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SAMITAL®: A new botanical drug for the treatment of mucositis induced by

oncological therapies

Article  in  Future Oncology · November 2013

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SAMITAL®: a new botanical drug

Drug Evaluation
Future Oncology
for the treatment of mucositis
induced by oncological therapies
Paolo Morazzoni1, Giovanna Petrangolini*1, Ezio Bombardelli1,
Massimo Ronchi1, Walter Cabri1 & Antonella Riva1
1
R&D Department, Indena SpA, Viale Ortles 12, Milan, Italy
*Author for correspondence: Tel.: +39 02 57496493 n giovanna.petrangolini@indena.com

SAMITAL® (Indena SpA, Milan, Italy) is a new multicomponent and multiacting

botanical formulation rationally designed for the relief of oral mucositis induced
by chemotherapy and/or radiotherapy in oncological patients. Each of the
individual botanical constituents of SAMITAL-standardized extracts of Vaccinium
myrtillus, Macleaya cordata and Echinacea angustifolia have a long history of
clinical use that corroborates their safety and activity in SAMITAL. A number of
pilot trials in oncological patients demonstrated that SAMITAL has good clinical
efficacy and tolerability as evidenced by its significant effects in terms of
reduction of mucositis, pain and a general improvement in patient quality of life.
Importantly, the use of this botanical formulation had the added benefit that
patients were able to complete their chemotherapy/radiotherapy regimen.
Phase II trials with SAMITAL as part of an overall clinical development program
are currently ongoing in Italy and are planned in the USA.

Mucositis is a potentially devastating complica­
tion of most oncological therapeutic regimens
that causes significant patient morbidity and for
which the current available therapy is in­adequate.
Mucositis, characterized by inf lammation,
ulceration, hemorrhage and overinfection of the
mucosal structures, can occur anywhere along
the GI tract and other mucosal linings. Oral and
gastrointestinal mucositis are frequent and seri­
ous side effects of chemotherapy (CT) and radia­
tion therapy (RT) in oncology [1]. Myelotoxic
conditioning regimens, which are required prior
to hematopoietic stem cell transplantation and
head and neck RT, are associated with the great­
est degree of oral mucositis. According to the
US National Cancer Institute, most patients
with head and neck cancer treated with CT
and/or RT (~80–100%) and with hemato­
logical malignancies undergoing hematopoietic
stem cell transplantation (70–80%) develop
severe oral complications, including mucositis,
with various degrees of severity [2–5]. In Europe,
the likelihood of developing mucositis induced
by CT and/or RT in head and neck cancer
patients is estimated to be approximately the
same (70–100%). Standard dose CT is associ­
ated with a 40% risk of all-grade mucositis, with
grade 3–4 oral mucositis (OM) developing in
5–20% of the patients. The severity of OM cor­
relates with both the number of cycles of CT and
mucositis [6]. Although the new targeted drugs
are considered to be less aggressive, they can still
induce OM [7,8]. OM is increasingly becoming
a dose-limiting toxicity for a number of treat­
ment regimens, as other side effects of cytotoxic
antineoplastic therapy or RT are more readily
controlled [5,9,10].
The pathological mechanisms underlying
mucositis are known [11,12] and include a first
step in which the mucosal tissue is injured by CT
or RT. This initial response to damage generates
reactive oxygen species, upregulating a number
of transcriptional factors, including NF-κB and
is followed by a sustained, amplified inflamma­
tory reaction. The last stage is characterized by
wound resolution and healing when toxic CT or
RT treatments are ceased. At all stages soreness
and pain can result, potentially limiting eating
and drinking and often requiring treatment
with narcotic analgesics. In addition to pain,
the ulceration of the mucosa is associated with a
risk of bacterial and viral infections. Specifically,
OM has been associated with an increased risk
of systemic infection with Streptococcus viridans,
presumably originating from the mouth.
OM symptoms, which generally appear Keywords
4–5 days after the start of oncological treat­
n botanical formulation
ment, can resolve 2–3 weeks after cessation of n chemotherapy n head and
treatments [1]. The severity of OM varies accord­ neck cancer n oral mucositis
ing to intraindividual variables and depends n radiotherapy n SAMITAL®

the history of mucositis with prior CT. For some on treatment type, duration and intensity [1,13],
agents, such as 5-fluorouracil (5-FU), the drug and may lead to a premature cessation of treat­
schedule may alter the incidence and severity of ment. All these aspects have a negative impact part of

10.2217/FON.13.165 © 2013 Future Medicine Ltd Future Oncol. (2013) 9(11), 1717–1725 ISSN 1479-6694 1717
 Drug Evaluation Morazzoni, Petrangolini, Bombardelli, Ronchi, Cabri & Riva
on health-related quality of life. Due to inflam­
matory lesions and ulcers of the mucosa, OM
is associated with considerable pain, dysphagia
and can interfere with nutrition (often leading to
the need for parenteral nutrition) and speech, as
well as an increased susceptibility to infections,
particularly by bacteria and fungi [9].
Despite the predictability of mucositis, its fre­
quency, debilitating symptoms, negative impact
on the treatment program, and health- and
economic-related costs of the patients, an effec­
tive therapy for OM is still elusive. A number
of guidelines and controlled clinical studies have
been published to establish treatment protocols
using topical, systemic and/or nonpharmaco­
logic interventions with varying success [14–18].
Treatment guidelines for mucositis emphasize
basic oral hygiene, with an interdisciplinary
approach to assessment of oral/dental care,
and pain management using validated instru­
ments prior to the beginning of cancer therapy.
In a recent Cochrane meta-analysis reviewing
131 studies with more than 10,000 patients, ten
interventions were found to have benefit in pre­
venting and reducing the severity of mucositis
associated with cancer treatment; however, the
strength of this evidence was variable [19]. Similar
conclusions were reached by another Cochrane
meta-analysis on the treatment of OM [20].
Therefore, mucositis remains a debilitating side
effect of CT and RT with high health and eco­
nomic costs and for which there is currently no
effective treatment. There is a general consensus
that further research is needed in the prophylaxis
and treatment of OM in cancer patients [5,19–21].
There are many therapeutic strategies at differ­
ent stages of development for OM, such as cryo­
therapy and low-level laser therapy. Kepivance®
(Biovitrum, Stockholm, Sweden; palifermin) is
the first and only pharmaceutical/biological agent
specifically approved for the treatment of OM.
The approved indication is limited to patients
undergoing stem cell transplantation for hema­
tological malignancies; consequently it is only
effective in a subset of oncological patients [17].
Potential role of phytochemicals in OM
Phytochemicals, plant-based bioactive com­
pounds, have been used traditionally and histori­
cally for medicinal purposes and form the basis
of many modern pharmaceuticals [22]. Generally,
phytochemicals are used for primary disease pre­
vention or as adjuncts to conventional therapies
but also in the oncological setting [23]. Western
and eastern phytotherapy lists an impressive num­
ber of plant derivatives with ‘documented’ clinical
1718 Future Oncol. (2013) 9(11)
efficacy. Both preclinical and clinical studies have
been conducted to evaluate the potential role
of herbal extracts and other phyto­chemicals in
the treatment of CT-/RT-induced OM. Cheah
et al. showed that grape seed extract ameliorated
intestinal damage in a rat model of CT-induced
mucositis, and protected intestinal epithelial cells
against 5-FU-induced cytotoxycity in vitro, most
likely due to the antioxidant and anti-inflamma­
tory properties of the proanthocyanidins con­
tained in the extract [24]. Similarly, the herbal
extract Iberogast® (Flordis Herbal Medicines,
New South Wales, Australia) was shown to
improve, at least in part, the histopathological
features of 5-FU-induced mucositis in mice [25].
Another herbal extract, obtained from Rhodiola
algida, has been demonstrated to have immune-
stimulating effects and to reduce the number of
oral ulcers in breast cancer patients undergoing
CT [26]. The efficacy of these botanical com­
pounds may be attributed to their antioxidant,
anti-inflammatory and immuno­modulatory
properties. In fact, RT- and/or CT-induced cel­
lular damage results in the generation of reactive
oxygen species and stimulation of proinflamma­
tory pathways, which causes tissue injury and
eventually ulcerations and inflammation of the
mucosa [27,28]. Three widely used plants have
been identified, based on their mechanism of
action, clinical efficacy and tolerability, namely
Vaccinium myrtillus (bilberry), Macleaya cordata
fruits and Echinacea angustifolia roots, and have
been used to develop SAMITAL® (Indena SpA,
Milan, Italy), a ‘multiacting’ formula targeted for
the management of OM in oncological patients.
The preclinical and clinical data on SAMITAL
is reviewed in the following paragraphs.
SAMITAL
Characteristics & functions
SAMITAL is composed by three highly stand­
ardized botanical extracts from V. myrtillus, M.
cordata dried fruits and E. angustifolia dried
roots. These three active extracts in SAMITAL
are classified as ‘herbal drug preparations’, and
are standardized and purified. The main active
constituents contained in the three botanical
extracts of SAMITAL are polyphenols, such as
anthocyanosides, alkaloids and alkylamides.
The US FDA’s ‘Guidance for Industry: Botanical
Drug Products’ released by the Center for Drug
Evaluation and Research (June 2004) allowed
the development of SAMITAL in the USA as
a botanical drug [29]. SAMITAL is provided as
granules for suspension in sachets. The current
dose of SAMITAL for the treatment of OM is
future science group
 SAMITAL® for the treatment of mucositis induced by oncological therapies
four sachets per day. SAMITAL is intended to
act locally; the contents of one sachet is generally
reconstituted with 20 ml of drinkable water to
allow the formation of a gel-like suspension to
be administered in small aliquots and to prolong
the exposure of the damaged oral mucosa to the
active ingredients. Originally it was formulated as
a soluble lozenge dosage form allowing a slow dis­
solution in the mouth. However, the poor patient
compliance, especially in OM grade 3–4 patients,
drove the formulation development towards a ‘less
aggressive’ oral dosage form.
V. myrtillus grows all over Europe and Russia,
and is harvested in a highly standardized man­
ner for pharmacological purposes in Europe.
The main active components in V. myrtillus
fruit extracts comprise a pool of 15 anthocyanins
(anthocyanosides), polyphenols that contain a
glycosidic residue. A number of pharmacological
activities have been documented for V. myrtil-
lus, including ophthalmic, anti-inflammatory,
wound-healing, antiulcer, antiatherosclerotic
and vasoprotective properties [30]. These activi­
ties are likely due to the mucus protective effect
and regeneration activity exerted by V. myrtillus,
through improving fibroblast proliferation and
stimulating glycosaminoglycan synthesis [30].
V. myrtillus extracts are commonly used for the
treatment of conditions linked with fragility and
altered permeability of small vessels and capillar­
ies [31,32], as well as for the symptomatic treatment
of diarrhea, a number of eye disorders (e.g., poor
night vision, eye strain and myopia), diabetes,
gout, rheumatism, burns and skin infections [23].
M. cordata (common name: plum poppy) is
a basally lignified, yellow lactiferous, perennial
herb belonging to the family of Papaveraceae.
The plants grow wild in foothills, forests, among
shrubs or tussocks on low mountains, riversides,
and between 100 and 800 m in China and Japan.
The benzophenanthridine alkaloids represent the
most important active constituents of M. cordata
fruit and extracts. These are known to exert
antibacterial/antifungal and antiviral effects, as
well as anti-inflammatory activities, as shown by
preclinical and clinical studies [33–35]. In particu­
lar, M. cordata blocks the cascade of proinflam­
matory cytokines through inhibition of NF-kB
activation [36].
E. angustifolia lipophilic extract is prepared
from E. angustifolia DC, a perennial herb har­
vested in a controlled, cultivated environment in
Europe. The constituents with known therapeutic
activity of the lipophilic extracts of E. angustifo-
lia roots are alkylamides showing high affinity
for the human CB2 receptor [37] and reported to
future science group
Drug Evaluation
act as agonists for TRPV1 receptors, suggesting
an activity on peripheral pain [38]. E. angustifolia
lipophilic extracts have also been used in Europe
for the prevention of viral and bacterial diseases,
due to their immunomodulatory activity [39,40].
Some of the compounds present in Echinacea
also have healing properties, as acknowledged by
the ABC Clinical Guide to Herbs [41] and WHO
pharmacopeia [42], which recommend using
Echinacea in wound healing.
Evidence from pharmacological studies sup­
ports the rationale of the fixed-dose combination
of SAMITAL in the treatment of OM. Preclinical
studies have in fact shown the ability of the three
known components of SAMITAL to interfere
with the mechanisms underlying OM, as refer­
enced and summarized in Table 1. Anthocyanosides
in the V. myrtillus extract may reduce tissue dam­
age and ulceration through their free radical
scavenging properties, as well as by increasing
wound healing and enhancement of mucosal bar­
rier protection [30,43,44] during the initial phases
of tissue injury induced by CT and/or RT. All
three ingredients of SAMITAL contributed to
varying extents and their roles were to: protect
the integrity of capillary vessels (V. myrtillus)
[31,32,45], block the cascade of proinflammatory
cytokines through inhibition of NF-κB activa­
tion (M. cordata) [36], modulate cannabinoid CB2
receptors and inhibit leukotriene and prostaglan­
din E2 synthesis (E. angustifolia) [46]. In addition,
benzophenanthridinic alkaloids (components of
the M. cordata extract) are thought to prevent
viral, bacterial and fungal infections by block­
ing growth of a wide variety of micro-organisms,
inhibiting bacterial nuclease, altering cell wall
permeation and likely playing an important role
in the mucositis phase of superinfection [47,48].
Last, it is important to point out that all stages
of OM are characterized by soreness and pain. The
high affinity of the alkylamides in E. angustifolia
for the human CB2 receptor as well as evidence
of agonism with TRPV1 receptors, suggests that
SAMITAL may reduce peripheral pain. Some
unpublished data by our group suggest that topi­
cal application to rat hippocampal slices reduce
synaptic transmission [Riva A et al. Analgesic effect
of SAMITAL ®: identification of molecules, synergies and
mechanism (2013), Manuscript in preparation].
Clinical data
From 2008–2011, a total of 140 oncological
patients (120 adults and 20 pediatric subjects)
with mucositis induced by CT/RT have been
treated with SAMITAL (formulated as oral
soluble lozenges or granules for suspension
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 Drug Evaluation Morazzoni, Petrangolini, Bombardelli, Ronchi, Cabri & Riva

Table 1. Summary of pharmacological actions of SAMITAL® and individual active constituents.

Pathology SAMITAL®/active constituent Possible mechanism of action
Tissue damage/ulceration Anthocyanosides in Myrtocyan ®
(Vaccinium myrtillus extract)
Inflammation Anthocyanosides in Myrtocyan
(integrated activities of (V. myrtillus extract)
the three ingredients)
Benzophenanthridine alkaloids in
Macloil® (Macleaya cordata
extract)
Alkylamides in Echinamid™
(Echinacea angustifolia lipophilic
extract)
Pain Alkylamides in Echinamid
(E. angustifolia lipophilic extract)
SAMITAL
Ref.
Reduction of damage caused by radiation or [29,42,43]
chemotherapy treatment via scavenging free
radicals, wound healing activity and mucosal
barrier protection
Reduction of edema and bleeding by [31,44]
protecting the integrity of capillary vessels
[35]
Inhibition of NF-kB activation and the cascade
of proinflammatory cytokines
Modulation of cannabinoid CB2 receptor, [36,45,55]
inhibition of leukotriene synthesis and
inhibition of prostaglandin E2 synthesis
Modulation of cannabinoid CB2 receptor and [36,37,45,55]
agonism with transient receptor potential
channel (TRPV1) receptor
Reduction of synaptic transmission Unpublished data†

Infections Benzophenanthridine alkaloids in Prevention of viral, bacterial and fungal [32,56]

Macloil (M. cordata extract) infections, and inhibition of bacterial
nuclease, therefore altering cell wall
permeation
†
[Riva A et al. Analgesic effect of SAMITAL®: identification of molecules, synergies and mechanism (2013), Manuscript in preparation].

3–4 times/day). The studies were conducted in
patients with head and neck cancer (including a
prophylaxis study), hematological malignancies
and in pediatric patients [49–55].
Although these studies were only ‘proof-
of-­c oncept’, they consistently showed that
SAMITAL was effective in controlling symp­
toms of severe mucositis, in improving the recov­
ery of lesions and in reducing their progression.
A positive effect on dysphagia was also observed
and associated with an improvement in painful
symptoms. Improved quality of life was observed
in all the patients who completed SAMITAL
treatment. Importantly, these improvements
allowed the schedule of CT/RT to be maintained.
SAMITAL was generally well tolerated in all
clinical studies. Adverse events were infrequent;
the most common events included vomiting,
nausea, dysgeusia, xerostomia and dysphagia.
However, all the events were of mild-to-moderate
severity and resolved with standard medical
treatment; no alterations of vital signs or labora­
tory abnormalities were found under SAMITAL
treatment.
An overview of the clinical studies conducted
with SAMITAL for the treatment of mucositis
induced by oncological therapies is provided in
Table 2 and results of each individual study are
described in the sections below. Although these
studies yielded promising results, it should be
noted that only one of them was placebo con­
trolled, and that, to date, no randomized
Phase III trials on the efficacy and safety of
SAMITAL have been conducted. Furthermore,
patients with different clinical characteristics
and cancer sites who were treated with differ­
ent CT and/or RT regimens were enrolled in
these studies, which could possibly confound the
outcomes reported. These confounding factors
have carefully been taken into consideration dur­
ing the design of new randomized studies with
SAMITAL.
Head & neck cancer
An Italian–Chilean clinical experience allowed
the treatment of 28 patients with different
types of head and neck cancer [54]. Both stud­
ies were approved by the Institutional Ethical
Committees. Seven patients in the Italian arm
were initially treated with SAMITAL in loz­
enge form (four lozenges per day). Thereafter,
when the revised formulation (granules for oral
suspension in sachets, four-times a day) became
available, seven other patients in the Italian
arm and 14 in the Chilean arm were included
in the study. Overall, mucositis significantly
improved in all 28 patients, and a 90% reduc­
tion in pain and dysphagia was observed. Three

1720 Future Oncol. (2013) 9(11) future science group

 Table 2. Clinical studies performed with SAMITAL® for the treatment of mucositis induced by oncological therapies.
Study number, study Overall number Mean age Sex Study design SAMITAL® formulation and dosage regimen Ref.
period† (country) enrolled/completed (years) (M/F) (duration)
Treatment of mucositis induced by CT/RT for head and neck neoplasms
SAM 01/10, 23 January 30/17 52.4 24/6 R, OL, PC One sachet q.i.d. for up to 7 weeks (50 days) [48]

future science group

2010–20 August 2010,
(India)
LLCT06-SmT-06A‡ Part 4, 14/14 69.5 11/3 Compassionate use One sachet q.i.d. for up to 7 weeks (50 days) [53]
2009–2010 (Chile)
SAM 01/08, 2008–2009 14/11 62 10/4 OL Seven patients: one lozenge q.i.d. until the end of CT/RT
(Italy) (at least 7 days)
Seven patients: one sachet q.i.d. for up to 7 weeks (50 days) §
Prevention of mucositis induced by CT/RT
INT 42/07, 2007–2010 (Italy) 37/6 54¶ 25/12 OL (comparing results with 17 patients: one lozenge q.i.d., 5 days/week (M–F) for up to [50,51]
published data) 7 weeks
20 patients: one sachet q.i.d., 5 days/week (M–F) for up to
7 weeks
Treatment of mucositis in other oncological areas (pediatric and hematological malignancies)
LLCT06-SmT-06A‡ Part 2, 20/20 Range: 11/9 Compassionate use One sachet q.i.d. for up to 3 weeks (21 days) [49]
2009–2010 (Chile) 0.3–17 (pediatric malignancies)
LLCT06-SmT-06A‡ Part 3, 25/25 39.7 19/6 Compassionate use One sachet q.i.d. for up to 7 weeks (50 days) [52]
2009–2010 (Chile) (hematological malignancies)

www.futuremedicine.com
Total number of reported subjects: total, 140 (120 adults and 20 pediatrics); SAMITAL: 130 (110 adults and 20 pediatrics).
†
Date initiated and completed (last patient, last visit).
‡
These patients have been classified into four groups for separate reporting, according to their clinical characteristics and etiology of mucositis, as follows: patients with severe mucositis of different etiologies (Part 1,
not reported because of the heterogenicity of the group); children with mucositis secondary to CT (Part 2); adults with mucositis secondary to CT (Part 3); and adults with mucositis secondary to CT/RT for head and
neck cancers (Part 4).
§
One patient was administered SAMITAL lozenges for 14 days followed by SAMITAL granules for suspension for 16 days.
¶
Median.
CT/RT: Chemotherapy and/or radiotherapy; F: Female; M: Male; M–F: Monday to Friday; OL: Open label; PC: Placebo controlled; q.i.d.: Four times a day; R: Randomized.
SAMITAL® for the treatment of mucositis induced by oncological therapies
Drug Evaluation

1721
 Drug Evaluation Morazzoni, Petrangolini, Bombardelli, Ronchi, Cabri & Riva
of the lozenge-treated patients (43%) dropped
out due to a stinging, burning sensation (n = 2)
and epigastric pyrosis (n = 1). On the introduc­
tion of SAMITAL granules for oral suspension,
no tolerability issues or side effects were reported.
A randomized, placebo-controlled, single-
blind, Phase II trial was conducted at the
Gokhale Hospital (Pune, India) and investigated
the safety and efficacy of SAMITAL in the treat­
ment of CT-/RT-induced OM in 30 patients
with head and neck cancer [49]. After receiving
approval by the League Health Independent
Ethics Committee, patients were randomly
assigned to receive either SAMITAL sachets or
placebo four times a day for up to 50 days during
scheduled CT/RT treatment. Severity of OM
was monitored according to a modified WHO
severity scale and pain and quality-of-life assess­
ments were based on the effect of symptoms of
OM on relevant daily activities, according to a
visual analog scale. Overall, mean scores indi­
cating the severity of OM were significantly
(p < 0.05) reduced from day 31 until the end
of treatment in patients receiving SAMITAL
(n = 20), while no significant improvements were
observed in the placebo group. Pain reduction
reached statistical significance, when compared
with baseline values, from day 4 until the end
of treatment with SAMITAL and only from
day 7 to 21 in placebo patients. SAMITAL sig­
nificantly ameliorated patient quality of life, as
shown by improvements in scores for relevant
daily activities including eating, drinking and
sleeping. All SAMITAL patients completed
treatment, while no patients assigned to placebo
were able to complete scheduled CT and/or RT.
No severe adverse events were observed.
A prospective, monocentric, single-arm
Phase II trial was conducted according to a
prophylactic approach to OM at the National
Cancer Institute of Milan, Italy (approved by
Ethical Committee of the National Cancer
Institute of Milan, Italy) [51,52]. The study
included a total of 37 patients with stage III–IV
head and neck squamous cell carcinoma assigned
to treatment with RT and platinum-based CT,
with at least ≥2 cm 2 of oral cavity mucosa in
the RT field. SAMITAL was administered four-
times daily, 5 days/week, from weeks 2–7 and
for an additional 2 weeks in the case of clinical
benefit. The primary end points were the inci­
dence of WHO grade 3–4 mucositis and com­
pliance to SAMITAL treatment. Secondary end
points included weight loss during treatment,
the proportion of patients requiring a feed­
ing tube and the incidence of grade 3 systemic
1722 Future Oncol. (2013) 9(11)
infections. The majority of patients (n = 24;
65%) experienced mucositis grade <3, and no
grade 4 mucositis were reported. The overall rate
of discontinuation of SAMITAL was 84% due
to emesis (39%), dysgeusia (19%), xerostomia
(16%) and dysphagia (13%). Considering only
patients that continued SAMITAL after the
fourth week, mucositis grade 3–4 reduced to
30%, with respect to 41% reported in those not
continuing SAMITAL. Overall, the incidence of
mucositis grade 3–4 was reduced with respect to
historical controls.
Hematological tumors
Bertoglio and colleagues assessed the efficacy
of SAMITAL in the reduction of the severity
and symptoms of OM in 25 adult patients with
hematological neoplasms after the approval by
the Ethical Committee of the Hospital Clínico
Regional de Valdivia (Los Ríos, Chile) [53].
The administration of SAMITAL resulted in
significant clinical improvements, when com­
pared with conventional therapy, with a reduc­
tion of pain, mucosal erosions, bleeding and
dysphagia/feeding impairment. SAMITAL ame­
liorated patients overall condition and quality
of life in 95% of patients. SAMITAL was well
tolerated, and was not associated with any local
or systemic pharmacological, allergic, toxic or
synergistic/antagonistic side effects. Of note,
patients treated with SAMITAL before the ini­
tiation of a new CT cycle experienced a reduc­
tion in the severity and duration of subsequent
CT-associated mucosal damages.
Pediatric patients
Twenty pediatric patients (aged 4 months–17
years) undergoing CT for hematological and
solid neoplasms were treated with SAMITAL
for gastrointestinal mucositis after protocol
approval by the Ethical Committee of the
Hospital Clínico Regional de Valdivia [50]. The
product was also administered prophylactically
to prevent recurrences with successive cycles of
CT. Overall, SAMITAL significantly decreased
the gastrointestinal mucositis grade after the first
episode with a reduction of mean scores from
3.2 ± 0.7 at baseline to 0.4 ± 0.6 at the end of
treatment (p < 0.001). In addition, SAMITAL
reduced pain, mucosal erosions, bleeding and
dysphagia/feeding impairment, improving the
patients’ overall condition and quality of life. In
addition, the need for parenteral nutrition was
reduced. Of note, treatment with SAMITAL
allowed CT cycles to be continued without
further relevant complications.
future science group
 SAMITAL® for the treatment of mucositis induced by oncological therapies Drug Evaluation

Conclusion & future perspective
Mucositis is a common side effect of CT/RT,
which causes significant pain and discomfort in
daily activities such as eating, drinking, swallow­
ing and talking, with the need in most cases for
parenteral nutritional support. It is very disabling
for patients and might also lead to suspension of
the CT/RT. Treatment guidelines for mucositis
in oncological patients emphasize the importance
of an interdisciplinary approach that takes oral
care protocols and pain management with several
analgesic drugs into account. Currently, despite
its negative impact on both the quality of life
and treatment outcomes of oncological patients,
mucositis still represents an unmet medical need
and new therapeutic approaches to this condi­
tion are eagerly awaited. So far, the only approved
drug, palifermin, is restricted for hematological
malignancies.
Preliminary data indicate that the new botani­
cal formulation SAMITAL, which contains
anthocyanosides, alkaloids and alkylamides,
could decrease the severity of CT-/RT-induced
mucositis in adult and pediatric patients, with
no treatment-related adverse events. These
data support a potential role for SAMITAL in
the effective management of therapy-induced
mucositis. It should be noted, however, that
no randomized Phase III trials on the efficacy
and safety of SAMITAL have been conducted
to date. Therefore, the currently available evi­
dence does not allow final conclusions about the
impact on clinical outcomes to be drawn, and
the use of SAMITAL remains investigational
until new data from randomized, placebo-
controlled Phase II and III trials become avail­
able to confirm its efficacy in the treatment of
mucositis. Moreover, in future studies, potential
confounding factors, such as tumor site and
treatment type, should be carefully restricted and
controlled in order to reliably assess the efficacy
of SAMITAL on OM.
Besides the described clinical studies, one addi­
tional prophylactic double-blind, randomized,
placebo-controlled clinical trial in patients
with head and neck cancer is ongoing in Italy
(EUDRACT No 2012-002046-20) after the
approval by the Ethical Committee of the Istituto
Oncologico Veneto (Padua, Italy). According to
the protocol, eligible patients are randomized in a
1:1 ratio in the two treatment arms using a strati­
fied block design. Randomization will be strati­
fied by site of disease and by CT regimen. In the
same clinical institute, a trial in pediatric patients
is being planned. Furthermore, in the USA a ther­
apeutic multicenter clinical trial in head and neck
cancer patients has been approved by the FDA.
Finally, a double-blind, randomized, placebo-
controlled clinical trial investigating the role of
SAMITAL in the management of gastro­intestinal
mucositis induced by CT has been planned in
Chile to complete the ongoing registration
procedure (Code ISPCh: RK308067).
Financial & competing interests disclosure
All of the authors are employees of Indena SpA (Milan,
Italy). The authors have no other relevant affiliations
or financial involvement with any organization or
entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the
manuscript apart from those disclosed.
Writing assistance was utilized in the production of
this manuscript. The authors received editorial assis-
tance from L Giacomelli and C Conte in the preparation
of this manuscript; this support was funded by
Indena SpA.

Executive summary
Background
„„Mucositis is a debilitating side effect of chemotherapy and radiotherapy with high health and economic costs, and for which there is

currently no effective treatment.

Potential role of phytochemicals in oral mucositis
„„Recent evidence indicates that botanical formulations may have a role in the treatment of chemotherapy-/radiotherapy-induced mucositis.

SAMITAL®
„„SAMITAL is composed by botanical extracts from Vaccinium myrtillus (bilberry), Macleaya cordata dried fruits and Echinacea

angustifolia dried roots.

„„The botanical constituents of SAMITAL, which have antioxidant, anti-inflammatory and immunomodulatory properties, may counteract

the pathogenic mechanisms underlying mucositis.

„„The results from pilot studies suggest that SAMITAL may help to control symptoms of severe mucositis, improve the recovery of lesions

and reduce their progression.

„„SAMITAL significantly reduced the severity of oral mucositis in head and neck cancer patients.

„„The use of SAMITAL remains investigational until data from randomized, placebo-controlled Phase III trials become available to confirm

its efficacy in the treatment of mucositis.

future science group www.futuremedicine.com 1723

 Drug Evaluation Morazzoni, Petrangolini, Bombardelli, Ronchi, Cabri & Riva
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