**3. Results**

#### *3.1. Characteristics of Selected Studies*

Firstly, a total of 402 articles were retrieved through databases searching (PubMed (*n* = 349), Scielo (*n* = 6), ProQuest (*n* = 29) and OVID (*n* = 18)), from which 68 papers were discarded by duplicity. After title, abstract, and full-text screening, a total of 314 articles were excluded following the selection criteria. Twenty studies were included in this review (Figure 1).

All trials and patients' characteristics are summarized in Table 1. On the whole, all individuals were treated using conventional cancer therapy methods, such as radiotherapy (*n* = 11, 55%), chemotherapy (*n* = 6, 30%), or both (*n* = 3, 15%). In some studies, sex was not specified (*n* = 2, 10%), and only women were included in studies dealing with specific carcinomas of the female reproductive tract (*n* = 4, 20%), such as endometrial, vaginal, uterine, and cervical cancers. The age range of the patients ranged from 18 to 75 years old (with a mean age of 57.41 years), enrolling a total of 2508 participants. All studies included were published between 1988 and 2020, and 15 studies (75%) were not registered in any clinical trial registry. Most of these studies were conducted in Asia (*n* = 9), Europe (*n* = 8), but also in America (*n* = 2) and Oceania (*n* = 1). As regards the use of probiotics, 10 of the selected studies (50%) used a single probiotic strain, while the remaining 10 (50%) used two or more probiotics combined. The presentation and forms of administration varied from study to study, with the most commonly used forms being capsules, gelatine, and yoghurt. The time of administration as well as the dose administered to the patients were also varied, which ranged from 1 to 24 weeks and 10<sup>6</sup> to 10<sup>11</sup> CFU/day, respectively. Finally, 17 studies (85%) revealed predominantly positive results when using probiotics to reduce the incidence of treatment-related side effects in oncology patients, while three studies (15%) reported no impact in their findings.



**Table 1.** *Cont.*


**Table 1.** *Cont.*


**Figure 1.** Flowchart depicting the article selection process.

The data synthesis revealed four categories related to the use of probiotic supplements for treatment-related side effects in clinical oncology. For that matter, these categories would study the effects of probiotic treatments for different treatment-related side effects in oncology such as gastrointestinal side effects, immune-related side effects, inflammatory side effects, and performance status-related side effects. These categories are described below.

#### *3.2. Gastrointestinal Side Effects*

Probiotics have been shown to be effective in the treatment of some common oncology treatment-related gastrointestinal adverse reactions, as demonstrated in 11 of 20 trials (55%) [25–31,33–36]. The main adverse effects identified and treated were mainly diarrhea, with other drawbacks being abdominal pain, nausea and vomiting, constipation, bloating, abdominal distension, and lactose intolerance caused by chemotherapy. The most commonly probiotic strains used along these studies were *Lactobacillus acidophilus*; *L. rhamnosus* GG ATCC 53103; and *L. casei* var. *rhamnosus*. Likewise, other probiotic strains used in combination were (*L. acidophilus* LA-5 along with *Bifidobacterium animalis* subsp. *lactis* BB-12), (*L. acidophilus* BMC12130, *L. casei* BCMC12313, *L. lactis* BCMC12451, *B. bifidum* BCMC02290, *B. longum* BCMC02120 and *B. infantis* BCMC02129), (*B. infantis*, *L. acidophilus*, *Enterococcus faecalis* and *Bacillus cereus*), (*L. acidophilus* LAC-361 and *B. longum* BB-536), (*L. acidophilus* plus *B. bifidum*), and (*L. casei*, *L. plantarum*, *L. acidophilus*, and *L. delbruekii* subsp. *thermophilus*; *B. longum*, *B. breve*, and *B. infantis*; *Streptococcus salivarius* subsp. *thermophilus*). The duration of treatment ranged from 1 to 24 weeks.

Conversely, 2 trials (10%) showed inconclusive results for their benefits to control stool constituency and flatulence, although their findings were promising to prevent radiotherapy-induced diarrhoea [32,37]. The probiotic strains used in these studies included: *L. acidophilus* NCDO1748, and (*S. thermophilus*, *L. delbrueckii* subsp. *bulgaricus*, and *L. casei* DN-114 001). The treatment for these studies ranged from 1 to 6 weeks and were observed only in women.

#### *3.3. Immune-Related Side Effects*

Despite having only one study [38], positive results of the probiotics on immunerelated side effects have also been observed. A combination of probiotic strains (*Bifidobacterium*, *Lactobacillus* and *S. thermophilus*) was used for 1 to 2 weeks, in which patients improved their immune and nutritional status as well as rehabilitation, showing improved cellular immune parameters and tolerance to abdominal pain, bloating and diarrhoea. These authors used glutamine along with fish oil in their treatment as it has been shown to enhance epithelial cell growth and repair of intestinal mucous membrane, prevent bacterial translocation and reduce barrier injury, among others, which may actually be able to work synergistically with probiotics to protect the intestinal mucosa barrier and reduce permeability. In this manner, radiation-induced injuries may be alleviated by these probiotic strains, while other eco-nutrients feed the intestinal membrane.

#### *3.4. Inflammatory-Related Side Effects*

Impact on inflammatory-related side effects such as oral mucositis was also reported in three trials (15%). Among these studies, two trials [20,40] showed positive and effective results in reducing the severity of oral mucositis when using different probiotic strains: (*B. longum*, *L. lactis,* and *E. faecium*) and *L. brevis* CD2. The treatment period for these studies was from 1 to 7 weeks. However, De Sanctis et al. (2019) [39] did not notice any significant changes in the severity of oral mucositis with *L. brevis* CD2, although their treatment lasted only 1 week due to premature closure of patient accrual. While it is true that radiochemotherapy-induced mucositis is a complex process and further prospective studies are needed to explore oral microbiota modulation in reducing its incidence, the findings of Jiang and collaborators (2019) [20] and Sharma and collaborators (2012) [40] strongly underpinned the probiotics used as a plausible strategy to manage mucositis-associated pain and reduce its incidence.

#### *3.5. Performance Status-Related Side Effects*

Concerning to the impact of probiotics in patients' general well-being and activities of daily life, three trials (15%) evaluated their effects over a 4-week treatment period [41–43]. Two of these studies used a single probiotic strain, *S. salivarius* M18 and *L. casei* LC9018 respectively, and the remaining study used a combination of *L. acidophilus*, *L. rhamnosus*, *B. longum,* and *Saccharomycesboulardii*. In line with the findings of Shao and collaborators (2014) [38], not only did Doppalapudi and collaborators (2020) [42] and Vesty and collaborators (2020) [41] observe clinical improvements driven by probiotic-induced changes in the oral microbiota but also a potential mechanism to improve these performance status-related side effects throughout other modulating host immune response and microbial interactions. Having said that, only one study [43] assessed the effect of probiotics in malignant pleural effusion, which is one of the most common complications in lung cancer. This complication can have a severe impact on patient performance and shortened survival, but interestingly, *L. casei* LC9018 has been shown to be a useful adjuvant in the treatment of this type of cancer and to prevent this complication.
