Note: Descriptions are shown in the official language in which they were submitted.
CA 02485449 2004-10-08
METHOD FOR PREVENTING MUCOSITIS DURING CANCER THERAPY
FIELD OF THE INVENTION
The present invention relates to methods of treating and/or preventing
mucositis resulting
from radio- and/or chemotherapy, as well as a glucan for use in a therapeutic
composition
for treatment and/or prevention of mucositis, as well as uses thereof.
BACKGROUND OF THE INVENTION
Mucositis is defined as inflammation and ulceration of the mucous membranes,
and is a
common dose-limiting toxic reaction to chemotherapy and radiotherapy. The
definition of
mucositis is often restricted to the oropharynx and lips, because of the easy
access of
these areas for evaluation. However, chemotherapy affects all mucous membranes
along
the gastrointestinal tract as mitotically active cells are sensitive to this
treatment.
Complications of mucositis may include fibrosis of salivary glands, muscles
and blood
vessels, loss of the sense of taste and, in extreme cases, osteoradionecrosis
(ORN) of
underlying bone.
2o In RTOG (Radiation Treatment Oncology Group) studies it has been
demonstrated a 25 % incidence, approximately, of grade 3 and 4 mucositis after
radiation
therapy delivered in standard conventional dose fractions. Other study groups
have
reported grade 3 mucositis rates approaching 50 %. Moderately accentuated
regimens,
such as concomitant boost or hyperfractionation, seem to double the incidence
of high-
grade mucositis, up to 50 °!° to 60 %. More aggressive treatment
schedules have
produced even higher incidences of mucositis; grade 3 from 66 % to 86 %, and
grade 4
from 7 % to 48 % (Trotti 2000). The prevalence of chemotherapy-induced oral
mucositis
has generally been reported as ranging from 30 % to 39 %. A prevalence of 75 %
has
been reported with 5-fluorouracil (Dodd et al. 1996).
so As immune compromised mucous membranes represent a potential opening for
local and systemic infections and subsequent complications, mucositis is a
serious
adverse reaction that might lead to reductions or delays in chemotherapy or
radiation
treatment, consequently having an adverse impact on the curative potential of
the primary
care. Furthermore, mucositis is very painful and may prevent the patient from
eating. The
quality of life is consequently significantly reduced in the affected
patients.
CA 02485449 2004-10-08
2
Oral mucositis (stomatitis) with ulcers can manifest itself already a few days
after
onset of chemotherapy and/or radiotherapy, and is precipitated by a direct
toxic effect on
the mucosal membranes. The direct toxic effect is caused by nonspecific
killing of rapidly
dividing basal epithelial cells resulting in epithelial thinning,
inflammation, decreased cell
renewal, and ultimately ulceration.
Postoperative radiotherapy is usually indicated in patients after resection of
advanced carcinomas of the head and neck. Recently two randomized phase III
studies
performed by the European Organization for Research and Treatment of Cancer
(EORTC) and an intergroup effort of Radiation Therapy Oncology Group (RTOG),
~o Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group
(SWOG)
demonstrated that adjunct cisplatin-based chemotherapy significantly improves
the local
and regional tumor control compared to radiotherapy alone. The disease-free
survival
was also significantly longer in both studies. However, this improvement in
efficacy was
accompanied by a higher incidence of acute adverse events of grade 3 or
greater,
~5 especially oral mucositis, in the group receiving combined treatment.
Despite of
increased toxicity, the authors conclude that the addition of concurrent
chemotherapy to
radiotherapy will be the new standard of care for physically fit patients with
head and
neck cancer (Bernier ef al. 2004; Cooper et al. 2004).
Aside from the direct effect of radiation or chemotherapy on mucosal cells,
2o mucositis might also be caused by therapy induced neutropenia. Drugs that
commonly
give dose-limiting oral mucositis are: methotrexate, dactinomycin, and
doxorubicin, but
also bleomycin, cytarabin, fluorouracil, and mitramycin induce this side
effect. The side
effect is dose- and schedule related. The combination of cisplatin and
continuous infusion
of fluorouracil for squamous cell head and neck carcinoma almost always
results in
25 severe mucositis (Sonis et al. 1990).
Patients undergoing chemotherapy often suffer from myelosuppression due to
their treatment, and this might induce indirect mucositis. Severe
granulocytopenia is
conductive to oral infections by Gram-negative bacilli, Gram-positive cocci,
fungi such as
Candida species, and viruses (particularly Herpes simplex). These infections
usually
30 occur at the site of direct mucositis or other oral trauma 12-14 days after
drug
administration (Sonis et al. 1990; Verdi 1993).
Atrophic changes are usually seen after a dose of about 2000 cGy administered
at
a rate of 200 cGy a day. Radiation following chemotherapy may lead to
especially severe
complications. The degree of damage is directly related to the dose of
radiation, but also
35 to factors as age, concurrent diseases (e.g. AIDS), oral hygiene, and
tobacco and alcohol
usage. Previous treatment may also affect the outcome. The general nutritional
and
health status of the patient also plays an important role in determining the
severity of the
CA 02485449 2004-10-08
3
complications and both of these can be adversely affected by the complications
themselves creating a vicious circle (Reynolds et al. 1980; Shannon et al.
1977; Baker
1982). If the complications are sufficiently severe they will lead to an
interruption of
treatment and thus, possibly, a complete or partial failure of therapy.
The previous notion that radiation injury of the oral mucosa is a purely
epithelial
phenomenon has been supplanted by the recognition that it, similar to
radiation injury in
other organ systems, is a dynamic process of complex interactions among many
cellular
compartments, resulting in a number of concurrent and sequential
pathophysiological
alterations that collectively constitute what is called radiation-induced
stomatitis or oral
mucositis.
Oral mucositis is heralded by an initial phase that is characterized by injury
to
tissues of the submucosa. During this phase, changes are mediated by reactive
oxygen
species (ROS) through the ceramide pathway, and by activation of a number of
transcription factors including nuclear factor-kappa beta (NF-KB). This
results in the
activation of early response genes, as well as direct oxidative alterations of
protein
functions, such as, proteins responsible for vascular thromboresistance.
Changes occur
in endothelial cells, mesenchymal cells, resident inflammatory cells, and
extraceUular
matrix. The initial injury precipitates the upregulation of a second set of
genes resulting in
direct and indirect signaling and early apoptosis of clonogenic stem cells in
the basal
2o epithelium. The signaling molecules are likely to be the proinflammatory
cytokines (tumor
necrosis factor-a , interleukin 1, and interleukin 6). These signaling
molecules also have
the ability to further amplify the upregulation of transcription factors
(e.g., NF-xB), leading
to production of additional proinflammatory cytokines, tissue injury, and
apoptosis.
Deficient renewal of mucosal epithelium occurs despite focal bursts of
hyperproliferative activity in response to upregulation of genes associated
with epithelium
healing. When epithelial apoptosis and necrosis exceeds hyperproliferative
activity, an
ulcerative phase with full thickness mucosal damage is the visible result. The
ulcerative
phase is exacerbated by local bacterial colonization, which results in a
barrage of cell wall
products that penetrates into the submucosa and amplifies the damage.
3o Eventually, healing occurs as healthy epithelium migrates from the wound
margins, stimulated by signals from the submucosa, and cytokines and other
mediators
drive additional local response, including angiogenesis.
Management of mucositis
Mucositis and ulceration in the oral cavity can be extremely painful and are a
major site of
potentially lethal infections. Although many phase I and II studies have been
performed
with products having shown promising results in animal models (see Velez et al
2004.
CA 02485449 2004-10-08
4
Quintessence Int. vol 35:129-136, Management or oral mucositis induced by
chemotherapy and radiotherapy: an update), very few, if any, treatments have
been
demonstrated to be effective in preventing or treating oral mucositis.
Several agents have been investigated in order to find optimal management
principles for
mucositis and even though some agents have shown prophylactic effect
(Meisenberg et
al., 1996), no agent has been shown to be efficient in all settings. Treatment
of mucositis
is today primarily supportive; strong analgesics in addition to oral hygiene.
No standard
therapy has been accepted.
Several authors have reviewed the literature on treatment and prevention
1o strategies for chemotherapy- and radiotherapy-induced oral mucositis, and
conclude that
further trials are needed (Clarkson et al. 2000; Worthington and Clarkson
2002; Sonis et
al. 2004) .
Both topical and systemic prophylactic agents as well as non-pharmacologic
prophylaxis are among the treatment regimens that have been tried in oral
mucositis.
~5 Some cancer treatment regimens make use of specific antidotes (e.g.
leucovorin) after
moderate-dose or high-dose methotrexate (Allegra and Boarman 1990) to reduce
the
toxic effect of the cancer drug. Due to the mechanism of action of antiseptics
and
antifungals, prophylactic chlorhexidine (Ferretti et al. 1990; McGaw and Belch
1985)and
nystatin or clotrimazole (Preston and Briceland 1995) reduce the risk of
indirect
2o mucotoxicity from bacteria and fungi. Sucralfate is a basic aluminum salt
of sulfated
sucrose which forms an ionic bond to proteins in ulcerations. This produces a
protective
barrier that promotes healing. Sucralfate has shown a modest benefit in
patients
receiving a cisplatin/fluorouracil regimen for various solid tumors (Pfeiffer
et al. 1990).
Oral cryotherapy/ ice chips have been shown to have effect in patients
receiving bolus
25 doses of 5-fluorouracil (Rocke et al. 1993), but unsuitable for patients
receiving
continuous infusion of 5-fluorouracil.
Interventions that have failed to show effect in oral mucositis, include the
application of prostaglandin E2 (Labar et aL 1993), to some extent allopurinol
(xanthine
oxidase inhibitor) (Loprinzi ef al. 1995), pentoxifylline (PTX) (Stockschlader
et al. 1993;
3o Attal et al. 1993; van der Jagt et al. 1994) and filgrastim, a granulocyte
colony-stimulating
factor (Gabrilove et al. 1988; Pettengell et al. 1992).
~glucans in radioprotection
35 "(3-glucan" is the common name for homopolysaccharides consisting of (3-D-
glucopyranosyl units. The backbone units are linked by (3-1,3- or (3-1,4-
linkages, or
CA 02485449 2004-10-08
combinations of these two. (3-glucans from different sources and isolated
through different
methods may have a variety of additional structural features like single
glucosyl units
attached to the backbone, ~i-1,6-linked side chains or ~i-1,3-linked side
chains at different
ratios.
5 It has been known for many years that injection of ~-glucan to animals
receiving
radiation can induce enhanced hematopoietic recovery (Patchen et al. 1984) and
increased survival rate (Patchen and MacVittie 1986; Hofer et al. 1995) from
cobalt-60
radiation. The increase in survival rate is hypothesized to be due to the
prevention of
radiation induced myelosuppression and stimulation of the bone marrow (Patchen
et al.
~0 1990; Hofer and Pospisil 1997), a theory that has been supported by recent
findings that
yeast (i-glucan is able to induce increased bone marrow mononuclear cell
colony
formation (Turnbull et al. 1999). All the above studies refer to parenteral
administration of
(3-glucans. No studies have earlier been carried out to examine the effect of
orally
administered ~i-glucan on radio- or chemotherapy induced side-effects such as
mucositis.
~5 In the present invention it was surprisingly found that water-soluble a-1,3-
glucan is
effective in preventing or treating oral mucositis and ulceration in cancer
patients
undergoing radiat ion treatments to head and neck. Accordingly, novel methods
of
prevention and treatment, novel use of ~-glucans, as well as novel use of ~i-
glucans for
manufacturing a medicament for preventing or treating mucositis are devised
herein.
CA 02485449 2004-10-08
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to prevention or treatment of mucositis. More
particularly, it
relates to a method of preventing or treating oral mucositis. In a preferred
embodiment,
the oral mucositis is radiation and/or chemotherapy induced oral mucositis.
The method
of the invention comprises applying a preparation comprising water-soluble
immunomodulatory (i-glucan to the susceptible or affected mucosal surface. The
preparation may be a rinse, mixture, gel, ointment, cream, or another suitable
formulation. Furthermore, water-soluble (i-glucan may be the only active
component in
the preparation or the a-glucan may be combined with one or several other
active
~o components like e.g. antiseptics and/or antifungals, e.g. chlorhexidine,
nystatin,
clotrimazole; sucralfate; analgesics; etc.
The water-soluble immunomodulatory (i-glucan used in the invention may be
isolated from several organisms. Glucans with known immunomodulatory
activities are
e.g. lentinan isolated from Lentinus edodes having a R-1,6-linked single
glucosyl unit for
~5 approximately every 3 main chain unit (Sasaki and Takasuka 1976). Similar
glucans
having ~-1,3-linked main chain with single (3-1-6-linked glucosyl units
attached thereto are
scleroglucan isolated from Sclerotium sp. (Singh et al. 1974; Farina et al.
2001 ) and
shizophyllan isolated from Schizophyllum commune (Akima et al. 1985). A
soluble ~3-1,3-
glucan can also be obtained from seaweed (Nelson and Lewis 1974) , and a water
soluble
2o a-1,3/1,4-glucan can be isolated from cereals (Estrada et al. 1997), or
derived from
lichens (Demleitner et al. 1992). Bacterial a-1,3-glucan, curdlan, from
Alcaligenes faecalis
can be made water solu ble and immunomodulatory (Seljelid et al. 1984).
Preferably, the
~i-glucan originates from yeast, fungi, cereals, algae, or bacteria. More
preferably, said
glucan originates from yeast. Even more preferably, said glucan originates
from the yeast
25 family Saccharomyces. In a particularly preferred embodiment, the (3-glucan
originates
from Saccharomyces cerevisiae. The water-soluble immunomodulatory R-glucan may
be
of any structure, however, it is preferably a water-soluble non-derivatized ~i-
1,3-glucan,
with side-chains anchored to the backbone through a ~i-1,6-linkage.
Preferably, the
backbone consists of (3-1,3-linked D-glucopyranosyl units, while the side
chains may
3o comprise ~i-1,3-linked and/or ~i-1,6-linked D-glucopyranosyl units. The
former type of
side-chains are termed (i-1,3 side-chains, while the latter are termed ~3-1,6
side-chains.
Preferably, said a-1,6 side-chains consist of 0 to 4 units. More preferably,
said side-
chains consist exclusively of ~i-1,3-linked D-glucopyranosyl units. The above
features are
important both for the current a-glucan's water solubility and
immunomodulatory activity
35 (Engstad 1994). As teached above, the glucan may contain certain amounts of
~i-1,6-
CA 02485449 2004-10-08
linked glucosyl chains, but these are to a certain extent negative with
respect to the a-
glucans immunomodulatory abilities (see Engstad 1994), the content of which
are
incorporated herein by reference. These undesired (3-1,6 side-chains are found
in other
non-derivatized soluble yeast ~3-glucans described in the literature
(Onderdonk et al.
1992) or patents (lamas et al. 1994; Kelly 2001). Accordingly, an especially
preferred
glucan is a branched a-1,3-glucan with (i-1,3 side chains anchored through a
~i-1,6-
linkage.
The (i-glucan concentration of the preparation may be in the range from 0.1 %
to
25 % by weight, preferably 0.1 % to 10 % by weight, more preferably 0.5 % to
2.5 % by
~o weight. The preparation may be administered either as a single daily
treatment or
repeated daily treatments before, and/or under, and/or after e.g. a cancer
treatment
regime or bone marrow transplantation. The preparation may be administered
orally to
contact the mucosal surfaces of the oral cavity, the pharynx and the
intestinal tract to
prevent and/or heal the formation of mucositis, e.g. in radio- or chemotherapy
treated
~5 cancer patients. Anal administration of the preparation is also possible.
The method of
the present invention may be applied to any animal, preferably a mammal, and
more
preferably a human being.
Another aspect of the current invention is a method for preparing a medicament
comprising the (i-glucan as described above. The process comprises first
isolating intact
2o yeast cell walls or any other source of ~i-glucan as described above. The
intact cell walls,
or alternative source, are treated with formic acid and optionally digested
with a ~i-(1,6)-
glucanase to form a gel with non-Newtonian viscosity and thixotropic
properties. This type
of gel is ideal for mucosal application. A general method for isolation and
manufacture of
the current (i-glucan is described in patent EP 0759089 the content of which
are
25 incorporated herein by reference.
A further aspect of the current invention is a glucan for use in a therapeutic
composition for treatment or prevention of mucositis, wherein said glucan is a
water-
soluble immunomodulatory (i-1,3-glucan. The ~i-glucan is as described above.
Preferably,
the water-soluble immunomodulatory ~i-1,3-glucan have a branched nature with ~-
1,3-
30 linked side chains anchored through a (i-1,6-linkage. More preferably, said
side-chains
consist exclusively of (3-1,3-linked D-glucopyranosyl units. In a preferred
embodiment the
mucositis is oral mucositis. The mucositis may be caused by radiotherapy
and/or
chemotherapy.
Yet another aspect of the current invention is the use of immunomodulatory (3-
35 glucan for manufacturing a medicament for the treatment or prevention of
mucositis in an
animal in need thereof. The ~i-glucan is as described above. Preferably, the
water-soluble
CA 02485449 2004-10-08
8
immunomodulatory ~i-1,3-glucan is branched with ~i-1,3-linked side chains
anchored
through a a-1,6-linkage. More preferably, said side-chains consist exclusively
of ~-1,3-
linked D-glucopyranosyl units. In a preferred embodiment the mucositis is oral
mucositis.
The mucositis may be caused by radiotherapy and/or chemotherapy. The animal
may be
any animal, preferably a mammal, and most preferably a human being.
All publications, patents and patent applications mentioned in this
specification are
indicative of the level of skill of those skilled in the art to which this
invention pertains, and
are herein incorporated by reference to the same extent as if each individual
publication,
patent or patent application was specifically and individually indicated to be
incorporated
1o by reference.
The theory underlying the invention is not part of the claims and the inventor
does
not wish to be bound by any particular theory explaining the invention. In
fact, it is fully
anticipated that the theory underlying the present invention will evolve as
science develop
and mature.
CA 02485449 2004-10-08
EXAMPLES
The following examples are meant to illustrate how to make and use the
invention. They
are not intended to limit the scope of the invention in any manner or to any
degree.
Example I
Herein is described the use of soluble (i-glucan (SBG) to prevent and or heal
oral
mucositis in conjunction to radiotherapy in a 30 year old male with head and
neck cancer.
SBG is a water soluble branched beta-1,3-linked yeast derived glucan with
intact beta-
~0 1,3-linked side chains anchored through a beta-1,6-linkage to the main
chain. A minority
of side chains show repetitive beta-1,6-linkages. The intramolecular ratio of
repetitive
beta-1,6-linkages versus beta-1,3-linkages is approximately 1:50, or less. The
patient
was diagnosed with cancer in the tongue in January 2002 and a surgical
excision of the
tumour was performed, whereafter local brachy therapy in the tongue was given.
In
~5 November 2002, 10 months after surgery, recurrence of the cancer was
diagnosed in a
lymph node in the neck, and the patient was readmitted to hospital for surgery
in
December 2002 and from January 2003 also radiotherapy to the neck region.
Radiotherapy (a total of 60Gy) was given 5 days per week for 6 consecutive
weeks.
Concomitant to the radiotherapy the patient took approximately 80-100 mg SBG
as a 20
2o mg/ml aqueous solution administered orally as a daily dose until 14 days
after ending
radiotherapy. The patient did not develop oral mucositis above grade I during
or after the
radiotherapy.
25 Example II
An exploratory, randomized, parallel group study comparing the protective
effect of
soluble ~-glucan or placebo in oral mucositis in head and neck cancer patients
receiving
radiation therapy is described. 40 patients undergoing radiation for
histologically
confirmed squamous cell carcinoma of the oral cavity or pharynx (1.8-2.0
Gy/day, 5 days
3o per week; totally 59.4-70 Gy) is included in the study. A cohort also
receives
chemotherapy. Soluble (i-glucan (SBG) as an aqueous solution is given orally
throughout
the whole radiation period at a daily dosage of 500-1000 mg as a 15 mg/ml
aqueous
solution to 20 patients, whereas 20 patients are treated with methylcellulose
as placebo.
SBG is a water soluble branched beta-1,3-linked yeast derived glucan with
intact beta-
35 1,3-linked side chains anchored through a beta-1,6-linkage to the main
chain. A minority
of side chains show repetitive beta-1,6-linkages. The intramolecular ratio of
repetitive
beta-1,6-linkages versus beta-1,3-linkages is approximately 1:50, or less.
CA 02485449 2004-10-08
The a-glucan treatment group shows reduction in number of patient having grade
2 or
higher oral mucositis as compared to the placebo group.
Having now fully described the present invention in some detail by way of
illustration and
example for purpose of clarity of understanding, it will be obvious to one of
ordinary skill
in the art that same can be performed by modifying or changing the invention
by with a
wide and equivalent range of conditions, formulations and other parameters
thereof, and
that such modifications or changes are intended to be encompassed within the
scope of
the appended claims.
CA 02485449 2004-10-08
11
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