Prevention of Febrile Neutropenia by Synbiotics in Pediatric Cancer Patients

Febrile neutropenia (FN) is a major life-threatening treatment complication in cancer patients undergoing intensive chemotherapy. Endogenous flora is considered to be one of the main sources of infections during neutropenia. Competitive inhibition of gut mucosal colonization by pathogenic microorganisms using synbiotics could represent one of the potential options for its prevention. Synbiotics represent combination of two components: probiotics and prebiotics. Probiotics are live microorganisms, which in form of drugs or food supplements administered at a sufficient dose help to maintain health beneficial microbial balance in the digestive tract of a human or other host. Prebiotics are food ingredients nondigestible for our digestive enzymes, but can be fermented by bacteria in our bowel and this way selectively stimulate growth or activity of specific saccharolytic bacterial strains. These changes in composition of our microflora may bring benefits on host well-being and health. Based on the results of human and animal studies, probiotics probably can not only decrease the level of gut colonisation with pathogenic bacteria, but may also lead to reduction in the duration of neutropenia, accelerate the restitution of the intestinal mucosa and boost immunity. Despite a significant number of studies on probiotics still only little evidence of their safety especially in immunocompromised patients is available.

To help find new options for increasing quality of healthcare for children cancer patients and also to evaluate safety of this new approach investigators designed double-blinded placebo controled multicenter study aimed to decrease the number of febrile episodes using prevention with synbiotic.

Febrile neutropenia (FN) is a major complication in cancer patients undergoing intensive chemotherapy. Endogenous flora is considered to be one of the main sources of infections in neutropenic patients. The first step in infection process is colonization of the intestine by pathogenic bacteria with their subsequent translocation through the intestinal mucosa and systemic dissemination.

The alterations of the intestinal flora occurs due to chemotherapy and also due to the use of broad spectrum antibiotics, which suppresses anaerobic growth of the normal gut flora leading to a damage of colonization resistance. Competitive inhibition of gut mucosal colonization by pathogenic micro-organisms using synbiotics could represent one of the potential options for the prevention of febrile neutropenia in cancer patients. Compared with the existing selective bowel decontamination with quinolones and/or trimethoprim-sulfamethoxazole, investigators may expect also reduction of the incidence of fungal and Gram-positive infections due to changes in the intestinal microflora. Based on the results of animal studies, probiotics could probably also lead to a reduction in the duration of neutropenia and boost immunity.

Synbiotics represent combination of two components: probiotics and prebiotics. Probiotics are live microorganisms, which in form of drugs or food supplements administered at a sufficient dose help to maintain health beneficial microbial balance in the digestive tract of a human or other host. Prebiotics are food ingredients nondigestible for our digestive enzymes, but can be fermented by bacteria in our bowel and this way selectively stimulate growth or activity of specific saccharolytic bacterial strains.

Lactic acid bacteria are currently widely used in prevention and treatment of certain infectious diseases. They stimulate the immune system, compete for substrate with pathogenic bacteria, produce bacteriocins, competitively inhibit bacterial adhesion sites, increase the transepithelial resistance and bind some mutagens.

Current evidence supporting probiotic use as adjunctive therapy to anticancer treatment is limited, especially in cancer patients treated with chemotherapy. Some of the reports support their beneficial effects on certain aspects of toxicity related to chemotherapy and radiation therapy; however, large properly designed clinical trials are needed to assess their real position as a part of anticancer treatment.

Eleven studies in cancer patients were included in meta-analysis to assess efficacy of probiotics. Results show that probiotics may reduce the severity and frequency of diarrhoea in patients with cancer and may reduce the requirement for anti-diarrhoeal medication, but still more studies are needed to assess the true effect. The importance of probiotics in the treatment of acute diarrhea is supported by meta-analysis of 34 randomized placebo-controlled studies, which showed significant reduction in diarrhea incidence with better effect especially in the pediatric group. Most of these studies were performed with the probiotic strain Lactobacillus rhamnosus GG (LGG). The duration of rotavirus diarrhea in children and diarrhea in immunocompromised HIV-positive patients was significantly shortened after administration of certain strains of Lactobacilli resp. Saccharomyces boulardii.

Investigators can find only anecdotal reports about use of probiotics in patients with neutropenia. In experimental models with cyclophosphamide-treated mice preventive treatment with immunomodulatory lactobacilli was successfully used to protect against myelosuppression and immunosuppression. Lactobacilli were able to induce an early recovery of neutrophils in blood, improve phagocytic cells recruitment to infectious sites and increase the resistance against the opportunistic pathogen C. albicans. In another similar study administration of heat-inactivated strain of Enterococcus faecalis shortened the duration of cyclophosphamide-induced neutropenia and speeded up the restitution of neutrophil count. The important feature of the lactic acid bacteria is ability to produce fatty acids with short chain, which is an important metabolite for colonocytes and this way they may participate in the faster restitution of the mucosa after chemotherapy.

Probiotics fall into the category of organisms classified as "generally regarded as safe". The safety concerns with probiotic administration in cancer patients are related mainly to risk of infection caused by probiotic bacteria and transfer of antibiotics resistance.

Many probiotics strains are naturally resistant to antibiotics, but majority of this resistance is intrinsic (chromosomally encoded) and therefore nontransmissible. This could be a danger, when probiotics become infectious agents, on the other hand probiotic strains with intrinsically antibiotic-resistance may benefit patients, whose normal intestinal microflora has become greatly reduced or unbalanced due to the administration of various antimicrobial agents. For some strains (e.g. LGG) the plasmid-free status was proven, but at the same time it was shown, that some strains may carry potentially transmissible plasmid-encoded antibiotic resistance genes, which could lead to the formation of new antibiotic-resistant pathogens. Therefore, one of the key requirement for probiotic strains is that they should not carry transmissible antibiotic resistance genes.

Despite the fact, that the incidence of infections caused by lactic acid bacteria is extremely low, there exists certain risk, that they can become pathogenic. In case reports probiotics are mentioned as causing local infections such as chest infections, digestive tract infections, urinary tract infections, and meningitis. Though reported lactobacilli bacteremia are very unusual and rare in the pediatric population. They were naturally more often observed in immunocompromised patients, such as in patients with bone marrow transplantation or in patients with AIDS, which also demonstrates low-virulency of these strains. Moreover, clinical isolates of L. rhamnosus captured in these cases had some significant phenotypical differences in one or more properties associated with virulence compared to those, which are used as probiotic strains. Concerns of iatrogenic infection are one of the main reasons for limited experience with administration of probiotics in granulocytopenic patients. In addition, due to chemotherapy it comes not only to neutropenia but also to local affection of gut mucosa and therefore hypothetically arise the possibility of bacterial translocation. This phenomenon is caused by a defective intestinal barrier, immunosuppression and also gut prematurity. It was described as the passage of viable indigenous bacteria from the gastrointestinal tract to extraintestinal sites and may result in the transfer of bacteria to other organs, thereby potentially causing bacteremia, septicemia, and multiple organ failure. However, evidence from animal model studies suggests that there is actually a reduction in the translocation of other bacteria when probiotics are given, as opposed to the transmigration of probiotic bacteria into the bloodstream.

The concerns around bacteraemia/fungaemia or blood culture growth are significant in cancer patients, but this risk needs to be considered alongside any potential benefit. Systematic review including 17 studies with cancer patients identified only five such case reports of the 756 cases described consuming probiotics. Moreover such cases were noted also in patients not known to be consuming probiotics. In addition, there is no evidence from population based studies of any increased risk of bacteremia or endocarditis due to probiotics and their incidence still remained extremely low despite current widespread use of probiotic. Even findings of some small studies in groups of specific immunocompromised patients (e.g., patients with HIV infection) support the safety of particular probiotic strains.

One of the most recent systematic reviews identified 11,977 publications, of which 622 studies (included 24,615 participants using a probiotics) were included in the review. Based on reported adverse events, randomized controlled trials showed no statistically significantly increased relative risk of the over all number of experienced adverse events (Relative risk (RR) = 1.00; 95% Confidence interval (CI): 0.93, 1.07, p = 0.999); gastrointestinal; infections; or other adverse events, including serious adverse events (RR = 1.06; 95% CI: 0.97, 1.16; p = 0.201), associated with short-term probiotic use compared to control group participants; long-term effects are largely unknown. Case studies suggested that participants with compromised health are most likely to experience adverse events associated with probiotics. However, randomized control trials (RCTs) in medium-risk and critically ill participants did not report a statistically significantly increased risk of adverse events compared to control group participants. In conclusion authors of this analysis state, that the available evidence in RCTs does not indicate an increased risk; however, rare adverse events are difficult to assess. However, despite the substantial number of publications, the current literature is not well equipped to answer questions on the safety of probiotic interventions with confidence, especially in group of critically ill patients. Nevertheless, in specific probiotics group, as lactobacilli and bifidobacteria, some authors report that current evidence suggests, that the risk of infection with these probiotic groups is similar to that of infection with commensal strains and though consumption of such products presents a negligible risk to consumers, including immunocompromised hosts. Moreover, this potential risk needs to be always considered alongside any potential benefit. Despite limited data, it seems that probiotic bacteria as live microorganisms could be safely administered even in setting of neutropenia. Future research should focus on selection of most effective and safe probiotic strains and their combinations, and/or administration of probiotics with prebiotics to increase their success in maintaining colonization resistance and in prevention of the adverse events of anticancer treatment.

In a comparable study phase I. probiotic strain was applied to 11 cancer patients to evaluate their benefits and safety. Subsequently, 14 patients with acute myeloid leukemia treated with chemotherapy were enrolled in phase II. None of reported febrile episodes was induced by probiotic strain and no severe adverse events were recorded. Despite limited number of patients, this was the first direct evidence of the safety of probiotics in patients receiving chemotherapy.

One of the causes of failed efficacy of probiotics in the prevention of febrile neutropenia may be the presence of other entries of infection such as central venous catheters. Also, the efficiency of colonization, mucosal damage due to chemotherapy dose and specific probiotic strain may be the causes of this. Another reason may be the inability of one probiotic strain to compensate all changes in the intestinal microflora induced by chemotherapy. One way to solve this problem may be use of combination of multiple probiotic strains. Appropriate selection of strains is required, cause they must not behave antagonistically to each other. Other option is to use combination of prebiotics with probiotics. This can lead not only to acceleration of gut colonization by probiotics, but also to stimulation of endogenous flora growth, which may enhance colonization resistance at another level.

Eligibility Criteria:
Inclusion Criteria:

* newly diagnosed cancer disease prior to initiation of chemotherapy
* Eastern Cooperative Oncology Group performance status = 0-1
* informed consent has to be given by patients, respectively their legal representatives
* age between 6 months to 19 years
* must be afebrile and no other signs of infection at least 24 hours before starting of prophylaxis
* must not taking other probiotic or prebiotic preparations or discontinued their use more than 14 days ago

Exclusion Criteria:

* impossibility of oral intake
* receiving any other type of experimental prophylaxis
* estimated survival time of less than 4 weeks
* allogeneic or autologous bone marrow transplantation
* inflammatory bowel disease