Chemotherapy for oral cancer patients

CANCER

Cancer is an abnormal growth of cells caused by multiple changes in gene expression

leading to dysregulated balance of cell proliferation and cell death and ultimately
evolving into a population of cells that can invade tissues and metastasize to distant
sites, causing significant morbidity and, if untreated, death of the host.

 The origin of the word cancer is credited to the Greek physician Hippocrates
(460-370 BC), who is considered the “Father of Medicine.”

 Hippocrates used the terms carcinos and carcinoma to describe non-ulcer

forming and ulcer-forming tumors.

 In Greek, these words refer to a crab, most likely applied to the disease
because the finger-like spreading projections from a cancer called to mind the
shape of a crab.

 The Roman physician, Celsus (28-50 BC), later translated the Greek term into
cancer, the Latin word for crab.

 Galen (130-200 AD), another Greek physician, used the word oncos (Greek
for swelling) to describe tumors. Although the crab analogy of Hippocrates
and Celsus is still used to describe malignant tumors, Galen’s term is now
used as a part of the name for cancer specialists – oncologists.

 Cancer can involve any tissue of the body and have many different forms in
each body area. Most cancers are named for the type of cell or organ in which
they start.

 Primary modality of treatment for early–stage disease (AJCC stage 1/11) :

surgery or radiation therapy.

 Previously surgery and radiation therapy was also applied to patients with
locally advanced disease(AJCC stage 111/1v) if it was found to be resectable.

 Patients with cancer judged to be unresectable were offered radiation therapy

only, with complete response rates of less 30%.

 Incase of only radiation therapy Treatment failure commonly occurred within

the first 2 years indicating that surgery and or radiation therapy could not
solely eradicate the cancer cells.

 Novel treatment and adjuncts continue to investigate…..

Oral cancer or cancer of head and neck

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 It comprises a heterogenous group of malignancies extending from lips to the
cervical esophagus.

 Oral cavity cancer is the sixth most prevalent cancer worldwide and comprise
about 85% of all head and neck cancers.

 Regions with a high incidence of oral cancer ( > 6.9/100,000] are : North
America, Brazil, Europe, South Africa, the Indian Subcontinent, and Australia
Areas with low incidence (< 3.2/100.000] are Central America, Chile, West
Africa, Middle East and China.

 Most oncologist consider radiotherapy or chemoradiotherapy (CRT) as first-

line therapy in oropharynx cancer due to the equivalent response rates
compared with surgery.

 Salivary gland tumors are commonly treated with surgery initially.

 In general, Stage I and Stage II oral cancers may be treated successfully with
either surgery or radiation therapy. Advanced Stage III and Stage IV cancers
are typically treated by surgical resection followed by radiotherapy (RT) or
CRT

 Chemotherapy: Treatment of cancer using specific chemical agents or drugs

that are destructive to malignant cells and tissues. The term comes from two
words that mean "chemical" and "treatment."

 Paul Ehrlich coined the term chemotherapy

 The discovery of the toxic action of nitrogen mustards on cells of the

haematopoietic system more than 50 years ago initially triggered research into
the development of cytotoxic agents.

 The initial promise of these drugs in the management of haematological and

other rare malignancies has not been sustained and cure of the more common
epithelial malignancies when metastatic, remains an elusive goal.

 Many of the current chemotherapeutic agents have been discovered as a result

of screening compounds for cytotoxic potency in vitro against murine and/or
human cancer cells or in vivo against rodent tumors models.

 With better understanding of the molecular basis of cancer there is now

interest in target directed drug therapies.

 Many forms of chemotherapy are targeted at the process of cell division.

 The rationale being that cancer cells are more likely to be replicating than
normal cells.

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  Accordingly human neoplasm that are currently most susceptible to
chemotherapeutic measures are those with a large growth fraction,

 That is a high percentage of cells in the process of division.similarly normal

tissues that proliferate rapidly (bone marrow, hair follicle and intestinal
epithelium) are subjected to damage by chemotherapy drugs.

 Unfortunately as their action is not specific, they are associated with

significant toxicity.

 An understanding of the principles of tumour biology and cellular kinetics is

helpful to appreciate the mechanisms of action of cancer chemotherapy.

PRINCIPLES OF TUMOUR BIOLOGY

 Cellular kinetics

CELL CYCLE:

 Uncontrolled cell division is a result of interference in the normal balance of

the cell cycle.

 The cell cycle is divided into a number of phases governed by an elaborate set
of molecular switches.

 Normal nondividing cells are in G0.

 When actively recruited into the cell cycle they then pass through four phases:

 G1: the growth phase in which the cell increases in size and prepares to copy
its DNA;

 S (synthesis): which allows doubling of the chromosomal material;

 G2: a further growth phase before cell division;

 M (mitosis): where the chromosomes separate and the cell divides.

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At the end of a cycle the daughter cells can either continue through the cycle, leave
and enter the resting phase (G0) or become terminally differentiated.

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TUMOUR GROWTH

 The kinetics of any population of tumour cells is regulated by the following:

• DOUBLING TIME: the cell cycle time, which varies considerably between
tissue types;

• GROWTH FRACTION: the percentage of cells passing through the cell cycle
at a given point in time which is greatest in the early stages;

• Cell Loss: which can result from unsuccessful division, death, desquamation,
metastasis and migration.

• Tumours characteristically follow a sigmoid-shaped growth curve, in which

tumour doubling size varies with tumour size.

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 • Tumours grow most rapidly at small volumes.

• As they become larger, growth is influenced by the rate of cell death and the
availability of blood supply.

Cell Signalling

 Cells respond to their environment via external signals called growth factors.

 These interact with cell surface receptors that activate an internal signalling
cascade.

 This ultimately acts at the DNA level through transcription factors that bind to
the promoter regions of relevant genes, stimulating the cell cycle and
influencing many important processes including cell division, migration,
programmed cell death (apoptosis).

ONCOGENES

 Protooncogenes are involved in controlling normal cell growth.

 Mutated forms, known as oncogenes, can lead to inappropriate stimulation of

the cell cycle and excessive cell growth.

 Alternatively, malignancy can also arise secondary to abnormal activation of a

normal gene.

The consequences of gene activation associated with tumour growth include:

• Excess growth factor production;

• Alteration of growth factor receptor genes so that they are permanently

switched on;

• Alteration of the intracellular cascade stimulating proliferation

TUMOUR SUPPRESSOR GENES

 These act as a natural brake on cell growth. Usually both alleles need to be lost
for their function to be affected.

 This can have several important effects, which include:

• Impairment Of The Inhibitory Signals Influencing Receptor Genes Or

Intracellular Signalling;

• Loss of the counter signals controlling protooncogene function;

• Inhibition of apoptosis often as a consequence of a mutation of p53 the

protein associated with DNA repair.

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Metastatic spread

 A tumour is considered malignant when it has the capacity to spread beyond

its original site and invade surrounding tissue.

 Normally cells are anchored to the extracellular matrix by cell adhesion

molecules, including the integrin's.

 Abnormalities of the factors maintaining tissue integrity will allow local

invasion and ultimately metastases of the tumour cells.

Mechanism of cell death

 There are two main types of cell death: Apoptosis And Necrosis.

 Necrotic cell death is caused by gross cell injury and results in the death of
groups of cells within a tissue.

 Apoptosis is a regulated form of cell death that may be induced or is

preprogrammed into the cell and is characterized by specific DNA changes
and no accompanying inflammatory response.

 It can be triggered if mistakes in DNA replication are identified.

 Loss of this protective mechanism would allow mutant cells to continue to

divide and grow, thereby conserving mutations in subsequent cell divisions.

 Many cytotoxic anticancer drugs and radiotherapy act by inducing mutations

in cancer cells which are not sufficient to cause cell death, but which can be
recognized by the cell, triggering apoptosis.

 Fractional Cell Kill Hypothesis And Drug Dosing

 Theoretically the administration of successive doses of chemotherapy will

result in a fixed reduction in the number of cancer cells with each cycle.

 A gap between cycles is necessary to allow normal tissue recover.

 Unfortunately, these first-order dynamics are not observed in clinical practice.

 Factors such as variation in tumour sensitivity and effective drug delivery with
each course result in an unpredictable cell response.

 Clinical responses to antitumor therapies are defined by arbitrary criteria that

have been used as part of the evaluation process in assessing the potential
utility of novel agents.

 Tumour size:

 – complete response is defined as the apparent disappearance of the tumour;

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  – partial response represents a reduction of more than 50 percent;

 – progression is defined as an increase in tumour size by more than 25 percent;

 – stable disease is an intermediate between partial response and tumour

progression.

 Tumour products:

 – biochemical or other tests can be used to assess response, including

circulating tumour markers.

CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS

Classification according to phase-specific toxicity

Cell-cycle-phase–specific drugs

• Most chemotherapy agents are cell cycle-specific, meaning that they act
predominantly on cells that are actively dividing.

• They have a dose-related plateau in their cell killing ability because only a
subset of proliferating cells remain fully sensitive to drug-induced cytotoxicity
at any one time.

• The way to increase cell kill is therefore to increase the duration of exposure
rather than increasing the drug dose.

• S phase–dependent

• Antimetabolites

• Capecitabine

• Cytarabine

• Doxorubicin

• Fludarabine

• Floxuridine

• Fluorouracil

• Gemcitabine

• Hydroxyurea

• Mercaptopurine

• Methotrexate

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 • Prednisone

• Procarbazine

• Thioguanine

M phase–dependent

Vinca alkaloidsa

 Vinblastine

 Vincristine

 Vinorelbine

Podophyllotoxins

 Etoposide

 Teniposide

Taxanes

 Docetaxel

 Paclitaxel

G1 phase–dependent

 Asparaginase

 Corticosteroids

G2 phase–dependent

 Bleomycin

 Irinotecan

 Mitoxantrone

 Topotecan

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CELL CYCLE-NONSPECIFIC CHEMOTHERAPY

 These drugs, for example alkylating agents and platinum derivatives, have an
equal effect on tumour and normal cells whether they are in the proliferating
or resting phase.

 They have a linear dose–response curve; that is, the greater the dose of the
drug, the greater the fractional cell kill.

Classification According To Mechanism

ALKYLATING AGENTS:

 These highly reactive compounds produce their effects by covalently linking

an alkyl group (R-CH2) to a chemical species in nucleic acids or proteins.

 The site at which the cross-links are formed and the number of cross-links
formed is drug specific. Most alkylating agents are bipolar, i.e. they contain
two groups capable of reacting with DNA.

 They can thus form bridges between a single strand or two separate strands of
DNA, interfering with the action of the enzymes involved in DNA replication.

 The cell then either dies or is physically unable to divide or triggers apoptosis.

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  The damage is most serious during the S-phase, as the cell has less time to
remove the damaged fragments.

Examples include:

• Nitrogen mustards (E.G. Melphalan and chlorambucil);

• Oxazaphosphorenes (E.G. Cyclophosphamide, ifosfamide);

• Alkyl alkane sulphonates (busulphan);

• Nitrosureas (E.G. Carmustine (BCNU), lomustine (CCNU));

• Tetrazines (E.G. Dacarbazine, mitozolomide and temozolomide);

• Aziridines (thiopeta, mitomycin C);

• Procarbazine.

HEAVY METALS

Platinum agents

 These include carboplatin, cisplatin and oxaliplatin.

 Cisplatin is an organic heavy metal complex.

 Chloride ions are lost from the molecule after it diffuses into a cell allowing
the compound to cross-link with the DNA strands, mostly to guanine groups.

 This causes intra- and interstrand DNA cross-links, resulting in inhibition of

DNA, RNA and protein synthesis.

 Carboplatin has the same platinum as cisplatin, but is bonded to an organic

carboxylate group.

 This leads to increased water solubility and slower hydrolysis that has an
influence on its toxicity profile.

 It is less nephrotoxic and neurotoxic, but causes more marked

myelosuppression.

 Oxaliplatin belongs to a new class of platinum agent.

 It contains a platinum atom complexed with oxalate and a bulky

diaminocyclohexane (DACH) group.

 It forms reactive platinum complexes that are believed to inhibit DNA

synthesis by forming interstrand and intrastrand cross-linking of DNA
molecules.

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  Oxaliplatin is not generally cross-resistant to cisplatin or carboplatin, possibly
due to the DACH group.

ANTIMETABOLITES

 Antimetabolites are compounds that bear a structural similarity to naturally

occurring substances such as vitamins, nucleosides or amino acids.

 They compete with the natural substrate for the active site on an essential
enzyme or receptor.

 Some are incorporated directly into DNA or RNA. Most are phase-specific,
acting during the S-phase of the cell cycle.

 Their efficacy is usually greater over a prolonged period of time, so they are
usually given continuously.

 There are three main classes.

Folic acid antagonists

 Methotrexate competitively inhibits dihydrofolate reductase, which is

responsible for the formation of tetrahydrofolate from dihydrofolate.

 This is essential for the generation of a variety of coenzymes that are involved
in the synthesis of purines, thymidylate, methionine and glycine.

 A critical influence on cell division also appears to be inhibition of the

production of thymidine monophosphate, which is essential for DNA and
RNA synthesis.

 The block in activity of dihydrofolate reductase can be bypassed by supplying

an intermediary metabolite, most commonly folinic acid.

 This is converted to tetrahydrofolate that is required for thymidylate

synthetase function.

Pyrimidine analogues

 These drugs resemble pyrimidine molecules and work by either inhibiting the
synthesis of nucleic acids e.g. fluorouracil, inhibiting enzymes involved in
DNA synthesis (e.g. cytarabine, which inhibits DNA polymerase) or by
becoming incorporated into DNA (e.g. gemcitabine), interfering with DNA
synthesis and resulting in cell death.

Purine analogues:

 These are analogues of the natural purine bases and nucleotides. 6-

Mercaptopurine (6MP) and thioguanine are derivatives of adenine and
guanine, respectively. A sulphur group replaces the keto group on carbon-6 in
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 these compounds. In many cases, the drugs require initial activation. They are
then able to inhibit nucleotide biosynthesis by direct incorporation into DNA.

CYTOTOXIC ANTIBIOTICS

 Most antitumour antibiotics have been produced from bacterial and fungal
cultures (often Streptomyces species).

 They affect the function and synthesis of nucleic acids in different ways.

 Anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin) intercalate with

DNA and affect the topoiosmerase II enzyme.

 This DNA gyrase splits the DNA helix and reconnects it to overcome the
torsional forces that would interfere with replication.

 The anthracyclines stabilize the DNA tomoisomerase II complex and thus

prevent reconnection of the strands.

 Actinomycin D intercalates between guanine and cytosine base pairs. This

interferes with the transcription of DNA at high doses. At low doses DNA-
directed RNA synthesis is blocked.

 Bleomycin consists of a mixture of glycopeptides that cause DNA

fragmentation.

 Mitomycin C inhibits DNA synthesis by cross-linking DNA, acting like an

alkylating agent.

SPINDLE POISONS

Vinca alkaloids

 The two prominent agents in this group are vincristine and vinblastine that are
extracted from the periwinkle plant.

 They are mitotic spindle poisons that act by binding to tubulin, the building
block of the microtubules.

 This inhibits further assembly of the spindle during metaphase, thus inhibiting
mitosis.

 Although microtubules are important in other cell functions (hormone

secretion, axonal transport and cell motility), it is likely that the influence of
this group of drugs on DNA repair contributes most significantly to their
toxicity. Other newer examples include vindesine and vinorelbine.

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 TAXOIDS

 Paclitaxel (Taxol) is a drug derived from the bark of the pacific yew, Taxus
brevifolia.

 It promotes assembly of microtubules and inhibits their disassembly. Direct

activation of apoptotic pathways has also been suggested to be critical to the
cytotoxicity of this drug.

Docetaxel (Taxotere) is a semisynthetic derivative.

TOPOISOMERASE INHIBITORS

 Topoisomerases are responsible for altering the 3D structure of DNA by a

cleaving/unwinding/rejoining reaction.

 They are involved in DNA replication, chromatid segregation and

transcription.

 It has previously been considered that the efficacy of topoisomerase inhibitors

in the treatment of cancer was based solely on their ability to inhibit DNA
replication.

 It has now been suggested that drug efficacy may also depend on the
simultaneous manipulation of other cellular pathways within tumour cells.

 The drugs are phase-specific and prevent cells from entering mitosis from G2.

There are two broad classes:

 Topoisomerase I inhibitors Camptothecin, derived from Camptotheca

acuminata (a Chinese tree), binds to the enzyme–DNA complex, stabilizing it
and preventing DNA replication.

 Irinotecan and topetecan have been derived from this prototype.

Topoisomerase II inhibitors

 Epipodophyllotoxin derivatives (e.g. etoposide, vespid) are semisynthetic

derivatives of Podophyllum peltatum, the American mandrake.

 They stabilize the complex between topoisomerase II and DNA that causes
strand breaks and ultimately inhibits DNA replication.

 Cytotoxic chemotherapy was initially used only for palliation in the treatment
of cancer of the head and neck.

 However the objective of chemotherapy in this field have dramatically

changed.

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  The role of chemotherapy now include radiation sensitization and
chemoprevention.

 The traditional role of systemic chemotherapy as palliative therapy for

recurrent/ metastatic head and neck cancer has changed in recent times with
the realization that appropriate combination of this modality with loco-
regional can result in improved outcomes.

CHEMOTHERAPY STRATEGIES

 Combination Therapy:

 Prevents resistance.

 Adjuvant Therapy:

 Administered after primary therapy (Surgery)

 Neo adjuvant Therapy:

 Given before surgery to reduce tumour size.

COMBINATION CHEMOTHERAPY

 Combinations of cytotoxic agents are widely used for many cancers and may
be more effective than single agents.

Possible explanations for this include:

• Exposure to agents with different mechanisms of action and nonoverlapping

toxicities;

• Reduction in the development of drug resistance;

• The ability to use combinations of drugs that may be synergistic.

• In practice, the predominant dose-limiting toxicity of many cytotoxic drugs is

myelosuppression and this limits the doses of individual drugs when used in
combination.

• ADJUVANT CHEMOTHERAPY

• This is the use of chemotherapy in patients known to be at risk of relapse by

virtue of features determined at the time of definitive local treatment (e.g.
tumour grade, lymph node status, etc.).

• The intention of adjuvant chemotherapy is therefore the eradication of

micrometastatic disease.

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 • Randomized trials assessing the use of adjuvant chemotherapy for the patients
with head and neck squamous carcinoma do not suggest a significant benefit.

NEOADJUVANT CHEMOTHERAPY

 Neoadjuvant, or induction chemotherapy, is the use of chemotherapy before

definitive surgery or radiotherapy in patients with locally advanced disease.

 The intention of this strategy is to improve local and distant control of the
disease in order to achieve greater organ preservation and overall survival.

CONCURRENT CHEMORADIATION

 This involves the synchronous use of chemotherapy and radiotherapy.

 Multiple randomized trials comparing concurrent radiotherapy and

chemotherapy with radiotherapy alone have shown significant improvement in
locoregional control, relapse-free survival and overall.

 survival rates in patients with locally advanced, unresectable disease.

 These results may reflect the influence of chemotherapy on micrometastatic

disease or its ability to enhance tumour radiosensitivity.

CHEMOPREVENTION

 This is a novel approach with the aim of reversing or halting carcinogenesis

with the use of pharmacologic or natural agents.

 Retinoids have been tested in head and neck carcinogenesis both in animal
models and against oral premalignant lesions and in the prevention of
secondary tumours in humans, with initial encouraging results.

 Studies are also looking at the benefit of using cyclo-oxygenase 2 (COX-2)

inhibitors in a similar role.

Factors Potentially Influencing Response Rate To Chemotherapeutic Agents

Tumor Factor:

 Histology

 Grade

 Tumor Volume

 Vascularity Of The Tumor

 Previous Treatment

Host factors

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  Medical comorbidity

 Performance status

 Compliance

 Immune status

 Extent of prior treatment

Drug factors

 Type and dose of agents

 Single agent vs combination therapy

 Route of administration

 Combination with definitive loco-regional therapy

 Timings of administration: sequential vs concomitant

 Therapeutic index: toxicity and side effects

CYTOTOXIC SINGLE AGENT

Cisplatin:

 It is a heavy metal compound

 It is believed to exert its activity by causing DNA cross-linking.

 This agent has extensively evaluated in patients with recurrent head and neck
squamous cell carcinoma.

 As a single agent, the response rate is in the range of 28%

 It is the only chemotherapy agent evaluated in a randomized phase 111 trial in

comparison with best supportive care.

 It can be given on weekly basis every 3 weeks as an intravenous bolus or by

continuous infusion.

 Typical doses used has been between 80 and 100mg/m2.

 Systemic treament with cisplatin may be difficult to tolerate with potential

adverse reaction of emetogenicity, electrolyte disturbance, nephrotoxicity,
peripheral neuropathy and ototoxicity.

 Currently it is given usually every 3 to 4 weeks with pre- and post-therapy

hydration plus mannitol infusion to protect renal function.

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 Carboplatine

 The platinum analogue carboplatin is associated with reduced nephrotoxicity

and emetogenicity.

 Infrequently used as palliative single agent however carboplatin has been

extensively examined in combination regimens.

 A National cancer institue ( NCI) sponsored study is currently examining the

3rd generation platinum analogue oxaliplatin in the palliative treatment setting.

 Other single agent with known clinical activity include methotrexate,

ifosfamide, 5-fluorouracil (5-FU), bleomycin, and the taxanes.

METHOTREXATE:

 It is an antimetabolites, exerts its cytotoxic effects through inhibition of the

enzyme dihydrofolate reductase.

 This enzyme is responsible for maintaining the intracellular pool of folates in a

reduced state, which is required for the synthesis of the purine nucleotides.

 For most oncologist this is the standard chemotherapeutic agent with which
other single agent and combination are compared.

 Methotrexate provided variable response rate ranging from 10% to 40% with
short median duration of response rates.

 Initial dose of 40mg/m2 can be given intravenously weekly.

 Several characteristics of methotrexate qualify its as an ideal palliative agent

but its inability to have a significant impact on duration of response or overall
survival requires further evaluation of other chemotherapy agents.

 Most commonly causes Mucositis or leukopenia.

5-fluorouracil

 One of the most frequently used chemotherapeutic agent for head and neck
cancer.

 It is usually used in combination with cisplatin.

 5-FU a pyrimidine antimetabolite, is converted intracellulary to

flurodexyuridine monophosphate, a potent inhibitor of thymidylate synthase
(which inhibits DNA synthesis).

 5-FU also forms FLUROURIDINE TRIPHOSPHATE, which interferes with

the function of ribonucleic acid.

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  As a single agent, it has a response rate of approximately 15%.

 Recently, it has been observed that 5-FU can be potentiated when used in
conjunction with leucovorin stabilize with the 5-FU and thymidylate synthase
ternary complex.

 Primary toxicity that have been encourtered palmar-planter erythrodysesthesia,

mucositis, myekosuppression and diarrhea.

 The doses most frequently used 800 to 1000mg/m2 by continuous infusion for
72 to 96 hours.

PACLITAXEL AND DOCETAXEL

• Members of the taxoid class, paclitaxel(taxol) and docetaxel (taxotere) have a

distinct mechanism.

• Paclitaxel functions to promote the assebly of the microtubles from tubulin

dimers and to stabilize microtubules by preventing depolymerization, resulting
in mitotic arrest at G2/M phase and subsequent apoptosis.

• This cytotoxic agent was originally discovered in 1971 and is derived from the
pacific yew tree, taxus baccata.

• Paclitaxel is formulated in cremophor, resulting in sever hypersensitivity

reactions in 2% to 4% of patients.

• Additional adverse event that have been reported include urticaria, angiedema,
dyspena, hypotention and anaphylaxis.

• All patients required premedictaion with corticosteroid, diphenhydramine, and

H2-antagonist to prevent adverse reaction.

• A varitey of infusion schedules have been evaluated to determine the optimal

method of administering paclitaxel without comparing efficacy.

• The response rate 20 to 40% in recurrent or metastatic disease.

• Peripheral neuropathy and myelosuppression are the primary treatment

limiting toxicites.

• The semisynthetic taxene docetaxel has a mechanism of the action similar to

paclitaxel’s in promoting microtubules stabilization.

• Docetaxel does not alter the number of protofilaments in the bound

microtubules, and it prevents formation of the centrosome rather than affecting
the mitotic spindle.

• In vitro studies have detemined docetaxel to be 100-fold more potent than

paclitaxel in BCL2 phophorylation, further modulating apoptosis.
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 • Docetaxel was detemine to be active and safe with an overall response rate of
42% .

• Principal toxicites of docetaxel include leukopenia, asthenia, peripheral

edema, peripheral neuropathy and hypersensitivity reaction.

• Docetaxel continues to be evaluated in palliative, induction and concurrent

radiation treatment.

GEMCITABINE, VINORELBINE AND IRINOTECAN:

 Gemcitabine is a synthetic pyrimidine antimetabolite with both cytotoxic and

radiosensitizing properties.

 Early phase 1 studies established a recommended phase 11 dose of

1000mg/m2 for 3 of 4 weeks.

 An EORTC multicenter phase 11 trail in advance and or recurrent head and

neck cancer established a modest overall response rate of 13% with primary
toxicities including fatigue and grade 1/11 elevated liver enzyme.

 Gemcitabine continues to be investigated in combination with other

chemotherapy agents and as an adjunct to radiation therapy.

 The semisynthetic vinca alkaloid vinorelbine disrupts microtubule assembly,

resulting in mitotic arrest.

 Vinorelbine is commonly adminstered at 30mg/m2 weekly overall response

rate in recurrent and advanced disease setting have been less than promissing
at 7.5% to 14%.

 Common toxicites encountered when vinorelbine is administered include

myelosuppression, constipation, asthenia and peripheral neuropathy.

 Irinotecan is a topoisomerase1 inhibitor with activity in several tumor cell

lines, including non-small cell lung carcinoma, colon cancer, pancreatic cancer
and SCCHN.

 Investigators at vanderbilt university examined CPT-11 125mg/m2 given

weekly for 4 weeks, every 6 weeks, to previously untreated patients with
metastatic and/ or recurrent cancer of the head and neck.

 Preliminary analysis revealed an overall response rate of 30%.

 Despite a favorable response frequent toxicites such as vomiting , diaarrhea,

neutropenia and infection resulted 60% of patients receiving a dose reduction.

 Other topoisomerase 1 inhibitors have been evaluated in the pallative care

setting but have proved ineffective.

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Combination cytotoxic chemotherapy regimens

Combination Chemotherapy With Cisplatin/5FU

Several randomized clinical trials have provided conclusive evidence for superiority
of cisplatin/5FU as the standard in this patient population.

The primary method of adminstration of this doublet regimen is cisplatin 100mg/m2

on day 1 and continuous-infusion 5-FU 1g/m2 on day to 4 or 5.

A large phase 111 randomized trial of combined PF versus each respective agent was
initiated by jacobs and associates; an improved overall response rate was determined
for this doublet regimen at 32% vs cisplatin 17% vs 5-FU 13% in advanced head and
neck cancer.

A large randomized phase 111 trial conducted by the southwest oncology group
determined that the response rate of cisplatin/5-FU (32%) and carboplatin/5-FU
(21%) exceeded that the single-agent methotrexate (10%)

Forastiere and colleagues randomly assigned 271 patients with SCC to one of three
arms:

1) Cisplatine (100mg/m2) / continuous-infusion 5-FU (1000mg/m2/day, days 1

to 4) repeated every 21days:

2) Carboplatin (300mg/m2/ continous-infusion (1000mg/m2/day, days 1to 4)

repeated every 28 days

3) 3) Methotrexate (40mg/m2 weekly)

Although the combined chemotherapy arms clearly had an improved response when
compared with methotrexate, median survival was found to be equivalent in all 3
arms.

Various methods of enhancing the cytotoxicity of chemotherapy agents have been

explored, including the use of interferon-a.

In vitro studies of interferon-a have revealed enchanced cytotoxic effects of 5-FU

when administered in combination.

Based on this premise, investigators examined the combination of cisplatin/5-

FU/Interferon-a in pilot trial.

 An overall response rate of 30% was seen.

 A larger phase 111 trial of PF with randomization to interferon-a was pursued

in pts with cancer of the head and neck who had a poor prognosis.

 After completion of the study, no statistical difference in response rate or

median survival benefits could be ascertained.
472
  Increased toxicities of anorexia, fever leukopenia and thrombocytopenia were
noted to occur in the interferon-a arm.

 Unfortunately these and other phase iii trial have been unable to established an
improved benefit in survival when a combined regimen is used, and increased
toxicity is often noted.

 A critical drawback to several of the earlier studies was the consideration of

response rather than overall survival in the setting of recurrent or metastatic
disease as the primary endpoint.

Combination chemotherapy with the TAXANES

Docetaxel(taxotere)/ Platinum Combinations:

 Novel combinations incorporating the taxanes have been initiated and

continue to be evaluated.

 Previously, several phase II clinical trials have examined the benefits of

docetaxel combined with cisplatin of 5-FU.

 The EORTC investigated the combination of docetaxel (100mg/m2) /

cisplatin (75mg/m2) every 21 days in taxane-naïve patients. A favorable ORR
of 53.7% was determined

 Majority of the adverse events noted were primarily hematologic, resulting in

anemia and leukopenia.

DOCETAXEL/5-FLUOROURACIL COMBINATIONS:

 À 2nd phase ii trial was initiated in a small group of 17 patients with recurrent
or metastatic SCCHN.

 Patient received docetaxel (70mg/m2, day 1) / 5-FU (800mg/m2, day 1 to 5)

every 28days.

 This clinical trial was treminated after first-stage interim analysis failed to
demonstrate a response.

 Toxicities noted to occur includes neutropenia and mucositis.

Docetaxel triplet regimes:

Combination of docetaxel 80mg/m2 day 1, cisplatin 40mg/m2 day 1 and 2 and

continuous infusion 5-FU 750mg/m2/day in 19 patients with recurrent or advanced

473
head and neck cancer, concluding an over all response rate of 44% with acceptable
toxicity.

Oral fluropyrimidine capecitabine (xeloda) is selectively activated by thymidine

phosphorylase, consequently prolonging the half life of 5-FU.

Therefore it is thought that its administration may mimic conyinuous –infusion 5-FU.

 Patients receivind docetaxel/cisplatin and capecitabine 1 to 3g/m2/day in two

divided doses day 1to 4 every 3 to 4 weeks.

 Overall this triplet regimen provided disappointing results with a pr in one of

ten head and neck cancer patients after a preliminary analysis.

 PACLITAXEL (TAXOL)/ PLATINIUM COMBINATIONS:

 Numerous studies have combined paclitaxel with cisplatin in the setting of

recurrent cancer of the head and neck resulting in a wide range of response
rate from 30% to 70%.

 Both high and low dose paclitaxel combinations have been created to
determine if a dose-response realtionship exist for 24 hour infusion of
paclitaxel. The myelosuppressive effects of paclitaxel often required
hematologic support with granulocyte colony-stimulation factor (G-CSF) if
high doses are to be administered.

 Eastern cooperative oncology group ( ECOG) conducted a randomized phase

iii study in 210 Patients of high doses of paclitaxel 200mg/m2 over 24 hours
and cisplatin 75mg/m2 / G/CSF versus low-dose paclitaxel 135mg/m2 over
24hours and cisplatin 75mg/m2 in patients with unresectable, recurrent or
metastatic head and neck cancer.

 No significant difference in response could be deteremined 35% vs. 36%

respectively.

 Profound grade iii/iv granulocytopenia developed in both the high and low
dose paclitaxel arms (70% and 78%).

 Each arm of the randomized study resulted in an unacceptable death rate of

10%.

 Consequently neither of these combination regimens is recommended for

continued evaluation.

 Investigation at loyola unvirsity medical center completed a single institution

trial in patients with cancer of the head and neck to evaluate the palliative
effect of carboplatin and paclitaxel a standard regimen in the treatment of
advanced NSCLC.

474
  Thirty seven chemotherapy navie patient received paclitaxel 200mg/m2 over
3hours) and carboplatin every 21 days.

 Patients were allowed to receive tologic support.

Paclitaxel Triplet Combinations

Investigators at the University of Texas MD. Anderson Cancer Center have

conducted a clinical trial examining the triplet regimen TIP paclitaxel (175
mg/2m), cisplatin 60mg/m2, ifosfamide (1000 mg/m2, (days I to 3). and
mesna given every 21 to 28 days. An ORR ORB of 58% was established: 9
patients achieved a CR. and 6 of these patients 67% remained disease free
after a median follow-up of longer than 16 months.

Disease site comparison established the improved response rate of patients

with distant disease compared with pared with patients with locoregional
disease involvement (80% vs. 30%, respectively; P = .003).

The primary adverse non hematologic toxicity was peripheral neuropathy in

almost half of the patients enrolled Grades Ill to IV neutropenia occurred in
90% of patients: neutropenic fever occurred in 27% of patients.

The role of the TiP regimen continues to be investigated toward the goal of
organ preservation.

CONCOMITANT CHEMOTHERAPY:

 It is administered with the intent of curing locoregional disease and controlling

the occurrence of distance disease.

 Theoretically systemic control may be feasible if the dose of chemotherapy

administered is equivalent to standard systemic doses when given in
combination with radiotherapy.

 Chemotherapy should act as radiosenstizer or an enhancer .

 Therefore combined chemotherapy provides potentially increased antitumor

activity, often at the risk of substantial local toxicity.

 Generally radiation therapy is administered in 2 basic schedules:

 Concomitant or in an interrupted fashion.

 The method of radiation delivery may also have an impact on treatment

outcome and acute and chronic sequela.

475
 The method of radiation delivery may also interrupted of radiation delivery
may also have an impact on treatment outcome and acute and chronic sequela.

 The radiation therapy oncology group (RTOG) has completed a randomized

phase 111 trial (RTOG 9003) in more than 1000 patients with locally
advanced cancer of the head and neck.

 The 4 arms were as follows:

1. Standard radiotherapy

2. Hyperfractionated twice daily radiotherapy

3. Accelerated fractional twice-daily radiotherapy

4. Accelerated fractional therapy with concomitant boost.

 After median follow up of 23 months, it was determined that hyperfunctioned

or acceleratyed radiotherapy with boost locoregional therapy provided
increased locoregional control and a trend towards improved disease free
survival in comparison with conventional radiation therapy.

 However, no improvement was noted in overall survival .patient given

accelerated split-course fractionation had outcome similar to those who had
received conventional radiotherapy.

 Clinical investigators continue to incorporate accelerated fractional hyper

fractionated and intensity-modulated radiotherapy approaches in an attempt to
maximize associated toxicity.

476
477
478
Collaborators N Location Regimen Results

3yr (os)

Brizel et al 1998 116 Squamous cell A: hyperfractionated bid 34%

carcinoma radiotherapy(75gy)
including the 55%
nasopharynx B: hyperfractionated bid
radiotherapy P=.07
(70gy)/cisplatin(12mg/m2/day)
and CIFU (600mg/m2/day,
days 1-5) weeks 1 and 6

Adelstein et al, 100 Excluding A: daily raditherapy (66-72gy) 48%(5yr)

2000 nasopharyngeal,
paranasal and B: daily radiation therapy/ 50%
salivary gland CIFU (1000mg/m2/day, day 1-
4, 22-25)/cisplatin
(20mg/m2/day,day 1-4, 22-25)

RANDOMIZED MULTI-AGENT CHEMORADIATION VS. RADIATION ALONE

479
Complications of chemotherapy
Oral cavity is a frequent site of the effects of aggressive chemotherapy with acute and
chronic oral complications developing in 40% to 75% of patients receiving treatment.

Significant risk factors for development of oral complication include the type of
malignancy, the chemotherapeutic agents used the cumulative dose, the method of
delivery and the degree and duration of myelosuppression.

Poorly maintained dentition, oral and dental disease, moderate to advanced

periodontal disease, ill-fitting prostheses and inadequate oral care during treatment
increase the severity of complications.

 All chemotherapeutic agents damage rapidly dividing cells.

 The mucosal membranes of the oral cavity have rapid epithelial turnover,
rendering them vulnerable to the effects of cytotoxic agents.

 Direct cytotoxicity results in interruption of the integrity of the mucosa and in

an increased risk for local or systemic infection in the immunosuppressed
patients.

ORAL COMPLICATIONS

• Mucositis/stomatitis

• Infections

• Hemorrhage

• Xerostomia

• neurotoxicity

Mucositis/Stomatitis:

 Direct stomatotoxicity or Mucositis a results of cytotoxic effect on the cells, is

the most common acute oral complications of chemotherapy.

 It may be seen as early as 3 days or more commonly 5, to 7 days afetr the start
of treatment

 Mucositis most frequently seen with cyclophosphamide, bleomycin,

cytarabine (ara-c), doxorubicin, daunorubicin (adriamysin), etoposide, 5-
fluorouracil, methotrexate, mitomycin, meracaptopurine, vinblastine,
vincristine and floxuridine.

480
 Condition regimens for bone marrow transplantation, continuous infusion or
frequent repetitive schedules are more likely to cause Mucositis than
equivalent doses of similar drugs given in a single bolus.

 Chemotherapy causes a decrease in the renewal of the basal epithelium.

 This results in atrophy and thinning of the mucosa as well as the development
of edema and erythematous burnlike lesions.

 These areas quickly ulcerate and coalesce to form large area of mucosal
denudation covered with a whitish-gray membrane.

 Areas of deeper ulceration with erythematous halos and necrotic centers may
develop, especially on the lips, ventral surface of tongue, floor of the mouth,
buccal mucosa and soft palate.

 Patients who develop Mucositis during their initial cycle of chemotherapy

usually continue to develop increasingly sever Mucositis during subsequent
cycles.

 Mucositis can become cumulative and is often the factors limits the amount of
chemotherapy that can be given, compromising treatment outcomes.

 Infectious stomatitis can occur indirectly from the myelosuppression caused

by chemotherapy.

 It usually occurs 7 to 12 days after administration of an agent, corresponding

to the nadir to the white blood cell count in the patient with neutropenia.

 Periodontal pockets and periapical pathosis may provide a reservoir of

pathogenic and opportunistic organism that cause local or systemic infections
during periods of myelosuppression.

 Marginal and papillary gingival inflammation can lead to breakdown of the

gingiva followed by ulcerative lesions that can extend to any region of the
mucosa.

481
Treatment

Management of Mucositis is primarily palliative.

Patients should be advised to eat a soft, bland diet and to avoid hard, abrasive foods
that can mechanically traumatize the tissues.

The oral mucosa should be cleaned as atraumatically as possible with ultrasoft

toothbrush or wet gauze.

 Sodium biocarbonate rinses used frequently clean and lubricate tissues,

prevent crusting, and soothe sore tissues.

 In mild cases, dilute chlorhexidine rinses can be used to decrease oral

microflora.

482
 For increased penetration of topical medication, tissues must be cleaned of
mucus and debris prior to application.

 Following emesis, patients should rinse their mouth with sodium biocarbonate
solution, swallow some water to clean the throat of acidic secretions, these
secretions can cause increased irritation and ulceration of the mucosa.

 Suspensions of topical anesthetic can be used to alleviated discomfort.

 Topical anesthetics, such as dyclonine hydrochloride(0.5%) and viscous

lidocaine hydrochloride (2%) sol. Can be effective in relieving discomfort but
also can be chemically irritating.

 Care must be taken not to mechanically traumatize anesthetized tissues.

 A 1:2 dilution with water decreases the profound numbing effect and can still
provide relief.

 Topical anesthetics can be combined with coating agent like magnesium

hydroxide or kaolin-pectin and diphenhydramine hydrochloride elixir in 1:4:4
mixture to produce a swish and expectorate or swallow rinse.

 A cool solution can increase relief

Eg ice cubes to dissolve in the mouth recommended.

 Sucralfate an antiulcer drugs, binds to ulcerated tissues by attaching to

proteins in the damaged mucosa. It forms an adhesive-like protective coating.

 Available in tablet form, it can be dissolved in water to make a rinse.

 Dyclonine or lidocaine can be added to solution to decrease pain and can be

swished and expectorated or swallowed up to six times per day.

 Zilactin: medicated gel contains tannic acid, forms an occlusive film over oral
ulceration, must be applied to dried tissue which often causes increased
discomfort and decrease patients acceptance.

 Kamillosan liquidim ( flower of chamomile plant) rinse (10 to 15 drops

dissolved in 120ml of warm water) 3 times a day, it thought to have anti-
inflammatory, spasmolytic and antibacterial action and helps promote
granulation and reepithelization of ulcerated tissues.

 Cryotherapy in the form of ice chip used for 5 min prior to drug administration
and for 25 min afterward can be associated with5-fluorouracil, possibly by
causing local vasoconstriction and reducing local delivery of the agent.

 Allopurinol rinses have been shown to be effective in protecting against

methotrexate induced Mucositis.

483
  In the future control of Mucositis may be found in cellular engineering and
manipulation.

 cytokine- stimulated neutrophil recovery using agent such as granulocyte

colony stimulating factor and granulocyte macrophage colony-stimulating
factors decreases the duration of Mucositis either by epithelial damage or by
decreasing the likelihood of secondary infection and delayed healing.

 Transforming growth factor beta3 and interleukin-2 have demonstrated

promising efficacy by transiently limiting the rate of basal oral epithelial
growth proliferation in vitro and in vivo there by modifying the frequency and
severity of chemotherapy-induced Mucositis.

Infections:

 Oral infection in immunosuppressed patient can become life-threatening.

 The incidence of infection varies with the type of malignancy, degree of

myelosuppression and host susceptibility.

 In hematological malignancy 50% of oral infection are caused by candida

albicans 25% by HSV, 15% by gram negative bacilli and 105 by gram
positive cocci.

 70% of patients being treated for solid tumors have oral infection cause by
fungi 10%, by HSV, 10% by gram –ve bacilli and 10% by gram +ve cocci.

 Although normal flora often is the cause of the infection, there is a shift in the
oral flora in immunosuppressed patients toward gram –ve organism
(pseudomonas, proteus, Escherichia coli and klebsiella) underlying oral
diseases such as periodontitis present an increase in anaerobes and spirochetes.

 Prolonged antimicrobial or corticosteroid therapy may encourage an

overgrowth of opportunistic organisms.

 Fungi account for most of the oral infections with candida albicans causing
both superficial and disseminated infections.

 Site commonly affected include the tongue, buccal mucosa, palate and
pharyngeal mucosa..

 Candidial infection may present not only as pseudomembranous but also as

hyperplastic, erythematous and angular cheilitis. The fungal colonies tend to
coalesce and spread, covering extensive area of the mucosal surface.

 Herpex simplex virus and herpes zoster are the most common viral pathogens
causing infection in the patients receiving chemotherapy.

484
  Reactivation of latent virus can cause herpetic Gingivostomatitis and labialis.

 Lesions can occur on any oral or perioral surface.

 Symptoms of itching, burning and pain followed by vesicles that quickly

rupture, leaving multiple ulcerations on an erythematous base.

 These lesions can mimic the ulceration that develop as result of the direct
stomatotoxic effects of chemotherapy.

 Lesions can enlarge peripherally causing extensive necrosis.

 They can take a protracted time to resolve, especially in the patient with
profound neutropenia.

 Opportunistic superinfection may occur concomitantly and is often a more

serious threat than the viral infection alone.

Treatment:

 Many patients are treated prophylactically against fungal infection if their

neutrophil counts are less than 1,500/mm3.

 Topical or systemic agents can be used depending on the degree of

immunosuppression.

 Topical NYSTATIN rinses (100,000 U 4 times a day) or

CHLORTRIMAZOLE troches (10mg 5 times a day) are typically effective.
With decreased salivary flow, troches may not readily dissolve and solutions
may be preferable.

 Patients should be instructed to thoroughly clean the oral cavity prior to taking
any antifungal medications.

 Dental prostheses should be removed to allow medication to reach all intraoral

tissues and treated to prevent reinfection. Toothbrushes should be disinfected
after each use.

 Bacterial infection: broad-spectrum antibiotics are usually indicated at the first

sign of infection to reduce the danger of gram –ve sepsis.

 Patients with neutrophil counts of less than 1,000/mm3 need i.v broad-
spectrum antibiotics.

 Platelet transfusions may be necessary if platelet count are less than

50,000/mm3.

 Viral infections are generally treated with acyclovir, either orally or

intravenously.

485
  If a patient is known to be a risk for HSV reactivation due to seropostivity and
prolonged myelosuppression treatment is generally started prophylactically.

 Early recognition of HSV is imp because HSV lesion are frequently mistaken
for chemotherapy-induced Mucositis, culturing can aid in differentiating
between the two.

 Herpetic lesions that become secondarily infected with fungus or bacteria

require combined treatment.

Hemorrhage:

 Intraoral hemorrhage can be treatment-induced thrombocytopenia and or

coagulopathy or by myelosuppression secondary to the neoplastic process.

 Bleeding is uncommon when the platelet count is more than 50,000/mm3, but
the chance of spontaneous bleeding when the platelets count falls below
20,000/mm3 exceeds 50%.

 Petechiae on the palate and gingiva are the most common signs of decreased
platelet count .

 Underling oral inflammation can exacerbate bleeding tendencies. Bleeding can

occur spontaneously or be precipitated by minimal trauma for oral hygiene by
minimal trauma from oral hygiene technique, mobility secondary to
periodontal disease, fractured restorations or teeth, dental prostheses, or
orthodontic appliances.

 Bleeding is usually oozing and intermittent and can occur at multiple sites,
masking control difficult.

 Clots are often friable and easily disrupted.

 Treatment usually includes transfusion of platelets or coagulation factors until

the bone marrow recovers.

 Prevention is best approach to avoid hemorrhage.

 Maintaining good oral hygiene and eliminating marginal gingivitis can help
decrease the chance of bleeding in a patient with thrombocytopenia.

 Daily rinsing with chlorhexidine is effective in reducing inflammation.

 When bleeding occurs application of periodontal dressing and local coagulants

such as topical thrombin can be used.

 Transfusions of platelets, whole blood or plasma may be necessary.

 In patients with profound bone marrow suppression, soft vinyl mouth guards
can be lined with xerofoam sprrinkled with avitene or filled with gelfoam or
486
 surgical sprinkled with topical thrombin and placed over the teeth and soft
tissue.

 Theses can be removed 8 hours, cleaned and replaced with a fresh liner.

 Vigorous mouthrinses should be discouraged to avoid dislodgment of clots.

 The patient should eat a soft diet to avoid mechanical chemical trauma, which
may reinitiate bleeding.

Xerostomia

 Quality and quantity of saliva can be reduced as early as 2 days after the
administration of some chemotherapeutic agents( particularly doxorubicin) or
as a result of other medications the patient may be taking.

 The duration of therapy can contribute to the degree of Xerostomia.

 Patients may complain of general dryness and develop thick, ropy saliva,
probably as a result of cytotoxic effects on parotid glands.

 There is a decreased salivary PH and shift in the oral flora toward more
cariogenic species. Loss of protective immunoproteins coupled with the
increased acidity and the presence of cariogenic microorganism can often lead
to an accelerated rate of decay similar to radiation caries.

487
  An increased rate of candidial overgrowth is also related to decreased salivary
flow.

 Xerostomia can make mucosal surface more susceptible to trauma and

subsequent ulceration and exacerbate existing Mucositis.

 With the exception of the bone marrow transplant patients who develop
chronic graft-versus-host disease, chemotherapy induced Xerostomia is
transient and resolve upon cessation of chemotherapy.

 Frequent rinses help to hydrate the mucosa.

 Patient should be encouraged to drink plenty of liquids, to avoid smoking and

alcohol and use sugarless gum or candy as a salivary stimulant.

 Dried lips can be coated with a lubricant containing flanolin or cocoa butter.

 Petroleum jelly should be avoided as it can promote bacterial growth.

 Moisturizing gels and artifical saliva preparations containing

carboxymethylcellulose or hydroxyethylcellulose, such as oral balance,
xerolube or oralube, can be used daily to prevwnt the development of
chemocaries until the completion of treatment.

Neurotoxicity

 Some chemotherapeutic agents( particulary the plant alkaloids vincristine and

vinblastine) can cause neurotoxity with nerve damage closely related to total
dose and duration of therapy.

 The neruotoxic effects usually manifest as pain and or neuropathy of the

extremities.

 Involvement of the cranial nerve can produce altered sensation, causalgia or

partial paresthesia of the perioral and intraoral areas innervated by the
trigeminal nerve.

 Patients can experience sever, bilateral throbbing pain that mimics that of
odontogenic or periodontal origin, especially in the region of the mandibular
molars.

 The diagnosis of neurotoxicity is difficult and complicated by the fact hat the
symptoms may resolve spontaneously only to return with increased intensity.

 The absence of clinical or radiographic odontogenic or periodontal pathosis.

 Knowledge of patients drug regimen and the presence of bilateral pain can aid
in identifying the cause.

 Treatment involves the use of systemic analgesics usually narcotis.

488
  Pain resolves when the chemotherapy is discontinued although residual
neuropathy may remain.

Dental treatment prior to chemotherapy

Pretreatment evaluation

 Preventive care and intense oral hygiene instruction should be part of a

patients initial workup.

 The initial examination should include a thorough head and neck examination,
oral and dental examinations and radiographic evaluation aimed at
documenting acute and chronic conditions that could produce or exacerbate
complications.

 Potential sources of infection: plaque, calculus, periapical pathosis, acute

dental abscesses, periodontal disease, caries, partially impacted 3rd molars and
irritation (defective restorations, ill-fitting prostheses)

 Resolving these problems prior to initiation of therapy helps to decrease oral

complications and prevent the development of local or systemic infection.

 Teeth with acute abscesses or symptomatic periapical pathologic conditions,

nonrestorable teeth and teeth with sever periodontal involvement should be
extracted at least 10 days prior to an anticipated neutrophil count of less than
1000/mm3 after consultation with oncologist.

 Alveolectomy and primary would closure should be obtained.

 Because hemostatic packing agent (gelfoam, surgicel) provide a good culture

medium for bacterial and fungal growth they are contraindicated.

 Prophylactic antibiotics should be given if the absolute neutrophil count is less

than 2,000/mm3. if there is not enough time to extract teeth with significant
periapical pathosis or symptomatic pulpal involvement pulpal therapy should
be initiated prior to chemotherapy to eliminate a reservoir of virulent
microbes.

 Endodontic therapy should only performed if there is at least a 7 day interval

between the treatment and profound myelosuppression ( neutrophil counts <
1000/mm3.

 Extraction can then be preformed as soon as the hematologic status allows.

 Caries should be removed to decrease the presence of bacteria intraorally.

 Rough or sharp tooth surface should be smoothed to decrease soft tissue be

removed.

489
 In children all mobile primary teeth should be removed as well as those that
are expected to be exfoliated during treatment to prevent bleeding.

 For patients expected to have profound or prolonged nadir counts, soft vinyl
mouth guard can be used in controlling hemorrhages or infection.

 Topical hemostatic, antifungal, antiviral and anesthetic agents can be placed in

the mouthguard to ensure increased contact between oral tissues and the
medications.

Dental treatment during chemotherapy

 Patients are at an increased risk of infection after chemotherapy is initiated.

 Any dental treatment should only be done after consultation with the patient
oncologist to coordinate treatment with the patients optimal hematologic
status.

 A white blood cell count greater than 1000/mm3 and platelet count greater
than40,000/mm3 with a normal coagulation profile are necessary prior to any
dental treatment.

 Antibiotic prophylaxis is required when the absolute neutrophil count is less

than 2,000/mm3.

 Patients with indwelling catheters also required prophylactic antibiotic

coverage.

 The optimal time to perform dental treatment is just prior to cycle of

chemotherapy, maximizing the time before nadir is expected.

 At any time symptomatic teeth with pulpal involvement can be opend,

debribed and closed with a temporary restoration.

 Decay can be excavated and sedative fillings placed.

 Generally extractions are contraindicated, except in extreme emergencies

when an infected tooth can be the source of systemic infection.

 Dental treatment following chemotherapy:

 Chances of complications from dental treatments are decreased during

remission.

 Therefore, regular dental examinations and routine oral hygiene sessions are
imperative, restorative, endodontic, periodontal and exodontic procedure
should be performed promptly to alleviate any potential dental problems
during subsequent episodes of illness and therapy.

490