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ICT XXX10. 1177/1534735418794885Integrative Cancer Therapies Thomsen and Vitetta

Review Article

Integrative Cancer Therapies

Adjunctive Treatments for the 1–21

© The Author(s) 2018
Article reuse guidelines:
Prevention of Chemotherapy- and sagepub.com/journals-permissions
DOI: 10.1177/1534735418794885
https://doi.org/10.1177/1534735418794885

Radiotherapy- Induced Mucositis journals.sagepub.com/home/ict

1 1,2
Michael Thomsen, MSc and Luis Vitetta, PhD

Abstra
ct
Background: Chemoradiotherapy-associated mucositis can manifest as pain, inflammation, dysphagia, diarrhea, weight
loss, rectal bleeding, and infection. Mucositis is a major dose-limiting side effect of chemotherapy, affecting nutritional
intake and oral and intestinal function. Despite several interventions being available, there is a need for safe and effective
preventative and treatment options for treatment-induced mucositis. The goals of this review are to discuss
interventions based on foods and natural products and present the research to date. Methods: A narrative literature
review identified 60 clinical studies examining various nutritional compounds and 20 examining probiotics. 9 studies on
probiotics for the prevention of diarrhea were also assessed on methodological quality and limitations identified.
Results: Several compounds have been posited as useful adjuvants for cancer treatment–related mucositis. Probiotics
demonstrate efficacy for the prevention and treatment of chemoradiotherapy-induced gastrointestinal toxicity without
significant side effects. Glutamine and activated charcoal were reported to reduce chemotherapy-induced diarrhea but
not radiation-induced intestinal mucositis. Honey has been reported to decrease treatment interruptions, weight loss, and
delays the onset of oral mucositis. Zinc, glutamine, and topical vitamin E were demonstrated efficacy for oral mucositis.
Conclusion: There is plausible clinical evidence for the administration of several adjunctive treatments for the
prevention and treatment of mucositis. Probiotics were reported to reduce the burden of intestinal mucositis and
treatment-induced diarrhea. Activated charcoal and glutamine are beneficial for chemotherapy-induced diarrhea, whereas
the administration of honey, zinc, and glutamine reduce the risk of developing oral mucositis during chemotherapy or
radiotherapy.

Keywor
ds
chemotherapy, radiotherapy, mucositis, diarrhea, probiotics, adjunctive compounds

Submitted September 11, 2017; revised July 4, 2018; accepted July 12, 2018

Introducti and serious reported side effect in the first 3 months

on
Chemotherapy- and radiotherapy-induced mucositis is a
significant burden for cancer patients (Table 1). Symptoms
of oral mucositis become apparent 5 to 10 days after che-
motherapy and may progress from erythema, cracking, and
1,2 1,3
inflammation to pain, bleeding, ulceration, and pain.
Pelvic radiotherapy is reported to induce changes in the
bowel habits of 90% of patients, with half of all patients
reporting that quality of life is significantly adversely
4
affected, and that serious complications can persist
4-6
decades post treatment cessation. Epidemiological
studies on can- cers of the head and neck report a
prevalence of oral muco- sitis of 80% for patients
undergoing radiotherapy and 40% of patients receiving
3 Sydney, New South Wales 2015, Australia.
chemotherapy. Moreover with high- dose chemotherapy,
mucositis can develop in 100% of bone marrow transplant
patients. Mucositis is the most frequent
follow- ing a transplant and is the most common condition
3
requiring systemic analgesics during cancer therapy. The
frequency of mucositis is also higher in patients receiving
continuous infusion therapy for breast and colon cancer.
7
Unlike oral mucositis, clinical data reflecting the long-
term effects of treatment-induced gastrointestinal mucosi-
tis are lacking. An important and debilitating symptom of
intestinal mucositis is diarrhea. Gastrointestinal mucositis
1
University of Sydney, Sydney, New South Wales, Australia
2
Medlab Clinical Ltd, Sydney, New South Wales, Australia
Corresponding
Author:
Luis Vitetta, Medlab Clinical Ltd, 66 McCauley Street, Alexandria,
Email: luis.vitetta@sydney.edu.au
 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-
NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction
and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages
(https://us.sagepub.com/en-us/nam/open-access-at-sage).
2 Integrative Cancer
Therapies
Table 1. Chemoradiotherapy-Induced Gastrointestinal Toxicities.

Intervention Pathophysiology Possible Symptoms

138-141
Radiotherapy Direct epithelial injury Mouth ulcers
Mucositis Pain
Loss of mitotic activity Anorexia
Acute inflammation Bloating dysphagia
Abscess formation Diarrhea
Swelling of vascular endothelial lining Lactose intolerance malabsorption
Tissue ischemia mucosal friability Nausea
Neovascularization progressive fibrosis Ulceration
Weight loss
IBS
ISBO
6,142-144
Irinotecan Cholinergically mediated diarrhea Rhinitis
Cytokine release Early-onset diarrhea
Altered motility Abdominal cramping
Villous blunting and crypt degeneration Malabsorption
TJ dysfunction Delayed-onset diarrhea
Changes to claudin-1 and occludin
Bacterial translocation
3 Integrative Cancer
Fluoropyrimidines Gastrointestinal mucositis Altered bowelTherapies
movement
8,145-
including 5-FU Villi shortening, increased crypt depth Diarrhea
149
Increased intestinal myeloperoxidase activity, reduced glutathione Lactose intolerance
(GSH) concentrations, and increased levels of
inflammatory mediators
Reduced expressions of occludin and claudin-1 and TJ dysfunction Malabsorption
SIBO
150,151
Paclitaxel Increase apoptosis of intestinal villi, increased intestinal Stomatitis
permeability, reduced white blood cell count, and induced
bacterial translocation
Vomiting
Diarrhea
Colitis
151,152
Oxaliplatin DNA denaturation and neuronal ablation Potentiation of 5-FU related GIT toxicities
Apoptosis of intestinal epithelial cells Anorexia
Inflammation Stomatitis
Bacterial translocation Nausea
Sepsis Emesis
Diarrhea/constipation
153
Lapatinib Increased jejunal crypt length, increased mitotic rate, and goblet cell Malabsorption
morphology
Altered bowel function
Diarrhea
154
Methotrexate Reduced claudin-1 and occludin expression and TJ dysfunction Inflammation
Increased proinflammatory cytokine production Sepsis
Neutropenia
Taxanes151 Ischemic colitis Nausea
Neutropenia Diarrhea
Mucosal edema Emesis
Hemorrhage Stomatitis
Inflammatory infiltrates Colitis
Ulceration Hepatitis

(continued)
Thomsen and Vitetta
3

Table 1. (continued)

Intervention Pathophysiology Possible Symptoms

Cisplatin, Decreased total surface area of villi Anorexia
151,155
carboplatin Reduced villus height and villus/crypt ratio Stomatitis
Decreased intestinal motility Nausea
Altered digestive and metabolic functions Emesis
Inflammatory infiltrates Diarrhea
Malabsorption
Anthracyclines151 Inflammation Stomatitis
Steatosis Ulceration
Anorexia
Diarrhea
Nausea
Emesis
Cytarabine, Necrotizing colitis Anorexia
gemcitabine151 Veno-occlusive disease Nausea
Emesis
Ulceration
Diarrhea

Abbreviations: IBS, irritable bowel syndrome; ISBO, intermittent small bowel obstruction; TJ, tight junctions; 5-FU, 5-fluorouracil; SIBO, small intestinal
overgrowth syndrome.

has been reported in 80% of patients treated with 5-fluoro-
8
uracil (5-FU). The frequency of chemotherapy-induced
diarrhea depends on the drug administered and the sched-
ule implemented. The highest rate of diarrhea has been
reported to occur with a weekly regimen of irinotecan and
5-FU bolus with 10% of patients going on to develop
grade
3 to 4 mucositis. Late-onset diarrhea may occur within a
week following higher dosages of irinotecan and after
approximately 2 weeks following a weekly administration
9 The inclusion criteria were any type of clinical trial
of lower doses. In stage III colorectal cancer (CRC), che-
motherapy with FOLFOX induced diarrhea in 56% of
patients, yet with FOLFIRI, the prevalence of diarrhea
increased to 89%. The risk of a first episode was highest
during the first cycle (35 %) and dropped to less than 10%
during subsequent cycles.
10
The frequency of treatment-induced gastrointestinal tox-
icity in CRC has been posited to likely increase with the
introduction of novel drugs and the use of more intense
combination regimens of polychemotherapy combined
6,10
with monoclonal antibodies. Targeted therapies,
including erlotinib, gefitinib, lapatinib, sorafenib, and
sunitinib, have been associated with a 2- to 8-fold
increased risk of all or high-grade diarrhea compared with
11
conventional chemo- therapy regimens.
Despite several interventions being available, including
cryotherapy and loperamide, for the control of oral
mucositis and diarrhea, respectively, there is a need to
further explore additional safe and effective preventative
and treatment options for treatment-induced mucositis and
related symptoms. The goal of this narrative review was to
present
an overview of the safety and efficacy reported for various
interventions posited to reduce the adverse effects of
antineo- plastic agents. The majority of clinical research has
focused on prevention or treatment of oral mucositis, while
intestinal toxicity has been less well reported.
Metho
ds
examin- ing the use of any oral or topical probiotic or
nutritional intervention with both the abstract and the
journal article written in English. All clinical trial designs
and methodol- ogy were included, namely, prevention as
well as treatment studies. The following databases were
used to retrieve jour- nal articles: PubMed, the Cochrane
Library, Science Direct, Scopus, Embase, and Google
Scholar, and searches were current up to November 2016.
Electronic databases were searched using the following
search string:
Probiotics OR Diet OR Food OR Nutrition OR
Micronutrients OR Vitamins OR Minerals OR Dietary
supplements OR Functional foods OR Honey AND
Chemotherapy AND Mucositis AND Chemotherapy
AND Diarrhea AND Radiotherapy AND Mucositis
AND Radiotherapy AND Diarrhea.
Examination of references in retrieved articles was also
conducted.
4 Integrative Cancer
Therapies
5 Integrative Cancer
Resul
ts
Fifty articles examining various nutritional compounds
were identified, 49 from PubMed and 1 from Embase.
13
Reports included 1 study on activated charcoal, 1 study
14
on β-glucan, 2 studies on multinutrient formulations,
2 studies on an amino acid–rich oral formulation,
study 19
with folic acid with B12, 5 studies on vitamin E,
24-40
intervention studies containing minerals, and 21 studies
41-61
with glutamine (Table 2). Moreover, 25 clinical trials
were identified examining honey alone or in combination
as a prophylaxis/intervention for oral mucositis (Table
62-87
3).
We also identified 19 probiotic studies (Table 4).
88-92,95-97,106
Nine placebo-controlled clinical trials
the prophylactic use of probiotic in intestinal mucositis
induced by chemotherapy, radiotherapy, or a combination
of both. Two trials did not include a comparator group.
Four studies examined the use of a probiotic in oral muco-
99,100,103,105
sitis, 3 studies were post-chemoradiotherapy
93,94,101
treatment trials, and 2 studies examined the febrile
102
incidence during chemotherapy.
Oral mucositis was most commonly assessed according
to the Radiation Therapy Oncology Group/European
Organization for Research and Treatment of Cancer objec-
tive grading system (RTOG/EORTC), the National Cancer
Institute Common Terminology Criteria for Adverse
Events (CTCAE), or the World Health Organization Oral
Mucositis Toxicity Scale. Intestinal mucositis was assessed
by changes in stool consistency, incidence and severity of
diarrhea, and the use of antidiarrheal medication. The most
frequently used assessment scales are the CTCAE diarrhea
grade and the Bristol stool charting system.
Bias and quality analysis were not performed as part of
this review, as several reviews have already reported on
bias and quality of studies for minerals, glutamine, honey,
and probiotics, the 4 types of interventions with sufficient
num- ber of trials to attempt conducting a systematic review
or meta-analysis. Although some studies had low bias, the
over- all assessment is that many studies have high bias and
most studies suffered from some methodological
107-112
weaknesses.
The systematic review and meta-analysis of 9 probiotic
trials for the prevention of chemoradiotherapy-induced
diarrhea found that while the trials were of generally good
method- ological quality, there were significant blinding
issues, and 1 study was published as a poster abstract only.
Ambiguous handling of incomplete outcome data and lack
of intention- to-treat analysis were noted as further bias
112
risks.
Reviewed
Interventions
Prophylactic activated charcoal has been shown to reduce
dose-limiting chemotherapy-induced diarrhea, thereby
optimizing irinotecan therapy, while reducing antidiarrheal
medication in an open-label, single-arm study. The study
involved 28 patients with advanced CRC receiving
2 Therapies
irinotecan 125 mg/m intravenously once a week for 4
weeks every 6 weeks. In cycle 1, patients received irinote-
can plus activated charcoal (5 mL aqueous solution
12 contain- ing 1000 mg activated charcoal in 25 mL of
water), given the evening before the irinotecan dose and
15,16 then 3 times daily for 48 hours after the dose. The use of
17,18 activated char- coal in the first cycle was associated
1
with a significant
12,20-23
17
reduction in the incidence and severity of diarrhea, reduced
the use of loperamide as a rescue medication, and was well
13
tolerated with excellent compliance (Table 2).
Beta-glucan is an immune-modulating polysaccharide
that was shown in a retrospective, controlled trial of 62
patients with CRC to prevent significant reductions in leu-
88-105
cocyte and neutrophil counts compared with chemotherapy
examined alone with a FOLFOX-4 regimen. The addition of β-glucan
was also associated with a lower incidence of oral
14
98,104 mucositis and diarrhea (Table 2).
Concurrent administration of folate and cobalamin
failed to reduce mucositis in a pilot study of 39 patients
with non– small cell lung cancer treated with pralatrexate.
Mucositis remained the dose-limiting toxicity of
19
pralatrexate treat- ment (Table 2).
A meta-analysis that assessed the effectiveness of oral
glutamine in radiotherapy-induced mucositis in head and
neck cancers reported that in 5 clinical studies (234
41,43,44,52,59
patients total), glutamine was shown to reduce
the risk and severity of radiotherapy-induced oral mucositis
compared with either placebo or no treatment (risk ratio
[RR] = 0.17,
107
95% confidence interval [CI] = 0.06-0.47). Oral gluta-
41,44,46,49,54-60
mine was also shown to be beneficial in 11 of
15 studies investigated in a systematic review investigating
the effects of glutamine for chemotherapy- or radiotherapy-
induced oral mucositis. Glutamine significantly reduced
the incidence of grade 2, 3, or 4 mucositis and/or reduced
weight loss as well as the duration, time of onset, and/or
108
maximum grade of mucositis. Four studies showed no
45,48,50,53
effect (Table 2).
A recent study found that 9 g glutamine in combination
with an elemental diet was associated with a significant
reduction in chemotherapy-induced oral mucositis in
esophageal cancer compared with no treatment or gluta-
mine alone. The incidence of grade 2 or higher of oral
mucositis was 60% in the control group, 70% in the gluta-
mine group, and 10% in the glutamine plus elemental diet
42
group. A further review of 9 randomized, controlled stud-
ies concluded that glutamine may reduce gastrointestinal
mucositis and diarrhea and improve nitrogen balance,
immune imbalance, and wound healing in chemotherapy-
113
induced toxicity (Table 2).
Glutamine has been shown to be a principal nutrient with
glucose supporting survival of mammalian cells and, unfa-
vorably, cancer cells. However, oral glutamine has been
reported to be unlikely to contribute significantly to tumor
114
growth, local invasion, and metastatic dissemination.
High baseline consumption of dietary glutamate has been
Table 2. Clinical Trials Investigating Nutrients for Oral and Intestinal Mucositis.
References Treatment Intervention Cancer Type Design (n = Subjects), Assessment Outcome

Oral mucositis
Karac et al14 Chemotherapy (FOLFOX-4) Beta-glucan 50 mg/day versus no CRC Retrospective, controlled (n = 62), Decreased incidence OM and diarrhea
treatment CTCAE
Casbarien et al15 Chemotherapy and radiotherapy Multinutrient formulation (Supportan) HNC Open-label study (n = 7), CTCAE OM none severe
Machon et al16 Chemotherapy and radiotherapy Multinutrient formulation (Oral Impact) HNC Prospective noncontrolled (n = 31), Decreased OM severity
 CTCAE
Harada et al17 Radiotherapy ± chemotherapy Amino acid–rich oral formulation OC Retrospective study (n = 74), CTCAE Decreased OM severity and increased Tx
(Elental) versus no treatment completion rates
Ogata et al18 5-FU-based chemotherapy Amino acid–rich oral formulation CRC Prospective pilot study (n = 22), Decreased OM severity (P = .0002)
(Elental) CTCAE
Azzoli et al19 Pralatrexate Folic acid IM/B12 oral NSCLC Nonrandomized, multicenter (n = NS decrease OM
39), CTCAE
12
Ghoreishi et al Cyclophosphamide-based Vitamin E 400 mg versus placebo ALL/AML/ RCT (n = 39), CTCAE NS decrease OM
conditioning regimen CML
Ferreira et al20 Radiotherapy Topical vitamin E, 400 mg versus placebo HNC RCT (n = 54), RTOG Decreased OM risk of 36%
21
Wadleigh et al 5-FU infusion/cisplatin or Topical vitamin E, 400 mg versus placebo HNC/OeC; RCT (n = 18), WHO OMAS Decreased OM (P < .05; vitamin E 60%
doxorubicin HCC/AML complete resolution)
22
El-Housseiny et al Chemotherapy Topical vitamin E 100 mg versus 40 mg/ OC Comparative randomized study Decreased OM severity (P < .05)
kg/daily IM (pediatric, n = 80), WHO OMAS
Khurana et al23 Chemotherapy Topically vitamin E compared with AL/NHL Single-blind, randomized (n = 72, Decreased OM severity (P < .05)
pycnogenol, glycerin, water pediatric), WHO OMAS with vitamin E
24
Büntzel et al Chemotherapy and radiotherapy Sodium selenite oral fluid 0.5 mg versus HNC RCT (n = 39), RTOG NS benefit
no treatment
Jahangard-Rafsanjani HDC HSCT conditioning regimen Selenium 200 µg versus placebo ALL/AML RCT (n = 64), WHO OMAS Decreased OM severity grade 3-4 (P < .05)
et al25
Watanabe et al
26
Chemotherapy and radiotherapy Zinc L-carnosine solution versus azulene HNC RCT (n = 31), CTCAE Decreased OM severity ⩾grade 2 (P < .05)
rinse
Lin et al27 Chemotherapy and radiotherapy Zinc chelate equiv 25 mg 2-4 times HNC RCT (n = 100), RTOG Decreased OM severity grade 3
daily versus placebo radiotherapy only
28
Lin et al Radiotherapy Zinc chelate equiv 25 mg 2-4 times NPC/OC RCT (n = 100), Kaplan–Meier survival Delayed development of severe OM in OC
daily
versus placebo method only
Ertekin et al29 Radiotherapy Zinc sulfate equiv 50 mg tid versus HNC RCT (n = 21), RTOG Decreased OM severity (P < .05)
placebo
Sangthawan et al
30
Radiotherapy Zinc sulfate equiv 50 mg oral syrup HNC RCT (n = 104), WHO OMAS NS benefit
versus placebo
Arbabi-kalati et al31 Chemotherapy Zinc sulfate eqiv. 50 mg tid versus HNC RCT (n = 50), WHO OMAS Decreased OM severity (P < .05)
placebo
Mehdipour et al32 Chemotherapy 0.2% zinc sulfate versus chlorhexidine AML Comparative randomized (n = 30), Decreased OM severity (P < .05)
gluconate mouthwashes Spijkervet scale
Mansouri et al33 HDC HSCT conditioning regimen Zinc sulfate equiv 50 mg bid versus HM RCT (n = 60), WHO OMAS NS benefit
placebo
Hayashi et al34 Radiotherapy or HDC HSCT Zinc sulfate/L-carnosine suspension or HSCT Comparative study (n = 66), CTCAE Decreased OM severity ⩾grade 2 (P < .05)
conditioning regimen lozenge and decreased pain (P < .01)

(continued)
5
Table 2. (continued)

References Treatment Intervention Cancer Type Design (n = Subjects), Assessment Outcome

6
35
Markiewicz et al Radiotherapy HDC HSCT Calcium phosphate mouth rinse versus AML/ALL NBCT (n = 40), WHO OMAS Decreased OM severity (P < .05) and
conditioning regimen topical mouth care with sage extract, decrease in pain NS
povidone-iodine, fluconazole, vitamin
A (10 g), and vitamin E (10 g) with or
without benzocaine (2.5 g) twice
daily
Lambrecht et al36 Chemotherapy and radiotherapy Calcium phosphate mouth rinse HNC RCT comparative (n = 58), CTCAE NS OM grade 3
(Caphosol) versus standard oral care
37
Raphael et al Chemotherapy or HSCT Calcium phosphate mouth rinse HM RCT (n = 34, pediatric), CTCAE NS benefit
conditioning regimen (Caphosol) versus standard oral care
38
Papas et al HDC HSCT conditioning regimen Calcium phosphate (Caphosol) versus ALL/AML/ RCT comparative (n = 58), NIDCR Decreased OM frequency/duration/severity
fluoride mouth rinse CML/HL/ (P < .05)
NHL/MM/
MS/BC/
OvC
39
Madan et al Radiotherapy 1% povidone-iodine versus 0.12% HNC RCT (n = 80), WHO OMAS Decreased OM severity scores (P < .05)
chlorhexidine, sodium bicarbonate,
plain water (control)
Vokurka et al40 HDC before PBSCT 1% povidone-iodine mouthwash versus HSCT RCT multicenter (n = 132), WHO NS benefit
saline OMAS
41
Tsujimoto et al Radiotherapy Glutamine 30 g, oral/day versus placebo HNC RCT (n = 40), CTCAE Decreased OM severity (P < .05)
Tanaka et al42 Radiotherapy Glutamine 9 g with or without elemental HNC RCT (n = 40), CTCAE Decreased OM severity (P < .05)
diet versus placebo
Huang et al43 Radiotherapy Glutamine 30 g, oral/day versus saline HNC RCT (n = 17), WHO OMAS NS benefit
Vidal-Casariego Radiotherapy Glutamine 30 g oral/day versus late or no HNC/Mel/ Retrospective cohort (n = 117), Decreased OM risk RR = −9.0% (95% CI =
et al44 treatment LC/OeC/ WHO OMAS −18.0% to −1.0%)
Lym
Jebb et al45 5-FU and folinic acid Glutamine 16 g oral/day versus placebo mCRC RCT (n = 28), WHO OMAS NS benefit OM or IM
Skubitz and Chemotherapy Glutamine 8 g oral/day KS Open trial (n = 14), CALGB Decreased OM severity (P < .05)
Anderson46
47 2
Anderson et al Chemotherapy Glutamine 4 g/m /dose/day versus Sar/NB RCT crossover study (pediatric n = Decreased OM duration/severity (P < .05)
placebo 24), patient questionnaire
48
Okuno et al 5-FU Glutamine 30 g oral/day versus placebo Not defined RCT (n = 134), assessed by physician NS benefit
Cockerham et al49 Paclitaxel and melphalan Glutamine 24 g oral/day mBC Retrospective analysis (n = 21), Decreased OM days/severity (P < .05)
CTCAE
Dickson et al50 HDC Glutamine 30 g oral/day versus placebo ALL/AL/ RCT (n = 58), BMT scale NS benefit OM and diarrhea
CML/MM/
NHL

(continued)
Table 2. (continued)

References Treatment Intervention Cancer Type Design (n = Subjects), Assessment Outcome

51
Daniele et al 5-FU and follinic acid Glutamine, 18 g oral/day versus placebo mCRC RCT (n = 70), CTCAE Decreased rescue meds (P < .05)
 Cerchietti et al52 Chemoradiotherapy L-Alanyl-L-glutamine, IV 300/400 mg/kg HNC RCT (n = 29), WHO OMAS Decreased OM severity (NS) and decreased
bw versus placebo pain (P < .05)
Li et al53 Chemotherapy Glutamine 30 g oral/day versus placebo BC RCT (n = 60), WHO OMAS NS benefit OM or diarrhea
54
Choi et al 5-FU/leucovorin Glutamine 10 g oral/day versus AST RCT (n = 51), CTCAE Decreased OM severity (P < .05)
supportive care
55
Peterson et al Anthracycline chemotherapy Glutamine, 7.5 g oral/day versus placebo BC RCT crossover (n = 326), WHO Decreased OM severity grade 3 (P < .05)
OMAS
Oesophagitis
57
Topkan et al Radiotherapy Glutamine 30 g oral/day versus no LC Retrospective (n = 63), RTOG Decreased grade 2-3 esophagitis (27.2%)
treatment
Topkan et al56 Chemotherapy and radiotherapy Glutamine 30 g oral/day versus no NSCLC RCT (n = 104), RTOG Decreased grade 3 esophagitis (P < .05)
treatment
Tutanc et al
58
Radiotherapy Glutamine 30 g oral/day versus no LC RCT (n = 46), RTOG Decreased grade 2-3 esophagitis (P < .05)
treatment

Chattopadhyay Radiotherapy Glutamine 10 g oral/day versus no HNC Randomized case-control study (n = Decreased grade 2-3 esophagitis (P < .05)
et al59 treatment 70), WHO OMAS
60
Gul et al Radiotherapy Glutamine 30 g oral/day versus no LC RCT (n = 32), RTOG Decreased esophagitis (P < .05)
treatment
Intestinal mucositis/diarrhea clinical studies
Vidal-Casariego Radiotherapy Glutamine, 30 g, oral versus placebo AC/PC RCT (n = 69), RTOG NS benefit on acute enteritis/diarrhea
61
et al
13
Michael et al Irinotecan Activated charcoal, 1000 mg CRC Single-arm open-label (n = 24), Decreased grade 3/4 diarrhea (7.1% vs 25%)
CTCAE

Abbreviations: CRC, colorectal cancer; CTCAE, Common Terminology Criteria for Adverse Events; OM, oral mucositis; HNC, head and neck cancer; OC, oral cancer; Tx, treatment; 5-FU, 5-fluorouracil; IM, intramuscular; NS,
nonsignificant; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia; RCT, randomized controlled trial; RTOG, Radiation Therapy Oncology Group; OeC, esophageal cancer;
HCC, hepatocellular carcinoma; WHO OMAS, World Health Organization Oral Mucositis Assessment Scale; im, intramuscularly; OC, oral cancer; AL, acute leukemia; NHL, non-Hodgkin’s lymphoma; HDC, high-dose
chemotherapy; HSCT, hematopoietic stem cell transplantation; equiv, equivalent; NPC, nasopharyngeal carcinoma; tid, three times a day; bid, two times a day; HM, hematologic malignancies; HL, Hodgkin’s lymphoma; MM,
multiple myeloma; MS, myelodysplastic syndrome; BC, breast cancer; OvC, ovarian cancer; NIDCR, National Institute of Dental and Craniofacial Research; PBSCT, peripheral blood stem cell transplantation; Mel, melanoma; LC,
lung carcinoma; Lym, lymphoma; RR, risk ratio; CI, confidence interval; mCRC, metastatic colorectal cancer; KS, Kaposi sarcoma; CALGB, Cancer and Leukemia Group B scale; Sar, sarcoma; NB, neuroblastoma; mBC,
metastatic breast cancer; BMT, Stanford University Bone Marrow Transplant toxicity scale; IV, intravenous; bw, body weight; AST, aspartate aminotransferase; NSCLC, non–small cell lung cancer, AC, abdominal cancer; PC, pelvic
cancer.
7
Table 3. Clinical Trials Investigating Honey for Oral Mucositis.

References Interventions Cancer Design; Assessment Outcome

Radiotherapy
 64
Biswal et al 20 mL of honey 15 minutes before and after HNC RCT (n = 40); RTOG Decreased OM grade 3-4 (P < .0005)
8

radiation versus standard oral care

Motallebnejad et al73 20 mL of honey 15 minutes before and after HNC RSB (n = 40); WHO OMAS Decreased OM (P < .05)
radiation versus saline rinse
Khanal et al
70
Swish honey for 2 minutes and expectorate, 20 mL OC RSB (n = 40); RTOG Decreased OM (P < .05)
versus lignocaine gel
Bardy et al63 Manuka honey or placebo golden syrup 20 mL HNC RCT (n = 131); RTOG NS difference
versus standard oral care

Jayachandran and Honey versus benzydamine and saline HNC RCT (n = 60); WHO OMAS Decreased OM (P < .05)
68
Balaji
Parsons et al85 Manuka honey versus standard oral care HCN RCT (n = 28, 18 honey, 10 control); NS difference
multisite mucositis scoring system
82
Charalambous et al Honey versus saline rinse HCN RCT (n = 30); RTOG Grade 3 xerostomia RR = 0.13 and grade 3
oral mucositis RR = 0.26, indicating that
honey is effective for both symptoms
78
Alvi et al 20 mL honey versus saline rinse HNC RCT (n = 60); WHO OMAS Decreased OM (P < .05)
Hawley et al67 Honey versus sugar-free gel HNC RCT (n = 106); RTOG, WHO NS difference
OMAS
76
Samdariya et al 20 mL of honey before and after radiation and HNC RCT (n = 78); Visual Analogue Pain Decreased severity pain score (P < .05)
salt-soda and benzydamine mouth gargles versus scale
salt-soda and benzydamine mouth gargles alone
Jayalekshmi et al69 15 mL honey before and after radiation versus plain HNC RSB (n = 28); RTOG Decreased OM (P < .05)
water rinse
Rao et al86 Honey applied before and after radiation versus HNC RSB (n = 50); RTOG Decreased OM (P < .002)
povidone-iodine
80
Amanat et al 20 mL honey before and after radiation versus HNC RCT (n = 82); RTOG Decreased OM grade 3 (P < .016) and
saline rinse grade 4 (P < .032)
Fogh et al65 10 mL liquid honey versus honey lozenge versus Small and non–small RCT (n = 107, 53 supportive care, Honey not superior to standard care
standard supportive care cell lung cancer 54 liquid honey honey, 56 lozenge
honey); CTCAE

(continued)
Table 3. (continued)

References Interventions Cancer Design; Assessment Outcome

Chemotherapy
 62
Abdulrhman et al Honey versus honey, beeswax, olive oil, propolis ALL RCT pediatric, (n = 90); CTCAE Faster healing (P < .05)
mouthwash mixture versus standard oral care
77
Allenidekania Honey versus chlorhexidine Pediatric cancer RCT (n = 23), WHO OMAS Decreased OM severity (P < .001)
84
Mishra and Nayak Honey ice chips versus plain ice chips ALL RCT (n = 40); WHO OMAS Decreased OM occurrence (P < .001) and
no difference severity
71
Kobya et al Honey 1 g/kg daily versus standard oral care HNC Quasi-experimental study children Decreased OM severity (P < .05)
multicenter (n = 83); WHO
OMAS
Chemoradiotherapy
75
Rashad et al 20 mL honey before and after radiation versus no HNC RCT (n = 40); RTOG Decreased OM grade 3-4 (P < .05)
honey
72
Maiti et al 20 mL honey before and after radiation HNC RCT (n = 55); WHO OMAS Decreased OM grade 3-4 (P < .05)
Berk et al81 Manuka honey liquid/lozenges versus supportive LC RCT (n = 163); CTCAE NS difference
care
74
Raeessi et al 300 g of honey, or ±20 g of instant coffee versus HNC RCT (n = 75); WHO OTS Decreased OM grade 3-4 (P < .05)
topical betamethasone
Francis and Honey mixed with turmeric powder versus Various Nonequivalent control group, Decreased OM (P < .05)
66
Williams standard care pretest posttest design (n = 60),
WHO OMAS
83
Farneti et al Sodium alginate, sodium carbonate, propolis, HNC RCT (n = 107), CTCAE NS difference
Aloe vera, calendula, honey, and chamomile
versus placebo
87
Yadav Honey with glycerin versus standard care HNC RCT (n = 107), CTCAE Decreased OM (P < .003)
79
Al Jaouni et al Honey versus standard oral care lidocaine, ALL, AML, Burkett’s Open, randomized trial (n = 40, Decreased OM grade 3-4 (P < .02)
mycostatin) lymphoma, Wilm’s pediatric), clinician defined OM
tumor assessment

Abbreviations: HNC, head and neck cancer; RCT, randomized controlled trial; RTOG, Radiation Therapy Oncology Group Grading System; OM, oral mucositis; RSB, randomized single blinded;
WHO OMAS, World Health Organisation Oral Mucositis Assessment Scale; OC, oral cancer; NS, nonsignificant; RR, risk ratio; CTCAE, Common Terminology Criteria for Adverse Events; ALL,
acute lymphocytic leukemia; LC, lung carcinoma; WHO OTS, World Health Oraganization Oral Toxicity Scale; AML, acute myelogenous leukemia.
9
Table 4. Clinical Trials Investigating Probiotics for Oral and Intestinal Mucositis/Diarrhea.

References Treatment Intervention Cancer Site Design Outcomes

Oral mucositis clinical studies
99 9
Sharma et al Radiotherapy plus cisplatin L brevis 2 × 10 CFU, 6 HNC RCT (n = 202), Decreased incidence mucositis grade 3-4 and
 lozenges versus placebo efficacy analysis = decreased completion of therapy (92% vs 70%;
10

188; CTCAE P < .05)

105 9
Sharma et al HSCT L brevis 2 × 10 CFU, MM/HL/NHL/AML/ Pilot, no control (n 29% no mucositis, 19% grade 1 mucositis, 33%
3-4
lozenges, no control RMS = 18); CTCAE grade 2 mucositis, 9.5% grade 3-4 mucositis,
and 65% <grade 2 dysphagia
100 9
Sharma et al HSCT L brevis 2 × 10 CFU, CML/MM/HL/NHL/ Pilot, no control (n 23% no mucositis, 19% grade 1 mucositis, 39%
4-6
lozenges AML/RMS = 31); CTCAE grade 2 mucositis, 13% grade 3 mucositis, and
7% grade 4 mucositis
103 9
Giammarco et al HSCT L brevis 2 × 10 CFU, 6 MM RCT (n = 16); 100% mucositis; NS difference between
lozenges versus OM assessment treatments (P >.05)
prevention including method not
chlorhexidine, saline rinses, specified
and nystatin
Radiotherapy adverse events prevention
studies L acidophilus NCDO Gynecological cancer RCT (n = 24) Significant reduction in incidence of diarrhea (P
97
Salminen et al Pelvic radiotherapy, (internal 1748 < .01); RR = 0.3 (95% CI = 0.11-0.81); control
and external) 80 Gy (tumor) + 6.5% lactulose, 2 × 1011 group all with diarrhea
and 50 Gy pelvis CFU qd versus dietary
counselling
Delia et al90 Pelvic radiotherapy (60-70 Gy) VSL#3 1 sachet tid versus Sigmoid rectal or RCT (n = 490) Reduced incidence (124/239 [51.8%] and 77/243
placebo cervical cancers [31.6%], P < .001); reduced severity 55.4% and
1.4%, P < .001); RR = 0.61 (95% CI = 0.45-
0.76)
Castro et al88 Radiotherapy L casei Shirota B breve Prostate cancer RCT (n = 40) Reduction in proctitis; improved QoL; RR =
(strain and dose not 0.54 (95% CI = 0.27-1.06)
provided) versus placebo
91
Demers et al Pelvic radiotherapy (44 Gy) L acidophilus LAC-361, Cervical and uterine RCT (n = 229) Reduced incidence grade 4 diarrhea; standard
B cancers dose; RR = 1.09 (95% CI = 0.76-1.59)
11
longum BB536, 1.3 × 10
CFU bid standard dose
versus high dose versus
placebo
Chemotherapy adverse events prevention studies
Österlund et al96 5-FU and leucovorin L rhamnosus GG, 1-2 × Colorectal cancer RCT (n = 150) Reduced grade 3 or 4 diarrhea (22% vs 37%, P =
11
10 .027); reduced abdominal discomfort; reduced
CFU + 11 g guar gum qd hospital care; fewer chemotherapy dose
versus no prophylactic reductions due to bowel toxicity; RR = 0.58
treatment (95% CI = 0.35-0.98)
Sharma et al106 Irinotecan and/or VSL#3 1 sachet bid versus Not defined RCT (n = 202) No significant difference in incidence of diarrhea;
fluoropyrimidines placebo RR = 2.76 (95% CI 0.89-8.51)

(continued)
Table 4. (continued)

References Treatment Intervention Cancer Site Design Outcomes

 Mego et al95 Irinotecan Colon Dophilus 10 × 109 Colorectal cancer RCT (n = 46) Reduction grade 3 or 4 diarrhea (0% vs 17.4%,
capsules CFU tid versus P = .11); reduced overall incidence of diarrhea
placebo (39.1% vs 60.9%, P = .24); reduced incidence
of enterocolitis (0% vs 8.7%) RR = 0.1 (95% CI
=
Chemoradiotherapy adverse events prevention studies 0.006-1.95)
Giralt et al92 Pelvic radiotherapy (45-50 Gy), 96 mL fermented yogurt with Cervical squamous RCT (n = 85) Improved stool consistency (P = .04); no
2
weekly cisplatin 40 mg/m L casei DN11400, 1.1 × cell carcinoma; difference to presentation of end point
11
10 endometrial (diarrhea) or use of loperamide; RR = 1.17
CFU/g yogurt tid versus adenocarcionoma (95% CI = 0.84-1.62)
placebo
89
Chitapanarux et al Radiotherapy and cisplatin 500 mg Infloran bid versus Cervical cancer (local RCT (n = 63) 45% grade 2-3 diarrhea placebo group and 9% of
placebo advanced) probiotic group (P = .002); antidiarrheal
medications reduced (P = .03); improved
stool consistency (P < .001) respectively; RR
= 0.21 (95% CI = 0.07-0.65)
Radiotherapy adverse effects prevention studies (no comparator
groups)
104
Timko Radiotherapy 50-67 Gy Colon Dophilus 2 capsules qd Abdominal and pelvis RNB (n = 42), Reduction in diarrhea and antibiotic use
abdomen/pelvis cancers stool diary
Scartoni et al98 Radiotherapy 30-80 Gy pelvis Dixentil 10 mL vial qd Large bowel Prevention/safety Reduction in diarrhea
urological, (n = 42)
gynecological
cancers
Radiotherapy treatment studies
93
Henriksson et al Radiotherapy 62-66 Gy pelvis Fermented milk, L lactis, L Pelvis and urinary RCT (n = 40), Reduction in chronic bowel discomfort
diacetylactis, L bladder cancers stool diary
cremoris versus nonactive
fermented milk
Urbancsek et al101 Radiotherapy to 50 Gy L rhamnosus 1.5 × 1011 Pelvis and abdominal RCT (n = 206), Reduction in self-ratings diarrhea grade and
abdomen CFU cancers stool diary feces consistency (P < .05)
4 weeks post radiotherapy
versus placebo
94
Lee et al Radiotherapy and Lacidofil with L Colorectal cancers RCT (n = 60); Decreased IBS (P < .05); increase in functional
chemotherapy 6 weeks to 2 rhamnosus Rome III; stool health scores (P < .05); increased FACT scores
years prior to enrolment in R0011, L acidophilus diary (P < .05)
study R0052,
11
Clinical trials investigating infectious 2 × 10 CFU 2 capsules qd
complications versus placebo
Wada et al102 Chemotherapy not further B breve M-16-V, 1 × 1011 Not defined RNB (n = 42)/ Reduction in febrile episodes, antibiotic use; no
defined CFU qd pediatric effect on diarrhea; no difference in WBC or
NK cells

Abbreviations: CFU, colony-forming unit; HNC, head and neck cancer; RCT, randomized controlled trial; CTCAE, Common Terminology Criteria for Adverse Events; HSCT, hematopoietic stem cell
transplantation; MM, multiple myeloma; HL, Hodgkin’s lymphoma; NHL, non-Hodgkin’s lymphoma; AML, acute myelogenous leukemia; RMS, rhabdomyosarcoma; CML, chronic myelogenous leukemia;
OM, oral mucositis; NS, nonsignificant; qd, one a day; RR, risk ratio; CI, confidence interval; NK, natural killer; VSL#3, L casei, L plantarum, L acidophilus, L delbruekii subsp bulgaricus,
B longum, B breve, B infantis, Streptococcus salivarius subsp thermophiles; Colon Dophilus, B breve HA-129 (25%), B bifidum HA-132 HA (20%), B longum HA-135 (14.5%), L
11

rhamnosus HA-111 (8%), L acidophilus HA-122 (8%),

L casei HA-108 (8%), L plantarum HA-119 (8%), S thermopilus HA-110 (6%), L brevis HA-112 (2%), B infantis HA-116; Infloran, 1 billion viv Lyophilisat and 1 billion B bifidum viv
Lyophilisat; Dixentil, L
acidophilus and L casei (strains not provided), zinc, galacto-oligosaccharides, and vitamins B /B /B and nicotinamide; tid, three times a day; QOL, quality of life; bid, two times a day; 5-FU, 5-
fluorouracil; 1 2 6
RNB, randomized nonblinded; IBS, irritable bowel syndrome; FACT, Functional Assessment of Cancer Therapy; WBC, white blood cells.
Thomsen and 12
Vitetta
 Thomsen and 13
shown in humans to be
Vitetta with no treatment, honey mucositis in acute mucositis between the
84
associated with a lower could reduce the inci- lympho- cytic leukemia, experimental and control
115
risk for CRC, and oral dence of oral mucositis and 2 trials in groups in weeks 4, 5, and
glutamine 2 days before after chemoradiotherapy chemoradiotherapy- 69
6 (P < .01). Compared
tumor implanta- tion has (RR = induced mucositis in with the active
been shown in rodents to 0.35, 95% CI = 0.18- children with various comparator, povidone-
110 79,87
increase natural killer cell 0.70, P = .003). Honey cancers. Only one iodine, honey significantly
65
activity, upregulate was also found to trial reported no effect. reduced radiation-induced
intestinal glutathione decrease treatment Medical manuka honey oral mucositis, decreased
metabolism, and decrease interruptions, weight loss, adminis- tered as a liquid the incidence of
tumor growth by 40% to and delay the onset of oral or as a lozenge was not intolerable mucositis,
116,117 treatment breaks, loss of
50%. Oral gluta- mucositis. Honey, superior to best supportive
mine administered during however, was care in preventing treatment d
chemoradiotherapy did not inefficacious in radiation esophagitis.
65 a y
nega- tively affect tumor decreasing the peak A single-blinded s (P < .0001 and < .0003),
control and survival in randomized controlled and did not affect the
mucositis score. Co et al
patients with stage IIIB trial (n = 28) found that radiation- induced tumor
reported statistical 86
non–small cell lung pooling showing that the 15 mL of natural honey response. Honey
56
cancer. As cancer cells risk ratio of having a was associated with a significantly reduced the
can manipulate host statistically significant severity of mucositis
treatment interruption was
metabolism favoring difference in degree (grades 3 and 4) compared
significantly lower with
tumor growth, depri- of oral with con- trol group at the
the use of honey versus
vation of dietary end of 6 weeks of
control 0.11 (95% CI = 80
glutamine or the use of 0.02- radiation treatment.
oral supplementa- tion for Honey ice cubes were
0.58) with a risk ratio
mucositis was reported shown to significantly
of developing severe
unlikely to adversely reduce the occurrence of
mucositis when honey
affect tumor growth chemotherapy-induced
during chemotherapy was administered as 0.45
oral mucositis in pediatric
treatments. Glutamine, with a CI of 0.09 to cancer patients compared
however, has been shown 2 with plain ice cubes on the
to be ineffective in . 5th (P = .001) and 15th (P
controlling acute 2 = .001) days of
radiation-induced 1 84
assessment.
61,118 .
intestinal mucositis. 1 A significantly higher
A Cochrane review of 2 number of patients
64,73,75
3 studies 0 developed grade 2 or
investigating honey Friend et al specifically above chemoradiotherapy-
concluded that it was examined pediatric trials induced mucositis in the
associated with a weak to and identified 4 con- trol arm compared
moderate benefit in the trials
62,71,77,79
with grade C with the experimental arm
87
prevention of evidence that honey was (P = .003).
radiotherapy- induced effective as a preventative Absolute risk reduction
119
oral mucositis. Three and adjunctive therapy for between honey and control
subsequent meta-analy- chemotherapy-induced for developing grades III
ses concluded that oral and IV oral mucositis was
oral mucositis in
administration of honey 121 found to be significant in a
children. Honey was
could prevent the study of pediatric cancer
found to reduce the
incidence of radiotherapy- patients receiving
frequency, duration, and
induced oral muco- sitis in chemoradiotherapy (P < .
stage of chemotherapy- 79
head and neck 05 ; Table 3).
109,110,120 induced mucositis.
cancers. Cho et al A meta-analysis of
Seven trials have been
concluded that oral randomized controlled
published since the meta-
administration of honey 109,110,120 trials (RCTs) examining
analyses report.
after radiotherapy could oral mucositis induced by
Four trials examined
prevent the development chemoradiotherapy, or
honey in radiotherapy-
of moderate to severe hematopoietic stem cell
induced mucositis in
mucositis and associated transplantation (HSCT),
109 head/neck and lung found that patients
weight loss. Xu et al cancers,
65,69,80,86
1 trial in
concluded that, compared pretreated with mineral
chemotherapy-induced supplementation delayed
 Thomsen and 14
the onset
Vitettaof mucositis and severe mucositis in
that fewer patients expe- patients with head and
rienced less peak oral neck cancers treated with
mucositis compared with 16
chemoradiotherapy. In 2
111
controls. other studies that
The analysis examined 7 examined the same amino
26-31,33
studies with zinc, 3 acid–rich oral formulation,
with cal- the first study found that
36-38
cium, 2 with the formulation was
24,25
selenium, and 2 associated with reduced
39,40
with iodine. severity of mucositis in
Significant study bias was squamous cell carcinoma
observed though and study treated
het- erogeneity, making it
difficult to make specific
clinical rec-
ommendations. Mineral
formulations did not
overall significantly
reduce mean duration of
mucositis, pain dura- tion,
111
or use of analgesics. Of
the 14 studies included in
the meta-analysis, the 3
26,32,122
excluded and 2
34,98
recent stud- ies are
presented in Table 2. Zinc
is essential for proper
immune function and for
the integrity of connective
tissue and cell membranes,
and 50 to 150 mg
elemental zinc daily was
reported to reduce oral
27-29,31
mucositis (Table 2).
Four studies examining
the effects of multinutrient
for- mulations that
consisted of a mixture of
open-label, retro- spective,
and prospective studies
were identified. In a small,
open-label study, it was
reported that oral or
parenteral administration
of a multinutrient
formulation was well tol-
erated in patients with
head and neck cancers
treated with
chemoradiotherapy
without developing severe
15
mucositis.
In another, multinutrient
formulation composed of
amino acids, omega-3
fatty acids, ribonucleic
acids, vitamins, and
antioxidants was shown to
be associated with less
Thomsen and 15
Vitetta
Thomsen and
with radiotherapy with or
Vitetta
without chemotherapy
when compared with no
formulation
administration. The
nutrient formulation was
also associated with
improved completion rates
17
of chemoradiotherapy.
The second study was a
pro- spective pilot study in
CRC treated with 5-FU-
based che- motherapy.
This study reported that
the multinutrient
formulation was
associated with a decrease
in the severity of oral
mucositis in
approximately 90% of the
patients dur- ing the first
course of treatment (P = .
0002) and maintained in
the second course of
18
treatment (P <.0001 ;
Table 2).
Vitamin E may reduce
mucositis by regulating
nrf2 acti- vation. Gamma-
tocotrienol has been
shown to prevent
5-FU-induced redox
signaling by regulating
nrf2 activation and cell
survival in human oral
123
keratinocytes. Applying
vitamin E directly to the
mucous membranes may
be more effective than
orally administered. Oral
vitamin E (400 mg twice
daily) was shown to have
no effect on the incidence
or severity of mucositis in
an RCT of 60 patients
with leuke- mia receiving
allogenic bone marrow
12
transplantation.
Despite this, topical
vitamin E was shown to be
beneficial in the treatment
of oral lesions associated
with mucositis in an RCT
of patients with solid
tumors (n = 17) or
leukemia (n = 1). Six of 9
patients receiving vitamin
E had complete resolution
of oral lesions compared
with 1 out of 9 in the
21
control group (P = .025).
105
16
In another study with 80 study drug were noted. day 24. The single-arm,
patients who developed The second pilot study by single-center, phase II
oral mucositis, 100 mg of the same research group study found that of the 31
a topical, but not oral, found that 20% developed patients enrolled, 7
application of vitamin E grade III or IV (22.6%) patients did not
was shown to improve mucositis.
100
In a repeat develop any mucositis, 6
22
muco- sitis. In a further pilot study, patients (19.4%) patients
study with 54 patients treated with HSCT were developed grade
with head and neck given the probiotic 1 mucositis, 12 (38.7%)
cancers it was found that lozenge 4 to 7 days before patients developed grade 2
vitamin E before, and for initiation of chemo- mucosi- tis, and 4 (12.9%)
the duration of therapy and continuing and 2 (6.5%) patients
radiotherapy, decreased until resolution of developed grade 3 and
the incidence of muco- mucositis or till grade 4 mucositis,
20
sitis. Topical vitamin E respectively. Median time
reduced the risk of to onset and for resolution
mucositis by of mucositis was 6 days
36%.
20
Both topically and 8 days, respectively.
applied vitamin E and the No adverse events were
oligomeric procyanidin reported with usage of
known as pycnogenol
100
study drug. However, in
were shown in an RCT to the fourth pilot study by
reduce mucositis in 72 another group using the
children although same formulation in
pycnogenol was not patients undergoing
effective for severe, grade HSCT, all 16 patients
23
4 mucositis (Table 2). developed various grades
A probiotic containing of mucosi- tis with no
lozenge, specifically with statistical difference
Lactobacillus brevis, has between the probiotic loz-
been shown in an RCT to enge and standard
103
reduce radiation- and treatment (Table 4).
chemotherapy-induced The majority of studies
oral mucositis in 200 investigated the
patients with head and prophylactic use of
neck cancers. Use of the probiotics for diarrhea,
probiotic was associated while a few investigated
with a reduced incidence the effi- cacy of probiotics
of mucositis grades III and in the treatment of irritable
IV (P = .001). Supportive bowel syn- drome or
treatment with the probi- diarrhea, weeks to years
otic was administered post treatment (Table 4).
during treatment and for 1 The studies used a variety
week post treatment of probiotic interventions
completion (radiotherapy and protocol designs and
99 outcomes, making it
and weekly cisplatin).
difficult to iden- tify
The same probiotic
lozenge formulation was which type of intervention
also examined in 3 studies and protocol was most
of patients undergoing ben- eficial. A systematic
HSCT for a variety of review and meta-analysis
cancers including multiple of probiotics for
myeloma. In the first pilot prevention of
study, of 21 patients, only chemoradiotherapy-
19% developed grade III induced diarrhea in people
or IV mucosi- tis with abdominal and pelvic
compared with the cancers found that probi-
expected 60%. No adverse otics were generally
events except occasional beneficial in treatment-
grade I/II nausea due to induced diar- rhea,
especially for grades 2 and
 Thomsen and 17
112
3.Vitetta
A recent meta- I
analysis that grouped 7 n
studies for the t
prophylactic use of
probiotics for cancer
e
therapy–induced r
124
diarrhea concluded that v
cur- rent evidence does not e
support widespread n
implementation of t
probiotics for the
management of diarrhea
i
secondary to cytotoxic o
therapy and the tyrosine n
kinase inhibitor, dacomi- s
tinib. The administration
of probiotic was begun on
the first day of cancer
S
therapy initiation and as a
such referring to pro- f
phylactic interventions e
may be inaccurate. The t
administra- tion of
y
prophylactic probiotics
must begin ideally 1 One study implementing
month prior to manuka honey mouthwash
chemotherapy/radiotherap found that while it
y initiation. demonstrated benefit in
In order to investigate ameliorating radiation-
the probiotic effect to induced weight loss and
reduce diarrhea induced by increase quality of life in
chemotherapy and/or the absence of cisplatin
radiotherapy, relative risks chemotherapy, it was also
were calculated for the 9 reported that undiluted
RCTs, and the results manuka honey caused
showed that 7 studies severe nausea, vomiting,
85
favored probiotics for and severe stinging. In
preventing chemotherapy- an additional study, Bardy
and/ or radiotherapy- et al found no difference
induced grade ⩾2 diarrhea between golden syrup and
63
(Figure 1). The co- manuka honey,
administration of probiotics suggesting that perhaps
with radiotherapy shows the high sucrose content
enhanced
efficacy in preventing
intestinal adverse effects
induced by radiotherapy
compared with
chemotherapy.

A
d
j
u
v
a
n
t
 Thomsen and 18
Vitetta

Figure 1. Forest plot of RCTs of chemotherapy-/radiotherapy-induced diarrhea.

RCT, randomized controlled trials; RT, radiotherapy; CT, chemotherapy; CRT, chemoradiotherapy; RR, relative risk, risk ratio.
 Thomsen and 19
wasVitetta
responsible for the oncol- ogy to enhance of 17 studies (N = 1530) yogurt- derived
antibacterial effect treatment or reduce found no reports of Lactobacillus species was
observed. Neither study adverse events associ- ated significant side effects recently reported in a
showed improvement in with chemotherapy or such as serious localized 54-year-old male patient
mucositis; however, radiotherapy is not part of or systemic infections with acute promyelocytic
compliance associated standard practice. The when administered to leuke- mia. The
with the taste and texture principal concern being patients receiving cancer bacteremia developed a
of the interventions was an that patients treated with treatments. Five case week after the patient
issue, which may have chemotherapy are reports showed probiotic- underwent high-dose
influenced the study frequently immune- related bacteremia, chemotherapy and
outcome. compro- mised and, fungemia, or positive autologous periph- eral
129
The common dose therefore, are at increased blood cultures. Wang et blood stem cell
administered in clinical risk of sepsis from al included transplantation. The
trials was 20 mL of honey, administering probiotic 11 studies in its safety pathogen was identified by
3 times daily. At this formulations. A analysis. Seven studies did strain-specific polymerase
dose, honey did not affect systematic review not report any adverse chain reaction anal- ysis to
blood sugar levels when events. Four studies be identical to the
initial fasting blood sugar reported various adverse Lactobacillus rhamnosus
132
level was below 150 events. The reporting of GG found in the yogurt.
mg/dL.
72
Patients adverse effects was,
undergoing radio- therapy however, very inconsistent
for head and neck cancers and poorly documented.
have been reported to be Although some infec-
prone to a range of dental tions were reported, no
125 probiotic bacteria growth
complications, and a
could be found in blood
concern was the added risk
cultures. Other adverse
of developing dental
effects included mild
caries, in spite of research
126 gastrointestinal upsets,
suggesting otherwise. fever, and anorexia, which
Radiation-related caries were also observed in the
are related to 112
control groups. Okawa
hyposalivation, shifts in
et al reported 1 death but
the oral microbiota, and
no evidence of an
altered saliva composition.
association with the
The rapid onset and pro-
probiotic intervention was
gression often leads to 130
extensive loss of dentition reported. A few
within short periods of probiotic trials have been
time. Honey contains performed in
102,131
known cariogenic children. A single-
substances including blinded study found that
glucose, fructose, sucrose, Bifidobacterium breve
and numer- ous acids, reduced the frequency of
including gluconic, acetic, fever, which was
lactic, butyric, and formic associated with a lower
acids, that may contribute use of intravenous
to cariogenic increased antibiotics compared with
risk.
127
However, honey placebo in children
has also been shown to receiving chemotherapy
prevent radiation-induced (1-13 years of age, n =
decrease enamel 42). No adverse events
102
microhardness in xeros- were reported. A safety
tomic patients compared and feasibility study did
with patients with normal not report Lactobacillus
sal- via.
128
None of the plantarum–associated
trials reported that the use bacteremia in children
of honey predisposed to undergoing allogenic
the development of caries. hematopoietic cell trans-
131
The use of probiotics as plant; however, a case
an adjunctive medicine in of septic shock caused by
Thomsen and 20
Vitetta
Thomsen and 21
P Dilaporkan bahwa L. brevis dan heterogenitas dari studi efektif dibandingkan
Vitetta
e menghasilkan arginine yang ditinjau umumnya dikonsumsi secara oral.
m deiminase dan menjadi sulit untuk Glutamine merupakan
b sphingomyelinase, yang menawarkan rekomendasi salah satu intervensi gizi
a
menghidrolisis faktor klinis yang spesifik. Pada yang paling banyak diteliti,
h
a pengaktifan platelet yang suatu review, suplementasi dan meskipun ada bukti
s diketahui terkait dengan mineral, termasuk zinc, yang menunjukkan bahwa
a mucositis oral pada terapi secara keseluruhan tidak glutamin dapat mengurangi
n radiasi.103 Arginine secara signifikan mucositis gastrointestinal
deiminase kemudian mengurangi durasi rata-rata dan diare yang diinduksi
Intervensi terbaru terus mengubah arginin menjadi mucositis, insiden nyeri, kemoterapi, European
dieksplorasi dan dibangun amonia dan citrulline, atau penggunaan Society for Clinical
dalam pemahaman ilmiah mengurangi jumlah arginin analgesik.111 Nutrition and Metabolism
dan klinis dari pencegahan yang tersedia untuk diubah Rekomendasi untuk (ESPEN)133 menyatakan
oral dan mucositis serta menjadi oksida nitrat - suplementasi zinc saat ini dalam pedoman terbaru
pilihan pengobatan yang mediator utama peradangan. dibatasi untuk pasien tentang nutrisi di pasien
mungkin tersedia untuk Lebih lanjut, daya tarik dengan kanker mulut yang kanker bahwa “ada data
klinisi dan pasien.13,112,121,133 probiotik yang diberikan menjalani pengobatan klinis yang tidak cukup
Pencegahan dan untuk mucositis oral dengan kemoterapi atau konsisten untuk
pengobatan mukosa mulut ditingkatkan ketika mereka radiasi sesuai dengan merekomendasikan
dan pencernaan dan terbukti tidak memiliki efek Asosiasi Multinasional glutamin untuk mencegah
mengurangi risiko merugikan yang serius. Perawatan Suportif dalam enteritis/diare yang
pembentukan dan/atau 99,103,105
Bagaimanapun Pedoman Kanker / disebabkan oleh radiasi,
progresi sekuens kerusakan manfaat lokal pada oral ini, Masyarakat Internasional stomatitis, esofagitis, atau
regimen kemoradioterapi tidak meluas ke usus, Oral Onkologi (MASCC / keracunan kulit.” Pedoman
merupakan faktor penting dengan didapatkanya 14 ISOO). MASCC / ISOO telah
yang mempengaruhi dari 16 pasien yang diperbarui dari
kualitas hidup pasien dan mengalami diare.103 rekomendasi terhadap
keputusan klinis yang Pada intestinal, terapi glutamin menjadi “tidak
relevan terhadap kanker telah ditemukan ada pedoman yang
pengobatan. Meskipun untuk mengurangi mungkin” untuk glutamin
diakui bahwa mucositis oral commensals seperti terhadap mukositis oral
dan intestinal mewakili Salah satu kelemahan
Bifidobacteria, Clostridium menggunakan suplemen atau gastrointestinal. 136
beban yang signifikan dari cluster XIVa, dan Keamanan glutamin juga
terapi antineoplasitic, zinc adalah dapat
Faecalibacterium menyebabkan mual dan telah ditinjau dalam
penerapan terapi ajuvan prausnitzii, dikombinasikan pandangan bukti yang
masih tetap menjadi bahkan muntah.
dengan peningkatan Suplementasi seng tidak muncul bahwa sel-sel
tantangan.134 Enterobacteriaceae dan ganas dapat menggunakan
Kemoterapi dan boleh dilakukan dengan
Bacteroides. Perubahan ini perut kosong, karena akan glutamin sebagai substrat
radioterapi memiliki efek menginduksi dysbiosis usus mitokondria. 137 Dosis
merugikan yang signifikan meningkatkan efek buruk.
dan berkontribusi pada Studi kebanyakan glutamin yang diselidiki
pada mikrobiota mukosa pengembangan mucositis, berkisar antara 9 hingga 30
oral dan gastrointestinal. menggunakan 220 mg seng
terutama diare dan sulfat, setara dengan 50 mg g setiap hari dalam dosis
Mucositis oral terkait bacteremia.135 Perubahan terbagi. Karena dosis yang
dengan bakteria dan sepsis unsur seng, 2 hingga 3 kali
yang merugikan pada sehari sebagai obat kumur lebih rendah telah terbukti
akibat Escherichia coli, mikrobiota usus bermanfaat dalam
Pseudomonas aeruginosa, atau kapsul/tablet.
mengisyaratkan bahwa Pemberian selenium mucositis oral, mungkin
dan Candida albicans. pemberian probiotik dapat bijaksana untuk
Bagaimana probiotik dalam studi klinis
mengurangi efek samping menggunakan dosis yang menggunakan spektrum
dipostulasikan untuk kemoterapi dan radioterapi. dosis terendah. Kebersihan
mengatasi efek samping berkisar dari 200 µg unsur
Ada bukti moderat selenium dua kali sehari25, mulut yang baik sangat
kemoterapi dan/atau bahwa zinc, selenium, penting jika intervensi
radioterapi, didapatkan hasil ke natrium selenit cairan
vitamin E, glutamin, dan oral 200 hingga 500µg satu dengan madu untuk
pengamatan terbaru bahwa madu mungkin bermanfaat mucositis
Lactobacillus brevis jam sebelum sesi
untuk pencegahan atau radioterapi.24 Penggunaan direkomendasikan. Arang
lozenges menghasilkan pengobatan mucositis oral. aktif dapat mengurangi
metabolit anti-inflamasi.103 vitamin E langsung ke
Namun, angka yang rendah mukosa oral mungkin lebih gejala yang terkait dengan
Thomsen and 22
mucositis yang diinduksi
Vitetta
kemoterapi termasuk diare.
Uji klinis yang menyelidiki
pemberian probiotik untuk
mencegah toksisitas yang
disebabkan oleh
pengobatan telah
menghasilkan hasil yang
beragam.124 Penelitian telah
menggunakan berbagai
parameter titik akhir
termasuk frekuensi tinja
dan konsistensi tinja
(dijelaskan secara terpisah
atau sebagai tingkat diare
2-4), penggunaan obat anti-
diare, dan pergeseran
mikroba yang disebabkan
oleh kemoterapi atau
radioterapi. Penggunaan
probiotik dalam
pencegahan atau
pengobatan kemoterapi
dan/atau toksisitas
gastrointestinal yang
diinduksi radioterapi
tampaknya bermanfaat dan
tanpa efek samping yang
signifikan. Pedoman
MASCC / ISOO
menunjukkan bahwa
probiotik yang
mengandung spesies
Lactobacillus digunakan
untuk mencegah diare pada
pasien yang menerima
kemoterapi dan/atau terapi
radiasi untuk keganasan
panggul,136 sedangkan
pedoman ESPEN
menyatakan bahwa tidak
ada data klinis yang cukup
konsisten untuk
merekomendasikan
probiotik untuk
mengurangi diare yang
diinduksi radiasi.
Thomsen and 23
Vitetta
 Thomsen and 24
dan saat ini Direktur 2000;8:366- epidemiology, and
Vitetta
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