26TH FEB 2013

RADIATION AND
CHEMOTHERAPY

Presented by :
DR. P.AKANSHA
MDS 1ST YR
DEPARTMENT OF PROSTHODONTICS
CONTENT
 INTRODUCTION

 RADIATION
FRACTIONATION
PRE & POST OPRERATIVE RADIOTHERAPY
EFFECTS OF RADIATION ON ORAL CAVITY
COMPLICATIONS
POSTIRRADIATION DENTAL CARE
 CHEMOTHERAPY
KINETIC CLASSIFICATION
CLASSIFICATION
MODE OF ACTION
PRINCIPLES OF TRATMENT
TOXICITY OF DRUGS

 CONCLUSION
INTRODUCTION
 Radiation therapy for malignant lesions in
oral cavity usually indicated when the lesion
is radiosensitive, advanced, or deeply
invasive and cannot be approached by
surgically.
 The modality of treatment of cancer are
surgery, radiotherapy and chemotherapy.
Both surgery and radiotherapy are local
treatments, either in combination or
individually both often effect a cure.
RADIATION
 The use of high-energy radiation from x-rays,
gamma rays, neutrons, and other sources to
kill cancer cells and shrink tumors.

 Radiation causes damage to DNA in both

normal and malignant cells. Cells unable to
repair this damage by time of next division ,
then they die in MITOSIS. Cancer cells divide
more frequently and repair less efficiently .
FRACTIONATION
 GRAY (Gy) named after pioneering British Radiobiologist
L.H.GRAY.

 Centigray (cGy) =0.01 Gy ,

 Radiobiologic principles explaining why fractionation

allows tumor control without local necrosis:
Repair
Reoxygenation
Repopulation
Redistribution
 
 Total x- rays dose into multiple small doses provides greater
tumor destruction than larger single dose.
 Also increases the mean oxygen tension in an
irradiated tumor , rendering the tumor cells
more radiosensitive. This results :
1) Rapid killing of tumor cells
2) Shrinkage of tumor mass after the first
few fractions.
3) Reducing the distance that oxygen must
diffuse through the tumor to reach the
remaining viable tumor cells.
 2Gy deliver daily, bilaterally throught 8 x 11
cm fields over oropharynx, for weekly
exposure of 10 Gy.
 Cobalt –

1. gamma radiation
2. Small implants containing radon or iodine -
125 placed directly in tumor mass.
3. Such implants deliver a high dose of
radiation to a small volume of tissues in a
shorter time period.
PREOPERATIVE RADIOTHERAPY
 Tumors will shrink prior to surgery making
operation easier.
 Sterilizing majority of viable cells , risk of
tumor dissemination at time of surgery was
reduced.
 Advantages -Blood supply may be better
than after surgery, leading improved
oxygenation.
 tumor seeding during surgery decreased.
 Disadvantage -loss of definitive tumor staging
and lower doses given concerning increase in
surgical morbidity.
POSTOPERATIVE
RADIOTHERAPY
INDICATIONS –
 Large infiltrating tumors.
 compromised margins of surgical resection.
 perineural spread.
 extension of tumor into deep soft tissues or
bone destruction.
 multiple lymph nodes,
 large lymph nodes,
EFFECTS OF RADIATION ON ORAL CAVITY
ORAL MUCOUS MEMBRANE
 At the end of 2nd week of therapy mucous
membranes begins to show redness and
inflammation (mucositis).
 The term mucositis is coined to describe the
adverse effects of radiation and chemotherapy
treatments. Mucositis is one of the most common
adverse reactions encountered in radiation
therapy for head and neck cancers, as well as in
chemotherapy, in particular with drugs affecting
DNA synthesis .
 Symptoms of mucositis vary from pain and
discomfort to an inability to tolerate food or fluids.
 Phase I: Initial inflammatory/vascular phase:
During this phase, exposed cells (epithelial,
endothelial, and connective tissue cells) in the
buccal mucosa release free radicals, modified
proteins, and proinflammatory cytokines, including
interleukin-1B, prostaglandins, and tumor necrosis
factor (TNF). These inflammatory mediators cause
further damage either directly or indirectly by
increasing vascular permeability, thereby
enhancing cytotoxic drug uptake into the oral
mucosa
 Phase II: Epithelial phase: In this phase,
chemotherapy and/or radiation retards cell
division in the oral mucosal epithelium,
leading to reduced epithelial turnover and
renewal, resulting in epithelial breakdown.
This results in erythema from increased
vascularity and epithelial atrophy 4 to 5 days
after the initiation of chemotherapy. At this
stage, microtrauma from day-to-day
activities such as speech, swallowing, and
mastication leads to ulceration
 Phase III: Ulcerative/bacteriological phase
(pseudomembraneous):
Epithelial breakdown ultimately results in the
ulcerative phase, which occurs within 1 week
of therapy. Loss of epithelia and furious
exudation lead to the formation of
pseudomembranes and ulcers.
In this phase, microbial colonization of
damaged mucosal surfaces by Gram-negative
organisms and yeast occurs, and this may be
exacerbated by concomitant neutropenia.
 Infectious complications arising in
neutropinic bone marrow transplantation
recipients are among the most challenging
aspects of aggressive myelosuppressive
antineoplastic drug therapy. There are
numerous reports that demonstrate the
importance of ulcerative mucositis as an
etiologic factor in the development of
systemic α-hemolytic streptococcal
infections in the neutropinic cancer patients
 Phase IV: Healing phase: The duration of this
phase usually lasts from 12 to 16 days, and
mainly depends on factors such as epithelial
proliferation rate, hematopoietic recovery,
reestablishment of the local microbial flora,
and absence of factors interfering with
wound healing viz. infection and mechanical
irritation
 TREATMENT
 Cryotherapy
 Allopurinol
 Propantheline
 Pilocarpine
Taste buds –
 Sensitive to radiation.
 During 2nd & 3rd week of therapy loss of taste
noticed by patient.
 Bitter & acid flavours are more severly affected
when posterior two thirds of tongue irradiated .
Salivary glands –
 Major of salivary glands are unavoidably exposed
to 20 to 30 Gy.
 A marked and progressive loss of salivary
secretion usually seen in 1st few weeks after
initation of therapy.
 The extend of reduced flow is dose dependent
and reaches essentially zero at 60Gy.
 Mouth becomes dry (xerostomia) , tender,
difficulty in swallowing, painful.
 After radiation therapy - the major salivary
glands , microbial flora undergoes a
pronounced change, rendering them in
acidogenic in saliva and plaque.
 Patients receiving radiation therapy shows
increase in rate of Streptoccocus mutans,
lactobacillus , and candida albicans.
RADIATION THERAPY –
 Clinically 3 types of radiation caries exist.

1. Superficial lesion attacking all surfaces of

tooth.
2. Cementum and dentine in the cervical
region.
3. Dark pigmentation of entire crown. Incisal
edges may markedly worn.
 Treatment –
1. Tropical application of1%neutral sodium
flouride gel for 5 mint. In custom made
applicator trays.
2. Avoidance of dietary sucrose.
BONE –
 Subsequent to irradiation , normal marrow
replaced with fatty marrow and fibrous
connective tissue ,
 Marrow tissue becomes hypovascular ,
hypoxic , hypocellular ,
 Endosteum becomes atrophic, shows a lack
of osteoblastic and osteoclastic activity ,
 Empty lacunae of compact bone, indicates
necrosis,
 Reduced mineralization leading to brittleness
of bone,
 When these all changes becomes so severe
results in bone death- then condition leads
to OSTEORADIONECROSIS.
COMPLICATIONS
ACUTE:- during or immediately after a course
of treatment.
 skin reactions.
 cutaneous erythema.
 blistering or moist desquamation.
 hyperpigmentation.
 mucosal reactions.
 xerostomia.
 mucositis.
Late effects:-which may come on in
subsequent months or years.
 Dental and bone effects.
 Bone and soft tissue necrosis.
 Periodontal disease.
 Wide spread radiation caries.
 Osteoradionecrosis.
 Telengiectasia.
 hypopigmentation and fibrosis.
 Neurological effects
 Hypothyroidism
 Visual problems like - dry eyes, corneal
ulcerations, cataracts, retinal damage.
POST IRRADIATION DENTAL CARE : 

 Dentures should not be used in irradiated

area for 1 year after radiotherapy.

 Oral hygiene and fluoride therapy is

recommended.

 Saliva substitute may be used to lubricate

mouth.
 Endodontic therapy should be undertaken if
post irradiation pulpitis develops.

 No attempts should be made to raise flaps or

obtain linear closure.

 Antibiotics should be administered and L.A

without adrenaline should be used.
CHEMOTHERAPY

 The term introduced by Paul Erlich.

 Anticancer drugs work by affecting DNA synthesis

or function, they do not normally kill resting
cells;

 The effectiveness of the drug is limited by the

growth fraction of tumor, thus, small rapidly
proliferating tumors are more responsive to
chemotherapy than the large ones.
 Its used for treatment of malignant tumors.it
selectively kills tumor cells by – cell kinetic
proliferation character , cell biology.

 It may be used in combination with

radiotherapy or surgery or as palliative
treatment where treatment for cancer not
possible.
KINETIC CLASSIFICATION OF
ANTICANCER DRUGS
Phase dependent –
 Kills cells exponentially at a lower dose but
reaches the plateau at a higher dose.
 As they kill cells only during a specific part of
cell cycle , as known “cell cycle specific
drugs”.
Non-phase depentent –
 It kills cell exponentially with an increasing
dose and;
 toxic for both- Go phase and cells in all
stages of cycle.
CLASSIFICATION OF
ANTICANCER DRUGS
CLASSES OF AGENTS AND MODE OF ACTION
 Four categories most commonly used
 chemotherapeutic agents:

 Alkylating agents;
 Antibiotics;
 Antimetabolites
 Miscellaneous: platinum complexes
procarbazine
plant alkaloids
ALKYLATING AGENTS

 Highly reactive, substitute alkyl groups for hydrogen

atoms of organic compounds (ex. DNA).

 Five classes: 1. Nitrogen mustard derivatives

2. Ethylenimine derivatives
3. Alkyl sulfonates
4. Triazine derivatives
5. Nitrozoureas

 Most of them contain more than one alkylating group and

therefore considered polyfunctional alkylating agents.
 As a class alkylating agents are considered to be cell-
cycle nonspecific
Nitrosoureas
 The nitrosoureas are distinguished by their
high lipid solubility and chemical instability.
 The lipophilic nature of the nitrosoureas
enables free passage across membranes;
therefore, they rapidly penetrate the blood-
brain barrier, achieving effective CNS
concentrations.
 As a consequence, these agents are used for
a variety of brain tumors.
ANTIBIOTICS

 The clinically useful antibiotics are natural

products of various strains of the soil fungus
Streptomyces.
 The directly bind DNA, and inhibit DNA and
RNA synthesis

 As a class they behave as cell-cycle

nonspecific agents.

 Examples: Doxorubicin, Actinomycin D,

 Bleomycin, Mitomycin C
PLANT ALKALIODS

Vinca alkaloid.
 Produced from the common periwinkle plant.
 The clinically useful alkaloids are large
complex molecules that exert their
antitumor effect by binding to cellular
microtubular proteins and inhibiting
microtubular polymerization, the essential
compounds of the mitotic spindle.
 Effect - mitotic arrest.
Taxanes –
 products of the yew tree. The toxicity of the
leaves or bark is caused by alkaloids taxanes.
 Paclitaxel – is a natuarl product, a new class
of antineoplastic agents, the taxanes, that
targets the microtubules.
 The taxanes are potent microtubule-
stabilizing agents, promoters of microtubule
assemly.
 They block cells in G2/M phases of the cell
cycle.
ANTIMETABOLITES

 Analogues of normal metabolites. The

interact with enzymes and damage cells by:

1. Substituting for a metabolite normally

incorporated into a key molecule.
2. Competing successfully with a normal
metabolite for occupation of the catalytic site
of a key enzyme.
3.Competing with a normal metabolite that
acts at an enzyme regulatory site to alter the
catalytic rate of the enzyme
MISCELLANEOUS AGENTS

 Examples: Methylhydrazine, nitrosoureas,

hydroxyurea,cisplatin, taxanes ,Hydroxyurea.

 First synthesized in 1869 and was found to be

bone-marrow suppressive in 1928.

 Used in treatment of cancer in the 1960s.

 It is an inhibitor of ribonucleotide reductase,
an enzyme essential to DNA synthesis, and is
consequently specifically cytotoxic to cells in
the S phase;

 Cisplatin – its heavy inorganic heavy metal

complex and only active cytotoxic agent in
cis form. Chloride ions are lost from
molecules after it diffuses into cell .
PRINCIPLES OF TREATMENT
1. ROUTES OF ADMINISTRATION :

 Intravenous route – most commonly used and

a known concentration of drug directly
delivered to central component of tumor.
 Orally – infrequently used because of
unpredictability of patient compliance and
variable absorption of drug.
 Subcutaneous & intramuscular – rarely
employed due to risk of thrombocytopenia.
 Intraperitoneal inj. – beneficial for drug
delivery to small tumor nodules on peritoneal
surface
2.COMBINATION CHEMOTHERAPY :
 3 principles governs the use of combinations
are
1. Active against the tumor when used alone.
2. Have different mechanism of action.
3. Have minimally overlapping toxicities.
 Several drugs attack the cells in different
ways its hoped that development of resistant
cells will be inhibited.

 If 3 guidelines are used then the dose chosen

for each individual drug will be close to that
used when the drug is given as a single agent
resulting in a minimum reduction in dosage
intensity.
3. SCHEDULE :
 Majority of I.V. drugs given as
short infusion
longer infusion preferred to reduce the
incidence of toxicity or to increase the
efficiency.
TOXICITY OF DRUGS

 Long term side effects of chemotherapy results

in :
1. An increase risk of secondary malignancy.
2. Infertility in some cases.
 Hematological toxicity -

Bone marrow suppression .

 Gastrointestinal toxicity –

nausea
vomiting
 Alopecia
 Pulmonary fibrosis
 Cardiac toxicity
1.cardiomyopathy
2. cardiac arrhythmias
 Renal and bladder toxicity –
1. hypocalcemia
2. hypomagnesemia
 Neurological toxicity –
1. loss of tendon reflexes
2. paresthesia
 3.Numbness in fingers and toes.
4. to stop the treatment – myalgia , neuritic
pain , peripheral sensory loss
5. drowsiness , confusion and
encephalopathy.
CONCLUSION
 Radiation therapy is a local treatment
modality. May be used alone for the
treatment for head and neck cancer, or it
may be used after surgery for combined
modality treatment of patients with high risk
cancer. Many of the problems associated
with radiotherapy can be minimized with
adequate pre therapy care and with
aggressive maintenance of oral hygiene.
REFERENCES
 King P, Perry M: Hepatotoxicity of chemotherapy.
Oncologist 6:162–176, 2001.
 Therasse P, Arbuck S, Eisenhauer E, et al: New
guidelines to evaluate the response to treatment of
solid tumors. J Natl Cancer Inst 92:205–216, 2000.
 John F. Ensley et al : Correlation between response
to cisplatinum-combination chemotherapy and
subsequent radiotherapy in previously untreated
patients with advanced squamous cell cancers of the
head and neck.oxfordjournal.org . 54:811–14,1984.
 Elisabeth le prise et al . A randomized study
of chemotherapy , radiation therapy, verses
surgery for localized squamous cell
carcinoma of esophagouse. J Cancer
res.73:1779-84, 1994.
 White,pharoah:oral radiology 5th edition.
Radiation biology, pg 25-45.
 K.D. tripathi: essentials of pharmacology for
dentistry.anticancer drugs , pg 297-304.