemen<sup>t</sup> of diarrhea and constipation, as well as highly effective in the treatment of inflammatory bowel diseases by improving bowel function [15,16]. For example, a probiotic mixture improved altered intestinal tight junction levels in mice with dextran sodium sulfate (DSS)-induced colitis [17]. Consequently, probiotics containing one or more strains could indeed restore the composition of altered gu<sup>t</sup> microbiota and improve certain parameters, leading to significant homeostasis in animal models of obesity, Parkinson's disease, and depression [15,18,19]. Similarly, immune function may improve after the administration of a probiotic combination. Treatment with Bifidobacterium longum, Lactobacillus lactis, and Enterococcus faecium significantly reduced the occurrence of radio- chemotherapy-induced oral mucositis, as well as increased CD4+, CD8+, and CD3+ T cells in oncological patients [20]. In that manner, 5-fluorouracilinduced intestinal mucositis has also shown an improvement after probiotic treatment by reducing TNFα, IL-6, and IFN-γ levels in mice [21].

In this context, corticosteroids and antiemetics are key elements in oncology to be used prior to the administration of chemotherapy to avoid side effects [5]. However, relatively little is understood about including probiotics in this preventive regimen due to beneficial results in intestinal disorders and altered immunity, which could be of grea<sup>t</sup> interest in reducing certain oncology treatment-related side effects, such as diarrhea, mucositis, or constipation. Therefore, this review aims to evaluate the efficacy of probiotic supplements to ameliorate chemo- and radiotherapy-related side effects in adults.

#### **2. Materials and Methods**
