Copyright B 2015 Wolters Kluwer Health, Inc. All rights reserved.

Fernanda T.M.M. Braga, PhD, RN

Ana C.F. Santos, MD, RN
Paula C.P. Bueno, MD
Renata C.C.P. Silveira, PhD, RN
Claudia B. Santos, PhD
Jairo K. Bastos, PhD
Emilia C. Carvalho, PhD, RN

Use of Chamomilla recutita in the

Prevention and Treatment of Oral
Mucositis in Patients Undergoing
Hematopoietic Stem Cell Transplantation
A Randomized, Controlled, Phase II Clinical Trial

K E Y W O R D S Background: Oral mucositis is a common inflammatory complication among

Hematopoietic stem cell patients undergoing hematopoietic stem cell transplantation (HSCT). Among its
transplantation therapeutic properties, Chamomilla recutita has anti-inflammatory effects.
Matricaria Objective: The aim of this study was to identify the dosage of the liquid
Mucositis extract of C recutita in mouthwash that is needed to reduce the incidence and
Nursing care intensity of oral mucositis in adult patients undergoing allogenic HSCT.
Methods: In a randomized phase II clinical trial, 40 patients were randomized
to receive routine care plus mouthwash containing a liquid extract of C recutita at
0.5%, 1%, or 2% (experimental groups) or standard care alone (control group).
Daily evaluation was performed using the measurement scale for oral toxicity
defined by the World Health Organization. Statistical analysis was performed,
in which the incidence, intensity, and duration of oral mucositis were compared
between each experimental group and the control group. Results: The
experimental group at the 1% dosage demonstrated reduced incidence, intensity,
and duration of oral mucositis compared with the control group. The formulation was

Author Affiliations: Ribeiräo Preto College of Nursing, University of Säo
Paulo, Ribeiräo Preto (Drs Braga, Silveira, C.B. Santos, and Carvalho); Amaral
Carvalho Foundation, Jaú (Dr A.C.F. Santos), and the Ribeiräo Preto Faculty
of Pharmaceutical Sciences, University of Säo Paulo, Ribeiräo Preto, Brazil
(Drs Bueno and Bastos).
Article extracted from the doctoral thesis ‘‘Chamomilla recutita (chamo-
mile) Mouthwash: Its Preparation and Application in Oral Mucositis,’’ pres-
ented to the Graduate Program in Basic Nursing, Ribeiräo Preto College of
Nursing, University de Säo Paulo.
Project was developed with financing from the National Council for Scientific
and Technological Development (Conselho Nacional de Desenvolvimento Cientı́fico
e TecnológicoYCNPq). UNIVERSAL Announcement MCT/CNPq 014/2010
(case no. 474499/2010-3).
The authors have no conflicts of interest to disclose.
Correspondence: Fernanda T.M.M. Braga, PhD, RN, Ribeiräo Preto College of
Nursing, University of Säo Paulo, Ribeiräo Preto, Ave Bandeirantes, 3900, Campus
Universit"rio. Ribeiräo PretoYSP, Brazil CEP 14040-902 (titareli@eerp.usp.br).
Accepted for publication June 23, 2014.
DOI: 10.1097/NCC.0000000000000194

322 n Cancer NursingTM, Vol. 38, No. 4, 2015 Braga et al

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

 well tolerated by patients and was safe, as no moderate or severe adverse effects
were identified. Conclusions: In this study, the use of mouthwash containing
1% C recutita extract can be associated with reduced incidence, intensity,
and duration of mucositis in adults patients undergoing allogenic HSCT.
Implications for Practice: The results of this investigation will help nurses
and other professionals in selecting the C recutita dosage used to manage oral
mucositis in patients undergoing HSCT.

O
ral mucositis is a common inflammatory complication
in patients undergoing hematopoietic stem cell trans-
plantation (HSCT), occurring in 76% to 99% of pro-
cedures. It results from the aggressive therapeutic regimen used
in the conditioning phase, which consists of high doses of chemo-
therapy with or without total body irradiation.1Y3 Initial signs and
symptoms of oral mucositis include erythema, edema, a burning
sensation, and sensitivity to hot foods. In subsequent stages,
ulcerative lesions, pain, difficulty swallowing, bleeding, and pseu-
domembranes can arise.4 Among patients undergoing allogenic
HSCT, the risk of developing an intense form of oral mucositis
is 2.88 times higher than that in patients undergoing autolo-
gous HSCT.1
Patients report ulceration and difficulty swallowing to be the
most uncomfortable symptoms of oral mucositis.5,6 Clinical and
economic consequences of mucositis include increased infec-
tions and complications caused by loss of the mucosal integrity,
increased duration of hospitalization, a need for total parenteral
nutrition (TPN), and the administration of narcotic and anti-
microbial medications.3,4,7 Measures to prevent and treat oral
mucositis have been investigated. In 2013, the Multinational
Association of Supportive Care in Cancer and the International
Society for Oral Oncology released a synthesis of clinical direc-
tives regarding oral mucositis. With respect to HSCT, the new
directives added the recommendation of using a laser (wave-
length at 650 nm, power of 40 mW) and maintained the in-
dication of palifermin.8 In a recent Cochrane review,9 it was
identified that the use of cryotherapy (ice chips) and keratinocyte
growth factor (palifermin) showed some benefit in preventing
mucositis. With regard to reduction of intensity, sucralfate is
recommended. Seven other interventions showed weaker evidence
of benefits (aloe vera, amifostine, intravenous glutamine, granulocyte-
colony stimulating factor, honey, laser, and antibiotic lozenges
containing polymixin/tobramycin/amphotericin).
Recent advances in our understanding of the pathobiology
of mucositis have encouraged the investigation of other therapeu-
tic options. The oral mucositis pathobiology involves a series
of steps mediated by proinflammatory cytokines, described as 5
interdependent phases: initiation, superregulation and genera-
tion of messaging signals, signalization and amplification, ulcera-
tion, and scarring.10Y12 From this perspective, researchers have
studied the relationship between proinflammatory cytokines and
mucositis development, suggesting a relevant role for interleukins,
tumor necrosis factor, and cyclooxygenases in the tissue changes
caused by this manifestation.13Y16
The species Chamomilla recutita (L.) Rauschert (Asteraceae)
has been used in traditional medicine for centuries. It is 1 of the
most studied and most recognized medicinal plants in the world.
Its therapeutic properties include anti-inflammatory action, favored
mainly by flavonoids, especially apigenin-7-glucoside.17,18 The
German herb regulation agency (German Commission E)
approves its use both internally and topically, with an indica-
tion for inflammatory changes in the skin and mucosal mem-
branes.19 Preclinical studies performed in vitro showed evidence
of the anti-inflammatory action of C recutita, revealing that the
plant extract can inhibit the production of interleukin-620 and
cyclooxygenase-2.21 Investigations in mice have suggested that
C recutita acts to reduce chemotherapy-induced oral mucositis.22,23
Given the high incidence of oral mucositis, its negative impact
on patients undergoing HSCT, the scarcity of therapies avail-
able for these patients, and the promising in vitro and animals
results obtained using C recutita, based on its anti-inflammatory
action, the aim of this study was to identify the dosage of liquid
extract of C recutita in mouthwash needed to reduce the inci-
dence and intensity of oral mucositis in adult patients undergoing
allogenic HSCT. We hypothesized that patients submitted to
HSCT who received the standard oral care protocol and mouthwash
with doses of 0.5%, 1%, or 2% of C recutita would have better
outcomes related to lower incidence and intensity levels of mucositis
when compared with patients who used the standard oral care
protocol. Furthermore, we hypothesized that, in patients who
used the mouthwash in 1 of the different doses, there will be a
positive effect on the secondary outcomes duration of mucositis
in days, days of use of TPN, and opioid analgesic. The end-
points of the study were the grafting bone marrow for the
patients who do not present mucositis and the healing of the oral
mucosa for the patients who did.
n Methods
Study Design
This study was a randomized, controlled, phase II clinical trial
(phase II RCT), with parallel groups. Different dosages of
C recutita in mouthwash were compared to assess how patients
undergoing HSCT responded in terms of the incidence and in-
tensity of oral mucositis. Patients were allocated to 1 of 4 inves-
tigative groups and treated with standard care without (control
group) or with mouthwash containing C recutita dosages of
0.5%, 1%, or 2% w/w liquid extract (experimental groups).
Allocation was through randomization into blocks, with a
computer program used to generate the randomization sequence.
Block sizes ranged from 8 to 12 patients each. A nurse who was not

Use of Chamomilla recutita in Mucositis Cancer NursingTM, Vol. 38, No. 4, 2015 n 323

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

participating in the study generated a list of numeric codes. Each
number on the list was individually placed in an opaque envelope,
sealed, and numbered, ensuring allocation secrecy. After the sub-
ject’s formal entry into the study (ie, after the subject met the
eligibility criteria), the nurse who coordinated the study opened
the envelope. The study was masked from the principal investigator,
care providers, and biostatistician. The patients were unaware of
the dose they were receiving in the mouthwash. Nevertheless, they
were not masked to the study as the vegetal mouthwash developed
maintained the natural color of chamomile. Hence, the researchers
chose not to use a placebo, as that would require the addition of
coloring to the solution, which could influence the outcome.
Setting and Participants
Patients were recruited between January and August 2011 at an
inpatient unit for adult and pediatric patients undergoing HSCT
at a Brazilian hospital specializing in cancer. Forty subjects were
eligible for inclusion in the study. The inclusion criteria were as
follows: older than 18 years, candidate for allogenic HSCT, and
complete oral cavity on the first day of conditioning. Subjects
younger than 18 years were not included, as studies reveal a
higher risk of developing mucositis in that age group in com-
parison with adults.24 Exclusion criteria were as follows: previous
adverse reaction to chamomile or to any plant in the Asteraceae
family and use of an oral or systemic anticoagulant, topical anti-
inflammatory agent, or other intervention for mucositis not
included in routine care.
Patients were randomly assigned to 1 of the 4 proposed study
groups, containing 10 patients each. In making up the sample,
we considered the instructions for performing studies with
phytotherapeutics. For a phase II clinical trial with medicinal
plants, these guidelines recommend a reduced number of par-
ticipants (10Y15) be used, as the aim of the study is to test the
effectiveness of the active principle in the proposed intervention.
The number of people should then be expanded in phase III.25,26
Intervention
Three scaled dosages of liquid extract (0.5%, 1%, and 2%) of
C recutita were incorporated into the mouthwash formula-
tion. The dosages were standardized according to the amount
of apigenin-7-glucoside, a flavonoid with potent anti-inflammatory
action. The mouthwash was prepared in a pharmotechnical lab-
oratory at a public university. It was developed based on dehy-
drated flower heads that were rigorously controlled until the
final product was obtained, thereby ensuring its safety and ther-
apeutic effectiveness. The physiochemical and microbiological
characteristics of the vegetable species, floral extract, and mouthwash
were evaluated according to the methods described in USP30-
NF2527 and by the World Health Organization (WHO).28
The plant was sampled and submitted to physiochemical
analysis to identify its botany, pureness, and integrity. As a
phytochemical marker for the species, the amount of apigenin-
7-glucoside in the plant was quantified by high-pressure liquid
chromatography with diode array detection, according to the
method described in the 30th edition of the United States
324 n Cancer NursingTM, Vol. 38, No. 4, 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pharmacopeia (USP30-NF25, 2007).27 The excellent quality of
the primary material was identified by its physiochemical char-
acter,27Y29 as shown in Table 1.
Next, the liquid extract was obtained as an intermediary
product (1:1) of the species, by the A percolation test, as
described in the first edition of the Brazilian Pharmacopeia30
(note: the liquid extract was standardized in 10.7 mg/mL of
apigenin-7-glucoside, 20.8% w/v of dry residue, and density
of 1002 g/mL). The liquid extract was distributed according to
the pharmaceutical formulation (Table 2) into 3 preestablished
concentrations. The final product was clean, transparent, and
yellow, with a relative density of 1.030 g/mL, pH range of 5.42
to 5.70, and total bacterial, fungal, and yeast count of less
than 10 UFC/g. The levels of the apigenin-7-glucoside marker
in the final mouthwash formulation were 0.054, 0.108, and
0.216 mg/mL for the 0.5%, 1%, and 2% dosages, respectively.
We decanted the mouthwash into plastic containers made of
ethylene polyterephthalate, with each container coded according
to its corresponding dosage.
Patients in the experimental groups were instructed to rinse
the oral cavity with 10 mL of the prescribed mouthwash twice
a day, 1 hour before meals (breakfast and dinner), for 1 minute
each, and then to spit out the mouthwash. Use of the mouthwash
began on the first day of conditioning and ended when the oral
mucosa was reestablished or the granulocyte count exceeded
500 mm3 for 3 consecutive days in patients who did not de-
velop mucositis. In the HSCT unit, standard care of the oral
cavity consists of training patients about brushing their teeth
and tongue at least 3 times a day and always after meals, using a
brush with extra-soft bristles and a nonabrasive toothpaste, and
removing dentures or orthodontic devices and rinsing with a
0.12% chlorhexidine solution twice a day.
The effectiveness of the intervention was evaluated by the
incidence and intensity of oral mucositis using the oral toxicity
measurement scale defined by the WHO. This scale evaluates
symptoms (pain), signs (erythema and ulceration), and oral
function (ability to swallow). The degree of mucositis can vary
from grade 0 (absence of mucositis) to IV (ulceration and no
Table 1 & Physiochemical Characteristics of the
Chamomilla recutita Inflorescences
Test Result Reference
Appearance Conforms Dehydrated flower
headsa
Organoleptic characteristics Conforms Aromatic odor,
agreeable, sweet;
bitter flavorb
Humidity level 8.82 Max. 12% m/mc
Total ashes 7.45 Max. 13% m/ma
Ashes insoluble in HCl 0.84 Max. 4% m/mc
Foreign bodies 1.25 Max. 2% m/ma
Level of essential oils 0.4 Min. 0.4% m/ma
Level of apigenin-7-glucoside 1.01 Min. 0.3% m/ma
Abbreviations: HCl, hydrogen chloride; Max, maximum; Min, minimum.
a
USP30-NF25 (2007).
b
Brazilian Pharmacopeia IV (1996).
c
World Health Organization (1999).
Braga et al
 wash and adverse effects. Three judges, including 2 nurses and a
Table 2 & Formulation of the Chamomilla
dentist, all specialists in HSCT, validated the instruments. The
recutita Mouthwash
researchers adopted the changes suggested by the judges, which
0.5% 1% 2% were related to how the items were presented.
Components Function (% p/p) (% p/p) (% p/p) In the first 24 hours after intake, the patient was provided
Liquid extract of Active 0.50 1.00 2.00 with information about the characteristics and objectives of the
C recutita study and was invited to participate in the research. A pro-
Sodium benzoate Preservative 0.10 0.10 0.10 fessional acting as research coordinator in the unit, who was not
Sodium saccharide Sweetener 0.02 0.02 0.02 involved in the data collection or application of the intervention,
Methylparaben Preservative 0.10 0.10 0.10 was responsible for verifying the patient’s eligibility and for allocating
Menthol Refresher 0.10 0.10 0.10 participants. The unit’s nursing team offered the mouthwash follow-
Mint aroma Corrective 0.16 0.16 0.16 ing an established protocol. The care providers were trained before
PEG 40 Tensoactive 5.00 5.00 5.00 the start of the study. The professional responsible for the research
Sorbitol Cotensoactivea 5.00 5.00 5.00
coordination explained the intervention protocol in detail to the
Glycerol Cotensoactivea 5.00 5.00 5.00
patients (time and volume of the mouthwash, instruction about
Purified water qsp Vehicle 100.00 100.00 100.00
the duration of the rinsing, monitoring of the execution of the
Abbreviations: PEG, polyethylene glycol; qs, quantity sufficient.
a
intervention, and registration of the accomplishment). The pro-
Synonyms: cosurfactant or coemulsifier. fessional responsible for the training monitored each professional’s
first execution of the protocol to ensure that the protocols were
ingestion of food).31 Grades of I to IV on this scale are considered
fully comprehended by the nursing team. All patients received
to indicate the presence of mucositis, and grades of II to IV in-
standard care of the oral cavity.
dicate the presence of ulceration in the oral cavity. The Cochrane
Data were collected daily, in the morning, by the research
review9 on interventions to prevent mucositis highlights that it
assistants, with the start and end of evaluation following the same
would be helpful if researchers used a simple mucositis index
criteria as established for offering the mouthwash. At the end
with a 0-to-4 scale to facilitate comparison between interven-
of treatment, patients responded to a questionnaire about the
tions. The recommended scales include the WHO.
organoleptic evaluation of the mouthwash. They also reported any
The application of this scale is considered easy to learn, it
occurrence of nausea, vomiting, or burning in the mouth while
demands relatively little time, its implementation does not need
using the mouthwash.
an invasive technique, and it has been used in a large number of
studies and oncology services.32Y34 In the literature, there are Ethical Considerations
many scales for the evaluation of mucositis, none of which is
universally accepted though. Although the WHO does not con- The Research Ethics Committee at the hospital where the study
sider the number and dimension of the lesions,12 it was chosen was performed approved the study (case no. 47/2009). All of the
because of its application characteristics, and because, as it is widely study’s participants signed, in duplicate, the Free and Informed
used in research, this can facilitate comparisons between the study Consent form before being included in the study, after having
findings and the existing literature, thus favoring decision making been provided with verbal and written information about the
in clinical practice. study’s objective, the procedures involved, and the voluntary
The patient’s perception of the mouthwash’s organoleptic nature of their participation. The study was registered in the base
characteristics (taste, smell, and color) and the presence of nausea, ClinicalTrials.gov.
vomiting, and burning in the mouth were measured by a Likert
scale. This scale contained 5 evaluation points, ranging from
Data Analysis
‘‘very agreeable’’ to ‘‘disagreeable’’ for each item of organoleptic The Statistical Package for the Social Science version 19.0 for
evaluation and from ‘‘never’’ to ‘‘very often’’ in the evaluation of Windows (license no. 10101111255) was used for the statistical
adverse effects. Other secondary variables evaluated were the du- analyses. Demographic and clinical data were presented in a descriptive
ration of oral mucositis and the use of TPN or of opioid analgesics, form (frequency, absolute, average, median, and standard deviation, as
evaluated as days of occurrence. appropriate to the type of variable). All other analyses were performed
by comparing each of the experimental groups with the control
Data Collection group. Fisher exact test was used to compare the incidence of
mucositis, and the Mann-Whitney U test was used to compare
Two previously trained and calibrated nurses (research assistants)
the other clinical variables (intensity and duration of the mucositis,
evaluated subjects daily and assessed the study variables. An in-
days of use of TPN, and opioid analgesics). The significance level
strument was developed for collecting data related to the char-
adopted was ! = .05.
acteristics of the subject (sex, age, and baseline pathology) and the
HSCT (conditioning regimen and sources of hematopoietic stem
cells). A second instrument collected information related to the n Results
signs and symptoms evaluated in the WHO’s oral toxicity mea-
surement and the use of opioid analgesics and TPN. A third During the period of data collection, 45 patients were evaluated
instrument concerned the organoleptic evaluation of the mouth- for eligibility. Five of these patients did not meet the inclusion

Use of Chamomilla recutita in Mucositis Cancer NursingTM, Vol. 38, No. 4, 2015 n 325

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

criteria. Thus, the sample consisted of 40 patients undergoing
allogenic HSCT. There were no follow-up losses or migration
between groups (Figure). Most of the included patients were
men (n = 25), with mean (SD) age of 36.4 (13.0) years. The most
frequent baseline pathologies were severe aplastic anemia (n = 9),
acute myeloid leukemia (n = 9), and acute lymphocytic leukemia
(n = 8). The types of conditioning used in HSCT were busulfan
and cyclophosphamide (n = 12), fludarabine and melphalan
(n = 10), and fludarabine and busulfan (n = 8) (Table 3).
Mucositis incidence was lower in the group that received
mouthwash at a 1% dosage (n = 3, 30%), compared with the
control group (n = 9, 90%) (P = .01). Four patients (40%) who
received the 2% dosage did not show signs or symptoms of mucositis
(Table 4). In terms of mucositis intensity (Table 4), the group that
received the 1% dosage had significantly lower scores on the
WHO scale compared with the control group. This group also
had fewer days of mucositis (mean, 1.9 days; median, 0 days) com-
pared with the control group (mean, 5.7 days; median, 5 days;
P = .01).
The experimental and control groups showed statistically simi-
lar and low rates for the number of days using analgesic medication
or TPN. The lowest mean number of days using opioids (0.7 days;
median, 0 days) was identified with the use of the 0.5% dosage,
whereas the control group had the highest numbers (mean,
2.5 days; median, 0.5 days). Patients who received the 1% dosage
used TPN for the fewest days (mean, 0.3 days; median, 0 days),
whereas the control group used TPN for the most days (mean,
2.0 days; median, 0.5 days). The 1% dosage group had the
fewest ulcerative lesions (n = 3, 30%), whereas the control group
had the most patients with ulceration (n = 7, 70%). The 0.5%
and 2% dosage groups each had 6 patients (60%) with ulcerations
in the oral cavity.
Figure n Flow diagram of enrollment, intervention allocation, and analysis for the study participants.
326 n Cancer NursingTM, Vol. 38, No. 4, 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Regardless of their group, most patients (84%) classified the
mouthwash as being ‘‘very pleasant’’ or ‘‘pleasant,’’ considering
the flavor to be sweet and refreshing. Only 2 patients who re-
ceived the 2% concentration and 1 patient who received the
0.5% concentration found the flavor nauseating. One patient
from the 2% group found the smell disagreeable, and 1 patient
from the 0.5% group said the smell was nauseating. All patients
indicated that they liked the color. Of the 30 patients who used
the mouthwash, 4 patients mentioned an adverse effect during
rinsing. One patient who used the 1% dosage had rare nausea.
The other 3 patients belonged to the 2% dosage group. One
noted infrequent burning in the mouth, 1 noted occasional burn-
ing and nausea, and 1 reported frequent nausea and vomiting. The
health team did not find any other adverse effects related to the
topical use of mouthwash containing C recutita.
n Discussion
Hematopoietic stem cell transplantation can be used for various
types of diseases, such as malignant and nonmalignant, auto-
immune, and genetic hematological diseases. However, it is con-
sidered a risky procedure for the patient because of the various
possible complications.35 Oral mucositis is 1 common and serious
complication among these patients, particularly among those un-
dergoing allogenic HSCT.1,11 Preventing oral mucositis can con-
tribute to improve the patient’s well-being and reduce clinical
complications during the hospitalization period. In this present
study, use of mouthwash containing C recutita at a 1% dosage re-
duced the mucositis incidence to 30%, compared with 90% in
the control group (P = .01). This finding suggests that, at this
dosage, the mouthwash probably acts to prevent oral mucositis.
Braga et al
 Table 3 & Clinical and Demographic Characteristics of Patients Undergoing Allogenic Hematopoietic Stem Cell
Transplantation (n = 40)
Dosage of Chamomilla recutita

Variables 0.5% (n = 10) 1% (n = 10) 2% (n = 10) Control (n = 10) Total (n = 40)

Sex
Female 5 3 4 3 15
Male 5 7 6 7 25
Age, y
Mean (SD) 39.1 (15.3) 32.8 (12.8) 36.8 (11.2) 37.2 (13.6) 36.4 (13.0)
Median 39.0 32.5 34.5 40.5 35.0
Range 19Y61 19Y58 22Y51 20Y57 19Y61
Pathology
Severe aplastic anemia 2 3 1 3 9
Acute myeloid leukemia 2 1 3 3 9
Acute L. leukemia 2 4 2 0 8
Chronic myeloid leukemia 1 0 2 1 4
Chronic L. leukemia 1 1 1 0 3
Non-Hodgkin lymphoma 0 1 1 1 3
Others 2 0 0 2 4
Conditioning regimen
BU-CY 4 3 3 2 12
FLU-MEL 2 2 3 3 10
FLU-BU 3 1 1 3 8
FLU-CY 1 1 2 2 6
VP-TBI 0 2 0 0 2
FLU-CY-TBI 0 1 1 0 2
Sources of HSC
Medulla ossea 6 4 6 6 22
Peripheral blood 4 4 2 4 14
Umbilical cord blood 0 2 2 0 4

Abbreviations: BU-CY, busulfan and cyclophosphamide; FLU-BU, fludarabine and busulfan; FLU-CY, fludarabine and cyclophosphamide; FLU-CY-TBI, fludarabine,
cyclophosphamide, and total body irradiation; FLU-MEL, fludarabine and melphalan; HSC, hematopoietic stem cells; L, lymphocytic; VP-TBI, vepesid and total body irradiation.
A previous study of 1315 patients at 19 centers examined 96 patients who received myeloablative conditioning for
the incidence of mucositis in HSCT, showing that 71.4% of HSCT found an incidence of 90.2%.2 These previous results
patients developed mucositis.1 Another study performed with are similar to those found here in the 0.5% group (70%) and
Table 4 & Distribution of Patients Undergoing Allogenic Hematopoetic Stem Cell Transplantation (n = 40) According
to the Clinical Characteristics of the Mucositis and the Number of Days They Used Total Parenteral
Nutrition (TPN) and Opioids
Dosage of Chamomilla recutita

Variables 0.5% (n = 10) 1% (n = 10) 2% (n = 10) Control (n = 10)

Incidence of mucositis
n (%) 7 (70) 3 (30)a 6 (60) 9 (90)
Intensity of the mucositis
Median 2.0 0b 2.0 2.0
Mean (SD) 1.6 (1.2) 0.7 (1.1) 1.6 (1.5) 2.1 (1.1)
Duration of the mucositis (days)
Median 3.5 0b 3.5 5.0
Mean (SD) 5.7 (5.5) 1.9 (3.4) 6.9 (9.4) 5.7 (4.0)
Days using TPN
Median 0 0 1 0.5
Mean (SD) 1.1 (2.0) 0.3 (0.9) 1.8 (2.2) 2.0 (2.9)
Days using opioids
Median 0 0 0 0.5
Mean (SD) 0.7 (1.2) 0.8 (2.5) 1.0 (1.7) 2.5 (3.5)
a
P = .01 by Fisher exact test.
b
P = .01 by Mann-Whitney U test.

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

the control group (90%) but are higher than those in the 1%
group (30%) and the 2% group (60%). The intensity of the
mucositis was lowest in the group that received the 1% dosage
(mean, 0.7) and highest in the control group (mean, 2.1). A
study investigating the use of palifermin to treat mucositis iden-
tified an average intensity for mucositis of 1.73 for the experi-
mental group and 2.47 for the control group.36 Another study
used a supersaturated calcium phosphate rinse and had an average
of 0.9 for the experimental group and of 1.8 for the control.37
In terms of using C recutita to manage oral mucositis, we iden-
tified 3 studies in the literature with an experimental research de-
sign. In 1 of these studies, which used a quasi-experimental definition,
a solution containing C recutita was probably effective in reduc-
ing the incidence and intensity of mucositis induced by chemo-
therapy and/or radiation therapy.38 The second study, an RCT,
indicated an absence of evidence for the use of C recutita to
prevent and treat oral mucositis induced by 5-fluoracil.39 The
third study, also an RCT, found evidence of the effectiveness of
C recutita in preventing and reducing the intensity of mucositis
in patients undergoing chemotherapy.40 Thus, our results con-
firm the findings of 2 studies38,40 regarding the ability of C recutita
to prevent and reduce the intensity of oral mucositis.
None of these previous studies involved a sample composed
of people undergoing HSCT, and none reported the dosage of
the active principle components or provided physiochemical or
microbiological analyses of the solution used. Such information
is desirable to conduct experimental clinical studies with medi-
cinal plants and to support the effectiveness of the therapeutic.26,41
In contrast, this study covered the period from the process of
obtaining the vegetable drug up to the preparation of the mouthwash.
Analyses of the physiochemical and microbiological profiles
showed the quality and integrity of the active principles present
in the vegetable drug and their microbiological safety.
Ulceration, which is 1 of the most uncomfortable symptoms
for patients with mucositis,5,6 was present in all of the groups
in this study. However, among those subjects who received the
1% dosage, ulceration was less frequent (30%). A multicenter
clinical study that evaluated the use of palifermin in reducing
the incidence and intensity of mucositis identified that the inci-
dence of grades II to IV according to the WHO scale (which
considers erythema and ulcerations) was 60% for the group re-
ceiving palifermin and 86% for the control group (P = .04).36
The results of the present study for the 0.5% and 2% dosage
groups were similar to those of the group that received palifermin.
However, the result for the 1% group was higher. This infor-
mation is relevant, considering that palifermin is the only medi-
cally indicated therapy used to prevent and treat HSCT-related
mucositis by the Multinational Association of Supportive Care in
Cancer and the International Society for Oral Oncology. Moreover,
the reductions in the incidence and intensity of the mucositis led
to a lower consumption of TPN and opioid medications,36 in
both the previous and the present studies.
Most patients gave the mouthwash good evaluations in terms
of flavor, smell, and color. Positive organoleptic characteristics
are desirable when formulating a mouthwash and are indispensible
for patients to tolerate the formulation. Four patients noted some
form of adverse effect when using the mouthwash, but only 1
328 n Cancer NursingTM, Vol. 38, No. 4, 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
patient had frequent nausea and vomiting. The health team did not
record any other event, showing that the formulation prepared for
this study was safe to use, independent of the C recutita dosage.
Considering that the chemotherapeutic medications administered
in the conditioning regimens for HSCT have a high emetogenic
potential, we consider the results obtained for nausea and vomiting
to be satisfactory. Only 3 patients had these conditions when using
the mouthwash. Two other studies that also used oral formulations
containing C recutita to manage mucositis had results similar re-
sults in terms of tolerance and side effects.38,39
An advantage of using C recutita is its low cost. Because it is
a widely cultivated medicinal plant,40 a C recutitaYcontaining
mouthwash could become an accessible therapy instituted by
many practices. Given that C recutita is a medicinal plant of
natural origin, the quantity of its chemical constituents could vary
with the cultivation temperature, water availability, quantity of
ultraviolet light, nutrient availability in the soil, and the harvest
period.42 Therefore, the use of standardized formulation allows
the formula to be reproduced, which is impossible when using
an infusion of its floral inflorescences.
Although the results of this phase II RCT suggest that the use
of a mouthwash with a dosage of 1% C recutita may reduce the
incidence and intensity of oral mucositis in patients undergo-
ing HSCT, certain limitations need to be noted. In particular,
the patients in this study were not masked. Moreover, we did
not use a placebo together with standard care in the control group.
As a phase II RCT, the small sample size is justifiable and desirable
for this research phase. To confirm the study findings, however, a
phase III clinical trial is needed, applying the method developed
here to a larger sample. Also, the present study sample included a
range of conditioning regimens and diseases, which are potential
confounders that need to be accounted for in future studies.
n Conclusion
In this study, the use of a mouthwash containing the liquid ex-
tract of C recutita at a 1% dosage (equivalent to 0.108 mg of
apigenin-7-glucoside per milliliter of product) can be associated
with the reduced incidence, intensity, and duration of mucositis
in adult patients undergoing allogenic HSCT. Mouthwashes at
dosages of 0.5%, 1%, and 2% were generally well tolerated by
patients and were safe, as no moderate or severe adverse effects
were identified. These findings provide grounds for a phase III
clinical trial involving a larger number of subjects. The results of
this investigation will help nurses and other health professionals
in choosing the dosage of C recutita to be used to manage oral
mucositis in patients undergoing HSCT.
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