Oral compound probiotic supplements can improve the quality of life for patients with lung cancer during chemotherapy: A randomized placebo‐controlled study

Abstract Background Chemotherapy is an important approach for lung cancer patients. The study was designed to evaluate the feasibility of the compound probiotic supplements in improving the quality of life for lung cancer patients undergoing chemotherapy. Methods This randomized, double‐blind, placebo‐controlled trial enrolled chemotherapy‐naive patients with lung cancer who were scheduled to receive platinum‐based doublet chemotherapy. All eligible patients were randomly administered (1:1) compound probiotic supplements (group BP‐1) or placebo (group C) for two chemotherapy cycles. The EORTC QLQ C30 questionnaire scores were evaluated before the first, second, and third cycles of chemotherapy. The primary endpoint was the difference in the EROTC QLQ C30 questionnaire score between the two groups after two cycles of chemotherapy. Results A total of 110 patients were recruited from March 2021 to January 2022. After undergoing two cycles of chemotherapy, group BP‐1 were significantly better in various dimensions of the overall quality of life, role function, nausea and vomiting, appetite loss, constipation, and diarrhea relative to group C (76.90 ± 18.31 vs. 58.89 ± 17.17; 93.33 ± 11.58 vs. 85.93 ± 15.06; 0.00 ± 0.00 vs. 27.04 ± 29.15; 6.67 ± 13.53 vs. 22.22 ± 18.80; 0.95 ± 5.63 vs. 28.15 ± 22.42; 2.86 ± 9.47 vs. 15.56 ± 16.82; p < 0.05, respectively). The incidence of nausea and vomiting, appetite loss, constipation, and diarrhea in group BP‐1 was significantly lower than in group C (0% vs. 71.43%, 16.67% vs. 57.14%, 2.38% vs. 63.27%, and 7.14% vs. 42.86%, respectively, p < 0.001). Conclusions Compound probiotic supplements can improve the quality of life and relieve chemotherapy‐related gastrointestinal side effects for lung cancer patients receiving platinum‐based doublet chemotherapy. (Chinese Clinical Trial Registry: ChiCTR1800019269).


INTRODUCTION
Despite significant improvements in the realm of anticancer strategies, whatever chemotherapy is administered as a monotherapy or in combination with other treatment paradigms encompassing surgery, radiotherapy, immune checkpoint inhibitors (ICIs), antiangiogenesis agents, targeted therapies, and beyond, it remains an important treatment strategy for almost all cancers, especially lung cancer, the most prevalent and fatal malignant tumor in the population. 1,2latinum-based doublet chemotherapy occupies an important role in the management of lung cancer; however, there are treatment-associated side effects which include nausea and vomiting, fatigue, appetite loss, pain, constipation, diarrhea, and many other debilitating symptoms that may deteriorate the quality of life for patients undergoing chemotherapy, and even necessitate dose reduction or discontinuation. 3,4hemotherapy can also damage the gastrointestinal epithelial cells and result in a disorder of the gut microbiome. 5,6ut microbiota has been proven to protect the intestinal mucosa, prevent intestinal inflammation, and build the immune ecology of the whole body. 7,8][13][14] Many strategies for controlling chemotherapy-related adverse events have been applied in clinical practice during the past decades, but the management situation is not optimistic in the real world. 3,15,16Emerging evidence favors the strategy of gut microbiota regulation for ameliorating chemotherapyrelated adverse events. 179][20][21][22][23][24][25] Nevertheless, whether administering compound probiotics can relieve chemotherapy-related adverse events for lung patients undergoing platinum-based doublet chemotherapy is rarely reported.This study attempted to determine whether oral compound probiotic supplements can reduce chemotherapy-related adverse effects and improve lung cancer patients quality of life during chemotherapy.

METHODS
This prospective, randomized, placebo-controlled, multicenter clinical study was conducted at three major cancer centers in Sichuan province, China:

Patients
This study intended to screen and enroll chemotherapy-naive patients with lung cancer who were scheduled to receive platinum-based doublet chemotherapy.The quality of life score of lung cancer patients during chemotherapy was around 60 (Figure 1).It was expected that it could be improved to 70 by using a compound probiotic preparation, taking the test level α as 0.05, assuming that the number of cases in both groups was equal, the minimum sample size to be included in each group was n1 = n2 = 49, N = 98, considering 10% of patients were excluded, the final number of cases would be 110.
Patients who met all of the following criteria were included: (1) pathologically confirmed with lung cancer (including non-small cell lung cancer and small cell lung cancer); (2) chemotherapy-naive; (3) aged between 18 and 75 years old; (4) Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2; (5) receiving chemotherapy for the first time with a regimen of cisplatin/carboplatin (AUC ≥5) in combination with one of these following agents: paclitaxel, docetaxel, gemcitabine, vinorebine, pemetrexed, etoposide, and who were supposed to receive two or more cycles of chemotherapy.
The main exclusion criteria were as follows: (1) Patients who received recent (within 2 weeks before chemotherapy) antibiotic therapy or proton pump inhibitor therapy, (2) patients who had recently (within 2 weeks before chemotherapy) taken some probiotic preparations, (3) patients with chronic gastrointestinal diseases or gastrointestinal metastatic tumor, (4) patients with severe systemic metabolic diseases or immune system diseases.
Based on the computer-generated program, enrolled patients were randomly assigned (1:1) to either the compound probiotic supplements group (group BP-1) or the placebo group (group C).A total of 110 random identification numbers were created by the computer before patients enrolled.Each enrolled patient was given an identification number based on the enrolment order and assigned to the corresponding group based on the identification number.The process mentioned above was performed by the Cancer Psychology and Health Management Committee of the Sichuan Cancer Society and was double-blind for both subjects and researchers.

Treatment
The enrolled patients were administered the platinum-based doublet chemotherapy regimen recommended by NCCN/ CSCO guidelines. 26he oral compound probiotic supplements (Hua Wei Yi probiotic solid drink, Yiga Bio-technology Chengdu Co., LTD, Chengdu, China) contained oligofructose (added at >93.69%), Bifidobacterium lactis Bi-07, Lactobacillus acidophilus NCFM, Lactobacillus rhamnosus HN001, Bifidobacterium lactis HN019.It was packaged in an aluminumplastic film bag and a maltodextrin-based placebo with the same appearance and taste.All compound probiotics/ placebos in this study were received from Yiga Biotechnology Chengdu Co., Ltd (via the Cancer Psychology and Health Management Committee of the Sichuan Cancer Society.The corresponding compound probiotic supplement/placebo with an identification number was assigned when a patient was enrolled.The Cancer Psychology and Health Management Committee of the Sichuan Cancer Society kept the assignment information list and was responsible for compound probiotic supplement/placebo distribution.The enrolled patients were given compound probiotic supplements/placebos at the beginning of the first cycle of chemotherapy, one sachet (2 g) dissolved in cold water or indoor temperature twice a day until the start of the third chemotherapy cycle.

Follow-up and data collection
All enrolled patients were evaluated for two chemotherapy cycles.The EORTC QLQ C30 questionnaire was completed independently by the enrolled patients prior to the first, second, and third cycles of chemotherapy.The scale consisted of 30 items, including five functional dimensions (physical function, role function, cognitive function, emotional function, and social function), nine symptom dimensions (fatigue, pain, nausea and vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties), and one dimension of overall quality of life. 27For the functional and overall quality of life dimensions, higher scores indicated better functional status and quality of life.In contrast, for the symptom dimensions, higher scores indicated more severe symptoms or problems.
The National Cancer Institute Common Toxicity Criteria (version 4.0) was used for the evaluation of adverse events.

Statistical analysis
The primary endpoint was the difference in the EROTC QLQ C30 questionnaire score between the two groups after two cycles of chemotherapy.For qualitative data, we used the chi-square test to determine whether there was a difference between groups BP-1 and C. The Mann-Whitney U or independent-sample t-test were used to compare the differences for quantitative data.The above statistical analysis was performed with SPSS version 27 software.Two-sided p-values < 0.05 were determined to be statistically significant.

Patient characteristics
From March 2021 to January 2022, 110 patients were enrolled, of whom one patient withdrew their informed consent and 18 patients were excluded due to protocol violation.A total of 91 patients were included in the final statistics.No significant differences were observed between the two groups at baseline (Table 1).

EORTC QLQ C30 questionnaire analysis
No significant difference was observed in the scores of the EORTC QLQ C30 questionnaire at baseline between the two groups (Table 2).
After 2 cycles of the study treatment, there was a significant difference in the dimensions, including overall quality of life (76.90± 18.31 vs. 58.89± 17.17, p < 0.001), role    2b).

Adverse events
No grade>3 adverse events were observed.There were no differences in adverse reactions between the two groups, except for the incidence of gastrointestinal reactions.In particular, the incidence of nausea and vomiting, constipation, anorexia, and diarrhea were lower in group BP-1 than in group C (Table 3).

DISCUSSION
Our study demonstrated that compound probiotic supplements can improve the quality of life and relieve platinumbased doublet chemotherapy-induced gastrointestinal adverse reactions for lung cancer patients undergoing chemotherapy.Previous clinical studies have also indicated that probiotics may ameliorate chemotherapy-induced adverse effects.Jiang et al. found that a probiotic combination (Bifidobacterium longum, Lactobacillus lactis, and Enterococcus faecium) can ameliorate the severity of oral mucositis via gut microbiota modulation for nasopharyngeal carcinoma patients who were undergoing concurrent radiochemotherapy. 28Probiotic combinations containing Bifidobacterium infants, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus have also been shown to be effective in attenuating chemotherapy-related gastrointestinal complications, especially diarrhea for colorectal cancer patients who were undergoing postoperative chemotherapy. 22As for lung cancer patients receiving platinum-based doublet chemotherapy, Clostridium butyricum can relieve chemotherapyrelated diarrhea. 25However, clinical studies exploring the usage of probiotics to mitigate chemotherapy-related adverse effects have predominantly concentrated on colorectal cancer and head and neck carcinoma, with fewer studies targeting lung cancer patients.In addition, there has been limited exploration regarding whether combination probiotic preparations containing Lactobacillus and Bifidobacterium can improve chemotherapy-related adverse effects for lung cancer patients.Our study provides preliminary evidence favoring the potential benefits of compound probiotic supplements to ameliorate chemotherapy-related adverse effects and the possibility of compound probiotic clinical application in managing chemotherapy-related complications among lung cancer patients.It is our inaugural endeavor to improve the quality of life for lung cancer patients who are undergoing chemotherapy through compound probiotic supplements.In this report, after two cycles of compound probiotic supplement/placebo treatment along with platinum-based doublet chemotherapy, a significant difference in some questionnaire dimensions was shown between the two groups.Most of all, the overall quality of life score in group BP-1 was significantly better than that in group C, and so was the score of role A randomized controlled trial reported a similar situation: the quality of life analysis of KEYNOTE-024 showed significantly higher scores in the QLQ-30 questionnaire for nausea and vomiting, constipation, and diarrhea in the chemotherapy group. 29The symptom control and quality of life investigation conducted in the LUX-Lung 3 trial performed the QLQ-30 questionnaire, revealing that 63% of patients in the chemotherapy group experienced nausea and vomiting, and 24% of patients experienced diarrhea following pemetrexed plus cisplatin treatment. 30Our study observed that the prevalence of nausea and vomiting in group C was 63.27% and 71.43% before the second and third cycle of chemotherapy, respectively; the incidence of diarrhea was 18.37% and 42.86%, respectively, which were close to the findings from the LUX-Lung 3 trial.Meanwhile, the incidence and the QLQ-30 questionnaire scores of diarrhea and vomiting in the BP-1 group were lower than those reported in the LUX-Lung 3 trial.These findings indicate that the compound probiotics supplements can relieve gastrointestinal side effects; for example, diarrhea and vomiting, thereby maintaining the patient's quality of life during chemotherapy.How do the probiotics work on improving the quality of life in patients receiving chemotherapy?
Chemotherapeutic agents can disturb the composition and diversity of the gut microbiota, correlated with adverse effects such as diarrhea, appetite loss, etc. 5,6,31 Considering the close connection between the composition of gut microbiota and short-chain fatty acids (SCFAs) production, 32 it is plausible to hypothesize that chemotherapy-related gastrointestinal reactions may be attributed to a decline in SCFA levels resulting from an imbalance in gut microbiota postchemotherapy.SCFAs have been demonstrated to attenuate chemotherapy-related toxicities due to their antiinflammatory, antioxidant, and protective characteristics. 32CFAs can also be against chemotherapy-induced intestinal injury via immunoregulation, promoting crypt cell proliferation and maintaining epithelial integrity. 32,33In addition, postoperative chemotherapy may lead to a decline in gut phylum Firmicutes levels for colorectal cancer patients, 22 which are known to be an important source of SCFAs. 34ifidobacterium and Lactobacillus are SCFA-producing microbiota; supplementation with compound probiotics can potentially reduce chemotherapy-related gastrointestinal adverse events for lung cancer patients by restoring SCFA levels and thus improving quality of life.Our aim is to validate this in future studies.
It is a pity that the sample size of this study was limited after 19 patients were excluded from the final statistical analysis.Further exploration of the variation of gut microbiota and SCFA levels are needed to elucidate the potential mechanisms of compound probiotic supplements to ameliorate chemotherapy-related adverse effects.In addition, many patients with early-stage lung cancer were included in our study, and our future studies will be focused on patients with advanced lung cancer.Our study observed that compound probiotic supplements could effectively alleviate gastrointestinal adverse events.We still need to explore whether compound probiotic supplements can improve other chemotherapyrelated adverse reactions and improve the quality of life of cancer patients in future studies.Probiotic agents have been reported to provide a survival benefit for lung cancer patients treated with ICIs. 35Our study focused mainly on the management of chemotherapy-related adverse effects and neglected the observation of treatment efficacy, which will be further explored in a subsequent study.However, this study is the first step in evaluating compound probiotic supplement intervention in improving the quality of life and relieving the symptoms of patients suffering from the adverse effects of chemotherapy.We have found a positive trend from the current study.We also plan further clinical trials to provide more robust evidence to confirm the advantages of compound probiotic supplements to lung cancer patients undergoing chemotherapy.
In conclusion, oral compound probiotic supplements can improve the quality of life and relieve chemotherapyrelated gastrointestinal adverse events for lung cancer patients receiving platinum-based chemotherapy.

F I G U R E 2
The prevalence of chemotherapy-related gastrointestinal reactions between group BP-1 and group C. (a) The incidence of chemotherapyrelated gastrointestinal reactions during the first cycle of chemotherapy.(b) The incidence of chemotherapy-related gastrointestinal reactions during the second cycle of chemotherapy; *p < 0.05; **p < 0.01; ***p < 0.001.
Thoracic Oncology Ward, West China Hospital, Sichuan University; Cancer Center, No.7 People's Hospital of Chengdu; Cancer Center, People's Hospital of Sichuan Province.The study was approved by the Ethics Committee of the West China Hospital of Sichuan University and conformed to the Declaration of Helsinki.The study was registered in the Chinese Clinical Trial Registry (registration no.: ChiCTR1800019269).All eligible patients provided written informed consent.