Table 2.

Characteristics and main findings of the included clinical studies

Author, year, country	Study type	Study group						Control group			Measured outcomes	Key results
		Age	Sex	Sample size	Type of cancer treatment	Strain and vehicle	Dose, CFU/g	Age	Sample Size	Interventions
(Christian, Suharsini et al. 2020), Indonesia [14]	Clinical experimental study	Children	-	11	Chemotherapy for leukemia (methotrexate and cytarabine)	Probiotics dissolved in a mouthwash (Probiotics contain mostly Lactobacillus species and Lactobacillus casei). Patients had to gargle for 1 min with the probiotic twice/day for 7 days. Patients continue gargling for 14 days.	-	Compared results to other studies	Compared results to other studies	Compared results to other studies	OAG	(1) There was a decrease in the OAG score 7 and 14 days after gargling with probiotics.
(De Sanctis, Belgioia et al. 2019), Italy [15]	Multicentric, phase III, open-label, randomized controlled trial	Mean age: 58,4 (34–74)	26 males and 6 females	32	IMRT + Cisplatin-based chemotherapy + cetuximab. Neo-adjuvant chemotherapy (docetaxel, cisplatin, and 5-FU) every 21 days for patients with nasopharyngeal cancer.	Lactobacillus brevis CD2 lozenges are to be dissolved in the mouth and then swallowed.	2 × 109 CFU/ml, 6 times/day, every 2-3 h, from the first day of RT to 1 week after the end of treatment	Mean age: 60 years	36	Bicarbonate mouthwash, 3x per day	CTCAE 4,0 for OM and QOL questionnaires	(1) There was no difference in the incidence of severe OM between intervention and control groups during RT. (2) No benefit of the use of L. brevis CD2, compared to the control arm, in reducing the incidence of severe OM, significant improvement of QOL, or acute toxicities such as weight loss, pain, and dysphagia.
(Sharma, Rath et al. 2012), India [17]	A randomized, double-blind, single-center, placebo-controlled study	Mean age: 52,35+/-9,43	94 males and 7 females	93	HNSCC - radical radiotherapy at a dose of 70 Gy in 35 fractions over 7 weeks by linear accelerator + chemotherapy of cisplatin 40 mg/m^2 weekly for 7 doses	Lactobacillus brevis CD2 lozenges are to be dissolved in the mouth and then swallowed.	2 × 109CFU/ml, 6 times/day, every 2-3 h, from the first day of CRT to 1 week after the end of treatment	Mean age: 50,09+/- 10,04	95	Placebo lozenges: a mixture of sugars and salts used as excipients in the active formulation	NCI CTC version 2.0 + QOL assessed using the FACT-HN questionnaire, version4	(1) No statistically significant improvement in QOL in the L. brevis CD2 arm compared to the placebo. (2) No significant adverse events attributed to the study product or placebo were identified. (3) The proportion of patients with grade III or IV mucositis was lower in the L. brevis arm (52%) than in the placebo arm (77%). (4) The proportions of patients with grade I and II mucositis were similar (19% versus 15%). (5) Study arm had considerably fewer individuals needing analgesics for mucositis-related discomfort.
(Sharma, Tilak et al. 2016), India [16]	Single-arm, single-center, phase II clinical study	Mean age: 29 years (10–70)	19 males and 12 females	31	High dose of chemotherapy + HSCT	Lactobacillus brevis CD2 lozenges to be dissolved in the mouth.	> 2 × 109 viable cells of L. brevis CD2, four to six lozenges per day (mean: 3), one lozenge to be taken every 2 to 3 h, beginning from 4 to 7 days before initiation of chemotherapy and continuing until resolution of OM until the 24th day after the end of treatment	Compared results to other studies	Compared results to other studies	Compared results to other studies	NCI-CTCAE scale.	(1) Only 19.4% of patients experienced severe OM (grades 3 and 4) (2) Median period for mucositis development and resolution was 6 days and 8 days, respectively. (3) L. brevis appears to be both safe and effective in avoiding OM.
(Topuz, Derin et al. 2008), Turkey [18]	Randomized, prospective, observational study	Mean age: 51 years (19–75)	12 males and 5 females	17	5-FU-based CT protocol	Oral lavage with kefir, and ingestion	Oral lavage (250 ml) with kefir to be swallowed after gargling. To be repeated on the first 5 days of each CT cycle, twice a day after meals.	58 (34–72)	20	Oral lavage with 0.09% NaCl twice a day on the first 5 days of each CT cycle	NCI- CTCAE scale and Oral Assessment Guide.	(1) Kefir had no significant influence on serum levels of inflammatory cytokines and no anti-mucositis role. (2) Kefir only inhibited Staphylococcus epidermidis.
(Mirza et al.; 2022), India [19]	Randomized, double-blind, placebo-controlled, parallel study	51 (19–75)	22 males and 1 female	23	Thirty-eight patients underwent definitive surgical resection before adjuvant RT. Eight patients received IMRT with concurrent chemotherapy with weekly cisplatin (40 mg/m2)	Oral suspension of Bacillus clausii UBBC07 containing 2 billion spores	5 ml (2 billion spores) 2x/ day, for 30 days or until completion of total fractions of radiation	31–60	23	Standard treatment (Benzidine hydrochloride mouth rinse along with baking soda) and 5 ml of distilled water twice daily	OM was assessed using the CTCAE scale. (1–4)	(1) Arm study had a shorter duration of remission and a smaller proportion of patients with high-grade OM (grade II and up). (2) Arm study had no RT-related side effects, such as diarrhea. (3) Findings suggest that radiotherapy may be complemented with probiotics to alleviate RIOM symptoms.

OM: Oral mucositis, CT: Chemotherapy, 5-FU: 5-Fluorouracil; RT: Radiotherapy, IMRT: Intensity modulated radiation therapy; HSCT: Hematopoietic stem cell transplantation; OAG: Oral Assessment Guide, CFU: colony-forming unit, CTCAE: Common Terminology Criteria for Adverse Events, NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events, RIOM: Radiation-induced oral mucositis, QOL: Quality of Live