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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5362_Библиотеки_им_академика_М_И_Перельмана.pdf
Carbon-based Nanocarriers for Sustained Drug Release in Dentistry 295
Fig. 10.1 Advanced local targeted drug delivery routes versus conventional drug delivery
agent. There is a need for striking an equilibrium amongst the size of particles and
its configurations so that the process is efficient [21]. Additionally, biodistribution
along with pharmacodynamics of drugs are improved due to increased circulation
time when nanomaterials are used as drug delivery agents [22, 23]. Nanomaterials
when biomodified with certain active molecules exhibit specific functions of distinct
targeting of receptors, environmental responsiveness there by facilitating in drug
accumulation and reaching effective dosage in the circulation [24, 25].
1.1 Carbon-Based Nanomaterials: The New Generation
Drug Delivery System
As per recent studies, despite of many available nanomaterials, Carbon based
nanomaterials particularly those with sp
graphene, fullerene and carbon dots are facing a lot of scrutiny due to their commendable execution in biomedical field of drug delivery due their promising physicochemical properties [26–29]. When given at required carbon-based nanomaterials
2
with sp
hybridisation show higher biocompatibility and lesser toxicity as demonstrated in preclinical experiments involving hemocompatibility, biodistribution and
biocompatibility [13]. Carbon based nanomaterials have been considered superior
to other traditional nano materials in t erms of: (1) Better drug loading capacity due
to greater pore volume and larger surface area; (2) controlled drug release from
drug delivery systems due to specific character of a pore structure that can be further
manipulated; (3) enhanced targeted drug delivery with better control that can improve
the efficiency of action of drug as well as reduce the side effects which is mostly
2
hybridised carbon like carbon nanotube,
296 A. Biswal
possible due to the surface of the nanomaterial that is modified with convenience;
(4) Advanced future opportunity for photo-thermal therapy is made possible due
to greater capacity of heat conversion by the material in near- infrared region; (5)
physical and biochemical stability along with increased biocompatibility; (6) better
loading of aromatic drugs for controlled release is mainly due to supramolecular
p–p stacking in the material; (7) real-time monitoring and therapeutic and diagnostic
applications are possible in vivo because of its efficient amalgamation with luminescent compounds and excellent optical properties [13]. For revolutionising the field
of applied biomedical drug delivery system there needs to be research conducted on
further advancement of nanomaterials based on sp
tion has led to investigation on nanomaterials based on carbon, acting as nano drug
carriers which includes: targeted drug delivery systems, sustained drug delivery,
immediate drug delivery systems and controlled drug delivery systems.
2
hybridised carbon. This evolu-
1.2 Local Drug Delivery Versus Conventional Drug Delivery
Methods
From decades, systemic drug delivery systems viz oral, parenteral, transdermal, intramucosal and others were used for oral infections and diseases. These conventional
methods were accompanied with a lot of disadvantages like drug resistance, reduced
bio-availability, dysbiosis, inability to control and target drug release with respect to
their use for oral diseases. To overcome these problems associated with conventional
systems of drug carriers immense research has been put forward to develop a drug
carrier system to deliver locally. Advantages of local drug delivery in the tissues
include: minimisation of adverse effects systemically, efficient utilisation of drug
leading to lesser wastage or loss, drug delivery becomes well organised and effective, drug gets delivered to the target tissue easily [30]. Hence local drug delivery
can provide a better and efficient drug delivery than their systemic counterparts.
2OralMucosa
2.1 Oral Mucosa Structure
In humans, oral mucosa comprises of epithelium i.e., stratified squamous epithelium, connective tissue and basement membrane separating them [31]. Staratum
basale which exists just next to basement membrane and it mainly contains basal
keratinocytes which contribute to the reconstitution of the epithelium post injury by
proliferation. Supra basal cells which are partially differentiated lie on its surface.
In oral cavity, the epithelium consists of two types: (1) keratinised epithelium and
(2) non-keratinised epithelium. Keratinized areas include attached gingiva and hard
Carbon-based Nanocarriers for Sustained Drug Release in Dentistry 297
palate where the most superficial layer comprises of keratinocytes that are well differentiated to produce keratin, which ultimately undergo death and desquamation [31,
32]. Oral mucosa specifically presents as a protective barrier and protects the soft
tissue and maintains a homeostasis with the external environment.
2.2 Sites for Drug Delivery
Localised drug delivery in oral mucosa can be used to treat many diseases and
conditions. Each disease requires specific drug penetration and retention profiles
like: (1) In OralCandidiasis which is a superficial infection(affects mostly superficial
epithelial cells) the drugs used for therapy needs to be targeted on to the surface of
epithelium rather than entering into the epithelium, (2) Oral dysplasia which is the
neoplastic transformation of epithelial cells itself should be treated by the drugs
which have the potential to penetrate the epithelium and remain sustained in the
epithelium accompanied with little or no wastage into the connective tissue or out
from the surface, (3) Oral Lichen Planus which is an autoimmune disease generally
alters the epithelium and connective tissue next to it. For a drug to be effective for such
diseases it would be preferable if the drug penetrated deep into the epithelium and be
retained there after it traverses the barrier of permeability, (4) Systemic diseases, the
drug should enter the epithelium after crossing the barrier and do not need retention
there, rather needs to be diffused into the circulation and lymphatics [30].
2.3 Permeability
In oral mucosa the barrier of permeability mainly comprises of epithelium’s higher
layers and its lipid content, desmosomal junction and membrane coating granules (MCGs) formed by differentiation of the supra basal cells [33, 34]. The MCGs
secrete some material into the intercellular spaces which are lipophilic in nature so
as to secure coherence of epithelium which facilitates hydrophilic materials to move
across the epithelium but with a slowed down momentum [31]. The barrier prevents
the entry of materials both exogenous and endogenous into the body and stops further
fluid loss from the tissues.
Oral epithelium acts as a barrier to permeability of materials and connective
tissue because of its high hydration levels that provides resistance to the movement
of lipophilic molecules across the membrane [32, 35]. Permeability of oral mucosa
varies in different regions due to difference in thickness of epithelium and degree of
keratinisation. Since keratinized epithelium display decreased levels of permeability
when compared to non-keratinized epithelium because of presence of MCGs and
not presence of keratin alone [36]. The permeability remains lowest in gingiva and
hard palate due to keratinisation and buccal mucosa and sublingual mucosa being the
most permeable [37]. To traverse the barrier of permeability in oral mucosa typically
298 A. Biswal
three ways exists i.e., (1) Through the trans-cellular and para-cellular spaces due to
passive diffusion, (2) carrier mediated transport, (3) endocytosis and exocytosis [32,
38, 39]. Dextrans, which has a weight of less than 20,000 Da molecularly, is quite
diffusible across the barrier but the same dextran molecule with a higher molecular
weight is not; this is an example to justify that the substances that are lipid soluble,
non-ionized and have a lesser weight molecularly diffuse across the membrane with
ease [40]. The ease of permeability of any substance is dependent on its (1) Lipophilic
nature, (2) lipophilic and hydrophilic regions and the partition coefficient existing
between them, (3) in intercellular spaces the substances existing and their diffusion
coefficient and (4) High pKa value [41, 42].
In disease affected mucosa permeability is often increased. Due to erosion and
ulceration the permeability barrier is lost and drugs can easily diffuse into the tissue.
But due to loss of barrier the drugs also tend to be easily lost from the ulcerated sites
[43] for example: there is also an increased permeability of mucosa affected by lichen
planus even though not ulcerated or eroded as stated in an unpublished manuscript
compiled by A. Cruchley,Bart’s and the London, Queen Mary, University of London.
Hence oral mucosa affected by pre-malignant and malignant lesions show altered
permeability to different drugs. In a study to assess the drug diffusion in leukoplakia
affected sites and unaffected regions around it, the study concluded that the region
around the lesion and the lesion itself exhibited greater permeability across the barrier
as compared to normal oral mucosa [44].
2.4 Advantages and Disadvantages of Drug Delivery in Oral
Mucosa
Oral mucosa as a potential local and systemic drug delivery site is quite advantageous
to the patient. For systemically administering a drug, oral cavity is the most accepted
pathway of delivering the compound to the body. Transporting drug in oral mucosa
locally is quite beneficial due to: (1) drugs are self-administered, (2) Better patient
acceptability,(3) Shorter recoverytime of oral mucosa after trauma and (4) decreases
the probable side effectsexperienced due to administering a drug topically for a longer
duration of time [38], (5) Highly hydrated environment for solubility of the drug, (6)
Sustained delivery is possible, (7) Permeability of various sites in the oral mucosa is
different and (8) Lower risk of developing allergic reaction due to presence of lower
levels of Langerhans cell present in oral mucosa as compared to skin. Oral mucosal
drug delivery has its own drawbacks viz; (1) It has to overcome the permeability
barrier, (2) Saliva might wash the drug away, (3) Taste has to be acceptable to the
patient, (4) Should not be swallowed by the patient [38], (5) since oral mucosa is
a highly enzymatic environment, care should be taken to develop a drug delivery
system that will be resistant to enzymatic degradation, (6) smaller surface area of
oral mucosa, (7) Risk of swallowing or choking on the delivery system.
Carbon-based Nanocarriers for Sustained Drug Release in Dentistry 299
3 Local Drug Delivery for Dental Diseases
Dental diseases are widespread and chronic in nature. Dental caries and diseases
affecting the periodontium are the most common diseases according to studies
conducted all over the world. There is a certain higher incidence of dental caries
amongst younger age group due to higher refined sugar in their diet as compared
to periodontal diseases that affect the older individuals commonly. Dental disease,
diseases affecting the oral mucosa and oral manifestations of systemic ailments can
be treated by administering drugs systemically as well as locally. Oral mucosa has
been proved to be a very attractive site with a lot of potential for local drug delivery as
well poses as novel opportunity for researchers to develop newer and advanced drug
deliverysystems. Dental caries, periodontal diseases, auto immune diseases affecting
oral mucosa, oral mucosal diseases and odontogenic infections are effectivelytreated
when drug is delivered locally due to advantages of better bioavailability, targeted
drug delivery, lower drug resistance and lesser cross reaction.
3.1 Odontogenic Infection
Dental caries
Out of numerous childhood diseases, dental caries, is accountable to be the most
common and preventable disease of odontogenic tissues [45–48]. It can affect people
of all age groups and is mainly the chief source of pain that can be correlated to oral
cavity and might result in tooth loss if not intervened in time [47–49]. It is a potentially reversible lesion of dental hard tissues i.e., it can be reversed with proper timely
diagnosis and intervention. Caries is not a self-limiting lesion by nature therefore if
adequate measures are not taken after its diagnosis it leads to numerous destructive
sequelae [48]. Therefore, it is imperative for all physicians to recognise dental caries
and its aetiology for better therapy. Caries is generally caused because of the acid
released from fermentation of carbohydrates (due to a diet rich in refined sugars)
by the oral microbial flora causing breakdown of mineralised structure particularly
enamel and dentin. Streptococci and lactobacilli are one of the few oral microbial
florae that causes fermentation of refined carbohydrates. Initially it begins as a subsurface demineralization which appear as white flecks or minute surface roughness
that is visible clinically and with time it advances to form a cavity with dentinal tubule
involvement and inflammation of pulp leading to swelling, hyperaemia, necrosis
abscess and many other disastrous sequelae systemically like endocarditis, etc. [50].
In India there was a multi-centric study recently directed to evaluate dental caries
prevalence and it was concluded to range from 27 to 64% in 12-yr-old children and
26–83% in adults [51]. Whereas, the prevalence range varies significantly in developed countries like 68% in Lithuania and 12% in Singapore which is quite low when
recorded at different times [52]. As observed in various studies across the world,
amongst pre-school children early childhood caries prevalence is assessed to be in
300 A. Biswal
the range of 30–60%. Dental caries aetiology is complex and cannot be associated
to a single causative factor and hence it is known to be multifactorial. The current
and most widely accepted theory of caries aetiology suggests it to be a disease with
a multifactorial aetiology with three factors playing a primary role i.e., human host,
oral microbial flora, the carbohydrate substrate and time being an inevitable fourth
factor. Apart from these primary factors there are several contributing factors that
affectthe progression of the disease like oral hygiene habits, frequency of ingestion of
refined carbohydrate, nature of the carbohydrate consumed, time of ingestion, quality
and quantity of saliva, tooth morphology etc. After tooth brushing the glycoproteins
present in saliva embody a coating made up of protein on to the surface enamel
regarded as pellicle that is invisible to naked eye. The pellicle is soon colonised by
various micro-organisms of oral cavity which start breaking down dietary carbohydrates and the pellicle is soon converted into an organised structure called plaque.
Amongst the bacterial flora of plaque, the imperative organisms are Streptococcus
mutans and Lactobacillus acidophilus which are held accountable for production
of acid, caries progression and cariogenic potential. S. mutans is known to initiate
dental caries and Lactobacillus is responsible for caries progression. In the presence of dietary carbohydrates these micro-organisms produce acid via the process of
fermentation and surface enamel gets demineralised to release free ions particularly
calcium (Ca
2+
) and phosphate (PO
−)
3
. However, remineralisation occurs because
4
of calcium and phosphate ions present in saliva which reverses the damage by acidic
environment.As the bacterial load in the plaque increases there is higher acid production which results in sub surface demineralisation that is clinically seen as white spot
of demineralised area. As the demineralisation progresses t he carious lesion causes
enamel breakdown and infects the dentin. Dentin has odontoblastic process which
when stimulated due to bacterial invasion elicits pain and sensitivity which are the
classic s igns and symptoms of dental caries. Hence the main cause of caries formation
is the drop in pH below the critical level of 5.5 (Fig. 10.2).
Current methods of treatment
Caries is initiated due to demineralisation of hydroxy apatite crystals of enamel.
Salivary calcium and phosphate ions counteract the demineralisation but it is determined by the concentration of these ions and amount of acid if remineralisation
will occur or not. Fluoride, an external agent is particularly used to prevent dental
caries. When fluoride is present in oral cavity on the dental surface, it combines with
hydroxy-apatite and form an active compound fluorapatite which is more stable and
caries resistant than hydroxy-apatite. Since a long time, fluoride has been used as
a preventive agent against caries. It is delivered into the oral cavity in any different
formulations like toothpaste, mouth rinses, varnishes, gels and tablets [46].
Present fluoride delivery systems have been associated with a major flaw of a
shorter duration of action. Oral cavity’s essential functions are aided by saliva that
maintains oral health by rinsing, lubricating, protecting oral tissues. Despite its important role it also dilutes and clears away topically acting active compounds including
fluoride which results in reduced availability, lesser efficacy and frequent application of drugs to maintain the therapeutic dose. A minute increase in concentration
Carbon-based Nanocarriers for Sustained Drug Release in Dentistry 301
Fig. 10.2 Treatment modes using carbon-based nanomaterials in odontogenic infections
of fluoride in saliva has been shown to decrease caries incidence in children significantly [53]. Conventional fluoride delivery systems like Varnishes, gels and paints
pose a serious problem of patient acceptance and repeated application. However,
newer methods like bio-adhesive drug delivery systems have been advantageous.
Nanoparticles composed of chitosan which is a biological polymer when combined
with fluoride along with a cross inking agent glutaraldehyde to overcome the drawbacks of conventional systems [54]. Another fluoride delivery system has been developed that contains gelatin or ethyl cellulose with fluoride which are prepared by
microencapsulation [55].
Nanoparticles have been quite elemental in newer strategies of caries prevention. Plaque biofilm harbouring streptococcus mutans are mainly targeted for caries
therapy. Metal ions specifically silver ions have been used since years as a bactericidal agent [56]. Silver nanoparticles are better effective since smaller the particle
size better is the bactericidal action [57]. Smaller the silver particle better is the
surface contact with the bacteria but despite its bactericidal advantage it possess
several disadvantages like pigmentation of teeth and cytotoxicity [58]. Newer particles are being investigated which have lesser drawbacks and safely tolerated like
chitosan when combined with silver fluoride nanoparticle. It successfully prevented
dental caries as well as staining.
Periodontal diseases
Amongst the most common odontogenic infections, diseases affecting periodontium
is quite prevalent. Its incidence is higher in older individuals. Periodontal diseases
are basically divided in two progressive stages i.e., Gingivitis and Periodontitis. Periodontal diseases start with gingivitis as an initial phase which indicates inflammation
302 A. Biswal
of gingiva [59]. It is reversible as compared to periodontitis where there is inflammation of periodontium and alveolar bone [60]. The main cause of periodontal diseases
is accumulation of bacterial plaque on tooth surface and gingival sulcus. The plaque
acts as a nidus of micro-organisms that cause inflammation which leads to recession
of gingiva or periodontal pocket formation, or both as the disease progresses.
Plaque is composed of glycoprotein and polysaccharide matrix with suspended
oral micro-organisms [61]. The bacteria laden plaque which acts as an irritant causes
inflammation of the periodontium and hence regarded as the initiator of periodontal
diseases. With time the biofilm transforms into calculus due to mineralisation by
salivary minerals [62]. As per various studies, plaque and calculus have a microbial
count of almost 100,000,000,000 bacteria per gram dry weight [63]. The bacteria in
plaque and calculus rather behave as a unit and when compared to their free-living
counterparts they are more resistant to action of antibiotics on them [60]. On the basis
of their location and nature plaque is categorised as, (1) Supragingival plaque and
(2) Sub gingival plaque. The presence of plaque above and below the free gingival
margin defines the above terms i.e., when plaque is present above the free gingival
margin it regardedas supragingival calculus and if it is present belowthe free gingival
margin penetrates in the sulcus it is known as sub gingival plaque [60].
Gram negative anaerobic micro-organisms are the causative agent of periodontal
diseases like anaerobic bacilli, cocci and spirochetes. In progressive and deeply
destructive lesions of periodontal diseases there are few organisms common associated like: (1) Porphyromonas gingivalis,(2)Prevotella intermedia,(3)Bacteroides
forsythus,(4)Actinobacillus actinomycetemcomitans and (5) Treponema denticola
[63]. There is a recurring association of P. gingivalis with destructive forms of adult
periodontitis and also in active lesion rather than edentulous mouth or gingivitis
[64]. In recurrent cases P. gingivalis is found in higher numbers and there is a signif-
icant reduction in successfully treated sites [64–66]. In various reported cases of
periodontitis caused by P. gingivalis there occurs elevationof systemic and local anti-
body in response to it [67]. There has been reported association of P. intermedia with
cases of refractory periodontitis that cause elevation of antibody in serum [68]. The
presence of B. forsythus has been actively recorded in ongoing periodontal lesions
rather than gingivitis or healthy gingival sites [69, 70]. A. actinomycetemcomitans
is the most predominant periodontal pathogen implicated in localized juvenile periodontitis [71]. Genco et al. suggested through their work that normal oral flora plays
an imperative part in pathogenesis of gingivitis whereas anaerobic pathogens that are
usually extrinsic in nature are more associated with periodontitis [72]. These microorganisms are a constituent of the oral microflora that is existing in subgingival
plaque.
Current methods of treatment
Treatment for periodontal diseases conventionally consists of oral prophylaxis i.e.,
scaling and root planning (mechanical or conventional) followed by systemic antibiotics. With newer treatment procedures local drug delivery has gained much patient
acceptance. Ideal drug deliverysystem in case of periodontal diseases involving periodontal pocket is composed of sustained release of the drug from a biodegradable
Carbon-based Nanocarriers for Sustained Drug Release in Dentistry 303
scaffold. These bio-degradable scaffolds are availablein a wide variety of forms like:
(1) fibres, (2) strips, (3) inserts/implants, (4) gels, (5) microparticles and (6) nanoparticles. These newer materials have superior characteristics of ease of administration,
patient acceptability and being effective. Usually, the drug delivery system when
administered as an injectable via a syringe in the periodontal pocket and progressively
it leads to the formation of an implant [73, 74]. Poly(dl-lactide) (PLA) and poly-(dllactide-co-galactide) (PLGA) are best intended to be biodegradable polymer implants
in periodontal pocket. These materials have lower toxicity and easily adapted to the
pocket. An example of the same can be seen in a study done on beagle dogs where
PLA and tinidazole in the form of an implant was used in vivo to check the drug
release which is maintained through manipulation of the solvent [75]. There are few
other successful studies involving PLGA based drug delivery system consisting of
PLGA and metronidazole with either sodium carboxymethyl cellulose (NaCMC)
or Carbopol (CP) to modify properties of drug release and physical attributes [76].
The addition of NaCMC and CP to the drug delivery system increased bioadhesive
properties of the implant and influenced delivery of polymeric solution into the periodontal pocket with ease. Polymeric microspheres composed of zein, PLGA and
tetracycline are also being investigated as a promising drug delivery system [77].
This formulation was highly accepted and exhibited no cytotoxicity in vitro. Electrospun PLA fibres with metronidazole, multi layered films have been investigated
for their local treatment in cases of periodontal diseases [78, 79]. Another novel drug
delivery system which was highly resistant to degradation in the oral cavity and its
traces were found in the oral cavity even after one month of administration consisted
of a gel composed of Poly acrylic acid (PAA),1% Alendronate and triethanolamine
[80]. Alendronate as an active compound is a stimulator of osteoblasts and inhibits
osteoclast mediated resorption which helps to counteract the potential complication
of advanced periodontitis i.e., bone loss. The gel showed improved rates of bone
deposition at sites of loss.
3.2 Non-odontogenic Infection
Oral mucosal infections
Non odontogenic infections vary vastly in their aetiology. They can have an autoimmune aetiology or may be associated with any micro-organism. In recent years
there has been a significant increase in immunodeficient diseases, due to which there
is a reappearance of oral mucosal infections as minor lesions [81–83]. When observed
in recent studies on HIV positive patients, 50% of them sufferfrom oral diseases [84].
Since the development of Highly Active Antiretroviral Therapy (HAART), the incidence of oral infections has lowered to drastic levels but HIV associated infections
still loom significantly with the most prevalent of them all being oral candidiasis [85].
Oral candidiasis, referred to as oral thrush has many predisposing factors like: longer
usage of broad-spectrum antibiotics, use of system steroids for a longer duration,
304 A. Biswal
hypo-endocrine lesions, Sjogren syndrome, malignancies, malnutrition and old age
[82, 86]. These above-mentioned factors collectively identify different immunodeficient patient groups. In cancer affected patients when subjected to chemotherapy and
radiotherapy, they develope oral mucosal infection secondarily [87]. Oral candidiasis; viral infections due to herpes simplex virus, varicella zoster virus, Ebstein bar
virus and cytomegalo virus; oral bacterial infection are few of the most prevalent
infections seen in patients undergoing Chemotherapy. In immune-deficient conditions, opportunistic infections become aggressive and have high mortality rates once
the infective source breaches circulation leading to widespread bacteraemia. In most
cases, high rates of morbidity amongst cancer patients undergoing chemotherapy
and radiotherapy for treatment are mostly due to opportunistic infections.
Current treatment involving local drug delivery
Oral mucosal infections have been predominantly treated either by systemic drugs or
anti-microbial agents administered topically. Most commonly anti-fungal drugs are
applied on the mucosa and there are not many options in terms of products are available in the market for treatment of viral infection of oral cavity. The drug preparations
available are not suitable for application intra orally since saliva flushes the drug and
causes its breakdown leading to lower availability at the desired site. So, the drug
preparations have to be designed in an efficient way to sustain the active compound
on surface of mucosa for sustained release of drug, better patient acceptance and efficient treatment [88]. Mucoadhesive materials like hydrogels (hydrophilic polymeric
networks that work as semi solid forms of drug delivery) are gaining popularity in
terms of localised treatment of oral mucosal infections [89, 90]. For Oral candidiasis,
Mendes et al. devised a hydrogel system for local drug delivery of broad spectrum
anti-fungal agent miconazole [91]. For controlled r elease of water insoluble miconazole, researchers encapsulated it in nanostructured lipid carriers (NLC) to improve
drug loading on to the polymer and gel embodiment. This form of drug delivery
lowered the drug dosage and also frequency of administration to increase therapeutic
efficiency. Polymeric delivery of antibacterials in the oral cavity was demonstrated
Tiyaboonchai et al. by the use of polyethylimine and dextran sulphate in the oral
cavity (DS) [92] (Fig. 10.3).
Oral carcinoma
Oral neoplasms can be benign or malignant. Oral carcinoma has been considered
as the most common malignancies occurring in various parts of Asia owing to the
increased use of tobacco forms and heavy alcohol consumption [93, 94]. Alcohol
acts as a synergistic agent in etiology of carcinoma. There are certain viruses which
are potential risk factors in carcinoma of head and neck like Human Papilloma Virus
(HPV) [95]. Squamous cell carcinoma is one of the most prevalent carcinomas of
oral cavity that constitutes 90% of all the cancers occurring orally [96].
Current methods of treatment
Oral carcinoma treatment consists of following modalities viz (1) radiation, (2)
surgery, (3)chemotherapy and (4) a combination of these. These treatmentmodalities