The previous studies have reported that adding probiotics to EN could improve immune function and decrease the incidence of diarrhoea in cancer patients [3, 21]. Yi et al. conducted a meta-analysis which confirmed that early EN supplementation with probiotics effectively decreased the risk of infections (risk ratio [RR], 0.53; 95% confidence interval [CI], 0.44–0.65), mortality (RR, 0.56; 95% CI, 0.38–0.82), gastrointestinal complications (RR, 0.19; 95% CI, 0.13–0.25), and shortened an intensive care unit stay (mean difference [MD], − 4.55; 96% CI, − 5.91 to − 3.19) in patients with severe head injury including also cancer patients [22]. Notwithstanding, the effect of the Lp299v on nutritional status and the improvement of EN tolerance as well as the quality of life of cancer patients receiving HEN has not been studied earlier. Moreover, the present study treatment length is 4 weeks in comparison with other studies with shortened observation period. At the beginning, the administration of probiotic was planned for 12 weeks as it was previously registered in ClinicalTrials.gov before intervention; however, we decided to reduce the treatment period to 4 weeks, due to high mortality of cancer patients qualified for HEN.
Probiotics can reduce gastrointestinal symptoms, such as nausea, bloating, and diarrhoea [20, 23]. In Zhao et al. prospective randomized and controlled trial, it was shown that a combination of fiber and probiotics with EN significantly reduced the incidence of diarrhoea associated with EN in postoperative patients with gastric cancer [3]. The incidence of diarrhoea during 7 days treatment was 60% in patients of FF group (fiber-free nutrition formula), 30% of FE (fiber-enriched nutrition formula), and 5% of FEP (fiber- and probiotic-enriched nutrition formula). The similar results were obtained by Xie et al. confirming that diarrhoea caused by EN occurred less frequently in the gastric cancer patients receiving probiotics compared to controls [21]. Importantly, studies have shown that probiotics efficacy is strain-specific [24]. Lönnermark et al. in a double-blind, placebo-controlled trial investigated the effect of Lp299v (in a dose 1010 CFU per day) on the incidence of antibiotic-associated gastrointestinal symptoms [25]. The significant reduction of the frequency of loose stools (odds ratio (OR), 0.69; 95% confidence interval (CI), 0.52–0.92; P = 0.012) and nausea (OR 0.51; 95% CI, 0.30–0.85; P = 0.0097) after administration of Lp299v was noted [25]. In the current study, the frequency of vomiting, flatulence, and stools were significantly reduced at week 4 compared to baseline in Lp299v group (p = 0.0346, p = 0.0117, p = 0.024, respectively); however, the significant differences between Lp299v and placebo group were not observed. Moreover, the frequency of flatulence was reduced week-by-week in Lp299v group and the number of stools started to decline in week 3 and 4, which was not noted in the placebo group. It may be associated with the modification of gut microbiota after administration of Lp299v. To sum up, the administration of Lp299v potentially may reduce the gastrointestinal symptoms in patients receiving HEN.
According to the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines, all cancer patients should be screened regularly for the risk of malnutrition [26]. In the above mentioned study by Zhao et al., the assessment of nutritional status in patients with gastric cancer (n = 120) receiving EN for 7 days was based on BMI (FF group 21.41 ± 2.20 kg/m², FE 21.73 ± 2.65, FEP 21.83 ± 3.12; p = 0.89) and laboratory parameters (the level of albumin – FF 37.71 ± 2.72 g/L, FE 37.01 ± 2.73, FEP 36.30 ± 3.28, p = 0.34; prealbumin – FF 192 ± 6.72 mg/L FE 188 ± 8.41, FEP 188 ± 7.43, p = 0.16; transferrin – FF 1.83 ± 0.27 mg/L, FE 1.70 ± 0.31, FEP 1.85 ± 0.35, p = 0.27; total lymphocyte count – FF 1.25 ± 0.42 × 109 /L, FE 1.15 ± 0.34, FEP 1.13 ± 0.32, p = 0.53) [3]. The statistically significant difference between 3 groups in terms of these laboratory parameters after 7 days of EN was not observed [3]. Similarly, in Xie et al. study including patients with gastric cancer (n = 140) receiving EN in combination with probiotics or placebo for 8 days, no difference was found between two groups after the treatment period [21]. In the current study, it was confirmed that Lp299v significantly increased the level of albumin in the blood serum in comparison with the placebo group (p = 0.032); however, the significant increase of the level of total protein was not observed (p > 0.05). Similarly, no significant changes were observed in TLC. The half-life of albumin is around 21 days. Therefore, it is not accurate as a laboratory parameter to determine short term alterations. This may be the reason why in the current study the changes of this parameter were observed on the contrary to the above mentioned studies (4 weeks vs 7 and 8 days). The concentration of albumin – being a negative acute phase protein – is decreased not only in malnutrition but also in the presence of inflammation [27]. The increase of the level of albumin after administration of Lp299v can suggest improvement in the nutritional status and/or the reduction of inflammation. Due to non-significant improvement in anthropometric measures, increase in albumin concentration during Lp299v can be interpreted as anti-inflammatory effect of probiotic administration. However, other laboratory parameters describing the inflammation, such as C-reactive protein or pro- and anti-inflammatory cytokines were not included in this study, thus the immunomodulatory effect of Lp299v in cancer patients needs further studies. The lack of significant improvement in BMI, fat mass, muscle mass, and TBW after 4 week administration of Lp299v were observed.
GLIM initiative proposed severity grading of malnutrition into moderate and severe stages [28]. It has been published in 2019; therefore, data regarding clinical complications of those criteria and cancer are limited. In 2019, Contreras-Bolivar et al. presented results of observational and prospective study, which confirmed that SGA (Subjective Global Assessment) and GLIM criteria (mainly with hand grip strength) are useful in diagnosing malnutrition having also similar predictive value regarding six-month mortality in cancer inpatients [29]. In the current study, 82.85% of ITT patients and 80% of FAS were severely malnourished according to GLIM criteria before intervention; therefore, it was almost impossible to improve their nutritional status.
The improvement of patients’ quality of life is one of the most important goals of multi-disciplinary anti-cancer therapy. The effects of 3 months HEN on QOL and nutritional status after esophagectomy were assessed by Wu et al. [30]. The participants were divided into 2 groups: undergoing Ivor Lewis minimally invasive esophagectomy with laparoscopic jejunal feeding tube placement (MIE group) and patients after open esophagectomy with naso-jejunal feeding tube placement (OE group). The results of this study confirmed that patients who received HEN had a lower risk of malnutrition compared to patients who did not receive HEN (PG-SGA score, 5.7 vs 7.9, p < 0.01). The QLQ-30 questionnaire including physical, emotional, and cognitive functioning was used to evaluate the QOL. The mean scores of the global quality of life, physical function, role function, and social function were significantly higher in the MIE group compared to the OE group. It was concluded that after 3 months of HEN, patients in the MIE group had fewer symptoms and superior improvements in functioning in comparison to patients of the OE group [30]. Moreover, probiotics have been tested to improve cancer patients’ quality of life. In double-blind, randomized, and placebo-controlled trial it was noted that administration of probiotics per 12 weeks improve cancer-related quality of life – Functional Assessment of Cancer Therapy (FACT) – (baseline vs. 12 weeks: 19.79 ± 4.66 vs. 21.18 ± 3.67, p = 0.04) and fatigue-related FACT (baseline vs. 12 weeks: 43.00 (36.50–45.50) vs. 44.50 (38.50–49.00), p = 0.02) in colorectal cancer survivors [31]. Ohigashi et al. study also confirmed that the administration of probiotics (containing Bacillus natto and Lactobacillus acidophilus) for 3 months may be effective in the improvement of QOL after colorectal resection (n = 77) [32]. However, none of the previous studies tested the efficacy of Lp299v in the cancer patient population. It was highly desirable since this strain was shown to be efficient in the reduction of gastrointestinal symptoms and as a consequence the improvement of QOL [33, 34]. In the current study, the self-assessment of QOL was significantly increased after week 4 compared to baseline (p = 0.0077) in patients receiving Lp299v; moreover, the significant improvement in the psychological domain and social factors was also noted (p = 0.028; p = 0.0414, respectively). In the placebo group, the improvement of QOL in Q1, Q2, psychological, somatic, and social factors were also noted; however, the differences were not significant compared to baseline. Furthermore, statistically significant differences between both groups were not observed (p > 0.05); therefore, it is not certain if the improvement of QOL in Lp299v is associated with the administration of probiotic or it is the results of EN. This study only indicated that Lp299v was not inferior to placebo in changing QOL in cancer patients receiving HEN.
The present study has some limitations. The most important one is that this trial was conducted in a single centre with small sample size; moreover, the group was non-homogenous. We planned to recruit 40 participants as it was previously declared in ClinicalTrials.gov. However, eventually we recruited 35 patients and completed the current study in ClinicalTrials.gov regarding this number of participants. It is difficult and takes a lot of time to include a larger number of participants especially with the same type of cancer for 4 week treatment period, among others due to receive consent agreement and high mortality of cancer patients qualified for HEN. Therefore, there is a need to create a multi-centre trial with larger sample size. A noticeable fact is that the majority of participants from the study were patients with advanced incurable cancer on palliative treatment. Improvement of nutritional status in this group is generally difficult or impossible to achieve. The main goal of nutritional treatment in this stage of the disease is to positively influence the quality of life.
Direction for future studies
This study showed possible directions for future investigations. Targeting a specific homogenous group of patients may bring more conclusive results. In our opinion individuals with early stages of cancer and good nutritional status/mild malnutrition may benefit more from probiotic intervention. Identification of microbiota changes will possibly enable researchers to determine the desired intervention method and study group.