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1. Principles of Radiotherapy &Principles of Radiotherapy &
Chemotherapy & itsChemotherapy & its
maxillofacial applicationsmaxillofacial applications
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2. RADIOTHERAPYRADIOTHERAPY

3. Contents…Contents…
Introduction
History
Radiation physics
Radiation biology
General concepts of radiation techniques
Altered fractionation therapy
Dental care of patients receiving radiation
Fate of irradiated cells
Effect of radiation on biological tissues
Complications
Nutritional care of patients receiving radiotherapy
References

4. Introduction…Introduction…

5. Introduction…Introduction…
Radiation
Radiation therapy- intention
Types of Therapeutic Radiation
Electromagnetic
radiation
Particulate
radiation
Electrons
Neutrons
Protons

6. Historical background…Historical background…
1895- Roentgen- applied a high voltage across a
vacuum crooks tube. inadvertently exposing some
photographic plates of “barium platinocyanide”. He
reported this discovery in 1896
1896- Henri Bequerel reported heavy metal uranium
emits rays that pass through paper and darken a
photographic plate in dark room
1898- Maril/Pierre curie - discovery of polonium and
radium new elements with property of emitting
penetrating irradiation - called it Bequerel rays
1899- Recorded cancer cure with x-rays
1920- Radiation was an accepted modality of treating
cancers

7. Production of X-rays…Production of X-rays…

8. Production of X-rays…Production of X-rays…
Electrons traveling from the filament to
the target, converts some of their
kinetic energy into x-rays photons by
the formation of
Bremstrahlung radiation
Characteristic radiation

13. Interactions of RadiationInteractions of Radiation
with Matter…with Matter…
Photons interact with atoms through
three processes that depend on the
energy of the incident photon and on
the characteristics of the absorbing
material
Photoelectric effect
Compton effect
Pair production

15. Radiation Biology…Radiation Biology…
Biological effects of ionizing radiation
are divided into 2 categories
Deterministic
effects
Stochastic
effects
Proportional
to dose
Probability of
occurrence of change
is dose-dependent

16. Radiation chemistry…Radiation chemistry…
Mechanisms of radiation cellular kill
Indirect action Direct action

18. Physical stage
Last for 10-18 sec during which ionizing radiation
interacts with molecules producing first either
ionization or excitation of electrons. Excited atoms
have their electrons shifted to different orbits & they
become chemically very reactive
Physiochemical stage
Duration of about 10-13 seconds, meta-stable stage,
when the energy transfer process produces various
reactive species (free radicals)
Chemical stage
Lasts for duration of about 10-6 sec only. 3 imp.
cellular molecules known to be affected are
Nucleic acids
Proteins
Lipids
Biologic stage
Duration of about 10-6 seconds to many years

19. Indirect effectsIndirect effects
Interactions of the peroxide radicals,
hydrogen and hydroxyl free radicals
with the organic molecules, which
produces organic free radicals
2/3rd of the biologic effects
RH + OH* R* + HO2
RH + H* R* + H2

20. Radiation effects at Molecular levelRadiation effects at Molecular level
Nucleic acids
Breakage of one or both DNA strands
Cross-linkage of DNA strands with in the helix, to
other DNA strands or to proteins
Change or loss of base
Disruption of H-bonds between DNA strands
Proteins
Changes in their 2º & 3º structure through disruption
of side chains or breakage of hydrogen or disulfide
bonds- denautration

21. Irradiation may also induce inter- & intra-molecular
cross linking
When an enzyme is irradiated the biologic effect is
amplified
Cytoplasm
Structural and functional changes
Changes in cell organelles such as mitochondria,
golgi bodies and ER as seen within minutes
A relatively large dose of 30 to 50 grays;
mitochondria show increased permeability
Permeability changes play minor role incases of
rapidly dividing cells exposed to moderate (2-4
grays) radiation

22. Relationship of Cell Cycle & Ionizing Radiation

23. Radiation effects at cellular levelRadiation effects at cellular level
Damage during late S & G2 phase- 1 arm of chr break
seen- chromatid aberration
Damage during G1 & early S phase- Both arms of chr
break seen at mitosis as 1 broken arm replicates into 2
broken arms- chromosomal aberration

24. Oxygen Effect
Ionizing radiation to cause biologic change is very
much dependent on amount of O2 pr in tissue
environment
Most potent radio-sensitizer
Cells in 100 % O2 environment Vs cells in cplt anoxia
O2 reacts with DNA damage & prevents its repair-
cellular death

25. Definitions…Definitions…
Radiosensitivity- ability of radiation to
biologically change cells comprising a tumour
or other tissue.
Radioresponsiveness- time required for these
changes to occur and can be measured in
terms of the rate at which clinical
manifestations of radiation induced biological
change takes place.
Radiocurability- ability of radiation to reduce
the no. of malignant cells below a critical level
such that no further clinical manifestation will
occur during remaining life time of host

26. Photon energy Teletherapy unit
40 to 100kV superficial
250kV orthovoltage
1.25MV supervoltage
4 to 25MV megavoltage
Super voltage gamma rays and mega
voltage are extremely penetrating and
are used for deep seated tumors

27. The Radiobiologic Basis of FractionationThe Radiobiologic Basis of Fractionation
Use of multiple fractions over many wks of
radiation therapy is based on the principle of
improving the therapeutic ratio between
normal tissue & tumor
Goal
This can be accomplished through the use of
multiple fractions and is explained by 4
radiobiologic process

28. Improving the Therapeutic Ratio
Repair
Re-oxygenation
Repopulation
Redistribution

29. Repair…Repair…
Both normal & malignant cells suffer
radiation induced DNA damage of 3 types
Lethal
Potentially lethal
Sub lethal
Each category of damage has its own
distinctive potential for repair
Repair may occur to a greater degree in
slowly dividing normal tissue compared to
tumors & this may contribute to a beneficial
therapeutic ratio

30. Re-oxygenation…Re-oxygenation…
Bulky tumors may have centers that relatively
hypoxic due to their location > 150
micrometers away from a blood vessel- max
diffusing distance of O2 from capillary
Tumor cells located in this region would be
more resistant to radiation due to the low
oxygen tension
As fractionated radiation therapy is
administered to tumor, better oxygenated
malignant cells located at outer regions of the
mass are preferentially killed - tumor mass
shrinkage - ↑ potential for cell kill

31. Repopulation…Repopulation…
In both tumors & normal tissues, there exist
clonogens that can proliferate during course
of fractioned radiation therapy
As cell death occurs over ensuing wks of
radiation therapy, an accelerated rate of
cellular proliferation may occur which is called
repopulation
This results in an ↑ in no. of malignant cells
despite ongoing radiation therapy & thus ↓ net
effect of T/t & ultimately will contribute to local
treatment failure

32. Redistribution…Redistribution…
When a tissue is irradiated a certain % of cells
are killed & these are generally located in
more radiosensitive phases such as G2 & M
The surviving cells go into a mitotic delay
such as in G2 arrest, or may progress into
next phase of cell cycle which may be more
radiosensitive
Net effect- ↑ in % of cells in more
radiosensitive phase

33. Fractionation…Fractionation…
Based on both lab & clinical research it is
apparent that the conventional fractionation
scheme may not be best for all tumors
particularly in H&N region
3 imp areas forms foundation of the evolving
use of altered fractionation
Tissue response
Duration of treatment
Fraction size and number

34. Altered fractionation techniquesAltered fractionation techniques
for radiation therapy…for radiation therapy…
Wilher’s identified hazard of accelerated
tumour clonogen repopulation during
conventional once-a-day radiation therapy as
one lively cause of T/t failure
4 primary fractionation factors
Dose per fraction
Total dose
Overall treatment
Treatment interval

35. Altered fractionationAltered fractionation
stratergies…stratergies…
Hyperfractionation
Decreased fraction size
Increased fraction number
Increased total dose
Maintain overall treatment time
Rationale : Allows safe delivery of high
tumours dose without increase in late
normal tissue toxicity

36. Strategy of hyperfractionation is to use an ↑ed
no of smaller doses per fraction than
conventional 1.8 - 2.0 Gy per day
It is smaller dose per fraction that is
associated with a lessening of late normal
tissue effects, thus allowing the safe ↑ of
approx 10 - 15% in total dose
This results in a net gain in overall tumour cell
killing over a standard once daily schedule

37. Acceleration
Decrease overall treatment time
Maintain or slightly reduce
Fraction size
Fraction number
Total dose
Rationale : Counteracts adverse effects of tumour
cell repopulation by decreasing over all treatment
time
Primary objective here is to diminish deleterious
effects of tumour cell proliferation during course of
radiation therapy

38. Accelerated hyperfractionation
Combined features
Generally delivers twice - daily fractions to
a high total dose (app. 70-75 Gy) with a
slight ↓ in overall T/t time (approximately 6-
6.5 weeks)

39. Dose escalation
This strategy employs an ↑ in individual
fraction size during a course of
radiotherapy specifically in pt receiving 1.2
Gy fractions, twice daily in initial phase of
T/t might escalate to 1-5 Gy fractions in
final T/t phase during the so-called boost
segment of H&N cancer T/t

40. Altered fractionation regimens for H&N cancerAltered fractionation regimens for H&N cancer
Total
dose
Dose/
Fraction
No. of
Fraction
Time
interval
Accelerated
fraction
-/↓ -/↓ -/↓ ↓
Hyperfractionation ↑ -/↓ ↑ -
Accelerated
hyperfractionation
- ↓ ↑ ↓
Concomitant boost -/↑↓ -/↓ ↑ ↓

42. Differential effects on tumours &Differential effects on tumours &
normal tissuenormal tissue
Differential ability of ionizing radiation to
sterilize tumour without unacceptable
damage to normal tissue is due to 5
major biologic differences b/w tumour &
normal tissue
No of normal clonogenic cells pr in
surrounding tissue > tumour

43. Repair takes place after radiation damage- ↓ in
tumour
Repopulation can occur after irradiation in
both tumour & normal tissue if viable
clonogenic cells remain - Normal tissue seems
to respond to radiation injury with more rapid
cell proliferation
O2 plays an imp role in radiation sensitivity-
some areas of tumour re-oxygenate during T/t
Cell position in cell cycle (resting, DNA
synthesis, mitosis)- If tumour cells are in a
vulnerable position in their cell cycle while
normal tissue cells are in a more resistant
phase- a better differential damage

44. General concept ofGeneral concept of
radiotherapeutic techniques…radiotherapeutic techniques…
Immobilization
Irradiated part be immobilized during radiation
therapy
Head cast, bite block, tape etc.
Simulation
A T/t planning session with a T/t simulator is
necessary for precise localization of tumour volume
& target volume to be irradiated
If accessible extent of tumour margins in oral cavity,
oropharynx & neck nodes are outlined by
radiopaque gold or lead wire

45. Radiotherapy techniques…Radiotherapy techniques…
External irradiation
Peroral irradiation
Interstitial irradiation
Surface irradiations

46. Clinical radiationClinical radiation
techniques…techniques…
Teletherapy Brachytherapy
DeepDeep
SuperficialSuperficial

47. The radiotherapeuticThe radiotherapeutic
techniques…techniques…
Parallel opposing portals
Ipsilateral wedge pair
Arc rotation
Intra-oral concentration
Interstitial or intracavitary implant

48. Parallel opposing portal techniqueParallel opposing portal technique
Commonly used for T/t of large lesions /
midline lesions- b/l LN metastases e.g. Ca of
nasopharynx, SP, base of tongue
Distribution of radiations is relatively uniform
throughout the en bloc irradiated vol but
without specific localization. Primary & LN are
irradiated by same portals

49. Ipsilateral wedge pair techniqueIpsilateral wedge pair technique
Eccentric lesions without contralateral nodal
metastasis i.e., tumours arising from parotid
gland, orbit, temporal bone, retromolar
trigone, buccal mucosa & floor of mouth
Often used as a boost technique following
parallel opposing portal irradiation
Drawback- hot spot

50. RotationRotation techniquestechniques
This may be a 360º rotation or 270º arc
rotation with or without wedges with an
isocentric megavoltage machine
May be used as 1º method for radiation
therapy or as boost to centrally situated
primary lesion following parallel opposing
portals or wedge pair techniques
For any rotation techniques, sensitive organ
such as eye must be excluded from the path
of radiation beam

51. Intra oral concentration electronIntra oral concentration electron
beam therapybeam therapy
Given with megavoltage electron or
orthovoltage radiation- early & acccessible
lesions of oral cavity
Electron beam therapy may be delivered
perorally sparing lips, teeth or mandible by
adopting a specially made apparatus to linear
accelerator
For lesions of oral cavity, in which IOC is not
possible, electron beam boost therapy may be
given through a submental approach

52. Interstitial or intracavitary implantInterstitial or intracavitary implant
Employing Ir192
or Cs137
sources
Effective in controlling small lesions of H&N
mainly Ca of skin, lip & oral cavity
Most I/o sites are unsuitable for this procedure
with availability of modern radiation therapy
equipment, most of lesions posterior to
circumvalllate papillae are irradiated by
external beam alone
Exclusively used for carcinoma of
nasopharynx as a boost to primary site

53. Brachytherapy…Brachytherapy…
Brachio in greek means short
Brachytherapy is the sub specialty of radiation
oncology which uses selected radioisotopes
and specialized instruments to directly
administer radiation to tumor bed
Placement of source

54. Depending on the technique employed- T/t
may involve a permanent implantation of a
radioactive source E.g. I 125
seeds
May involve temporary exposure after which it
is removed, E.g. intracavitary insertion of I 125
seeds for localized recurrent nasopharyngeal
Ca
Brachytherapy radiation travels only a short
distance to the desired target region
Its dose intensity has a rapid fall off with
distance according to the inverse square law
[I~ 1/ D2]
This causes sharp ↓ in dosage in surr tissues
The dose rate can be low and continuous
LDR - 40 to 200 cGy / hr
HDR – 1200cGy / hr

55. May be used as primary T/t or more commonly
as local boost on conjunction with external
beam radiation therapy
Used with curative intent, but can be used for
highly selective pts for palliative therapy also
The isotopes commonly used are I 125
& Ir 192
In H&N tumor sites commonly considered for
possible brachytherapy include
Lip
Floor of the mouth
Oral tongue
Base of the tongue
Buccal mucosa
Tonsillar region
Nasopharynx
Skull base
Neck nodes

56. The size & volume of primary lesion, anatomic
extent, topography, adjacent vital organs any
prior therapy and medical and psychological
condition must be critically evaluated
In oral cavity T1 & T2 lesions can be treated
with brachytherapy alone or with external
beam therapy alone
Complications such soft tissue necrosis &
bone necrosis should be kept in mind
Brachytherapy shd not be performed if implant
cannot encompass tumor region with margin
or if region is technically not approachable

57. Neutron therapy…Neutron therapy…

58. Clinical preparation forClinical preparation for
radiation therapy…radiation therapy…
Comprehensive pre-T/t evaluation
Baseline blood studies- cplt blood count,
chemistry panel & thyroid function tests
(including TSH)
Dental management
Baseline ophthalmologic evaluation
Nutritional status evaluation
Specialized care- alcoholics & smokers

59. Clinical Course ofClinical Course of
radiotherapy…radiotherapy…
Routine status evaluation at least once a week
Special attention paid to the development of a
sore mouth or throat, dysphagia, hoarseness,
taste problems, xerostomia, skin
symptomology & even ear symptoms when
the portal includes the external auditory canal
and/or Eustachian tube
Mucositis, oral Candida & dermal reactions
The general condition, weight status and cplt
blood count to be monitored

60. May develop acute parotitis- within 1st
12 hrs
after initiation of irradiation to portals
including parotid gland
During 2nd
wk of T/t- 2,000 cGy dosage, pt shd
be checked for development of tumoritis, a
mucosal inflammation which indicates true
extent of tumor & thus may necessitate
modification of the portal
If tumors do not show regression/ progress
during radiotherapy- immediate reevaluation-
surgery
Progressive wt loss & dehydration- 4th
– 5th
wk

61. Post T/t Follow Up…Post T/t Follow Up…
Risk for locoregional recurrence
Post radiation complications
CT or MRI
Thyroid function tests
Complete endocrine screening
Dental service for an indefinite time

62. Pre-op radiotherapy…Pre-op radiotherapy…
Principles
Shd be applied chiefly to apparently resectable
tumours
Zone of irradiation shd be larger than anticipated
surgical excision
Dose is rarely of a curative
Multiportal megavoltage or 60 Co beams should be
used when location of irradiated volume permits.
Superficial tissue will be spared and postoperative
complications will be reduced
Interval of 3-6 wks usually allowed b/w 2
procedures
Preoperative irradiation delays definitive surgery
Indications
To improve operability of a primary lesion or a
fixed lymph node

63. Test dose of radiation in a patient in whom full
course radiation therapy is being seriously
considered
Benefits
Allows time for pts to undergo vigorous supportive
therapy (nutritional, pulmonary, cardiac) to optimize
their condition in preparation for subsequent
surgery
Prevention of marginal recurrences
Prevention of implantation of tumor cells at surgery
& control of subclinical disease at 1º site & in LN
Post-op- scarring & disruption of normal
vasculature- any remaining malignant cells in
surgical bed may be in a suboptimal environment
with respect to their oxygenation & thus may not
respond as well to radiation

64. Drawbacks
Delay of surgery by perhaps to 2 to 3 mths
Impaired postoperative healing
Dosage
180 to 200 cGy/ fraction, 1 fraction/ day 5 days/ wk,
to a total dosage of 5,000 to 6,000 cGy
After completion of T/t- 4 to 6 wk gap prior to
surgery- allow for patient recovery, ↓ in acute
inflammatory rxns, to allow for a maximum clinical
shrinkage of tumor
Test dose- 5,000 cGy at a conventional fraction size
of 180 to 200 cGy- reevaluation

65. Optimum interval between pre-op irradiation &
surgery
Pre-op dose is vital factor in defining the optimum
interval- higher doses demand longer interval
Also various according to cell type. For most
tissues a 3 week interval after Cancerocidal dose is
minimal and 6 week interval is optimum
Arguments against pre-operative irradiation
Radiation impair wound healing
Delay of definitive surgery
Gross shrinkage of cancerous mass tempt surgeon
to perform less radical resection or it can provoke
patient to delay definitive surgical therapy
Can’t cure already developed occult distant
metastasis
↑ cost

66. Post-op radiotherapy…Post-op radiotherapy…
Indications
When estimated risk of locoregional recurrence is >
20 %
Advanced T3 or T4 lesions
Positive or close margins of resection
Perineural/vascular invasion
High-grade histology
Concern of surgeon with respect to adequacy of
procedure, irrespective of the status of the surgical
margins on final pathology review
Surgical margins- high risk for recurrence
Invasive carcinoma,
Carcinoma in situ,
Margin < 5 millimeters
Surgical margins initially positive but ultimately
rendered negative with further resection
Tumor borders that are infiltrating

67. Benefits
No delay in surgery
No radiation dose limitations
No influence on the extent of initial surgery
No effect on wound healing
Allows for a full surgical & histopathologic
evaluation of the extent of tumor
Sterilization of residual microscopic disease which
can result in improved local control
Drawbacks
Delay in initiation of radiation therapy due to wound
complications from surgery
Scarring & vascular modifications from surgery may
↓ tissue oxygenation- adversely affect radiation
tumor cell kill

68. Indications for Post-opIndications for Post-op
Radiotherapy for Cervical NodeRadiotherapy for Cervical Node
Metastasis…Metastasis…Indications
Extracapsular extension
Lymph node size > 3 cm (N2aN3)
Multiple ipsilateral lymph node involvement (N2b)
Bilateral or contriateral lymph node metastasis (N2c)
Massive nodel metastases > 6 cm (N3)
Surgical procedure (e.g., excisional or incisional
biopsy) prior to definitive surgery
Perineural/vascular invasion
Use of post-op radiotherapy after rnd results
in the following control rates
N1: 83 to 91 percent
N2 : 82 percent
N3: 61 to 66 percent

69. Factors influencing the conductFactors influencing the conduct
of postoperative irradiation…of postoperative irradiation…
Surgically treated cancer is not usually radiosensitive-
high dose of radiation needed postoperatively if cure
is the aim
Pts referred for postoperative irradiation have
advanced cancers that for one reason or the other
extend beyond the anticipated limit- need for general
portal is obvious
Resection reduces no of cancer cells requiring
irradiation. Normal healing process produces
connective tissue with limited ability to recover from
the insult of vigorous irradiation. The transected
cancer excesses in the connective tissue scar may be
some what protected by hypoxia. Thus a less
favorable therapeutic ratio may be treated by surgery.

70. Time Interval from Surgery toTime Interval from Surgery to
Radiation Therapy…Radiation Therapy…
Studies showed that a delay of 7 wks or more
was associated with ↑ locoregional failure rate
& ↓ survival
Schiff & colleagues noted delay beyond 6 wks
subsequently developed a locoregional
recurrence
Sloan – Kettering cancer center- start within 6
wks with adequate doses

71. Locoregional recurrence afterLocoregional recurrence after
primary radiation therapy…primary radiation therapy…
Therapeutic challenge
Careful evaluation- metastasis
Majority of recurrences occur within 2 to 3 yrs
following completion of T/t
Surgery- T/t of choice
Non surgical cases- radiation therapy
Limitation
Evaluation
General condition of the patient
Time interval since completion of initial radiation
therapy
Radiation dosage initially administered to the tumor
and adjacent vital organs
Tolerance of radiation therapy and development of
any complications

72. Anatomic location, extent of recurrence and
adjacent vital organs
Condition of previously irradiated tissues
Symptoms related to recurrence
Life expectancy.
Contraindications to re-irradiation
Poor general condition
Recurrence less than 6 months from initial radiation
therapy
Prior ultra high radiation doses
Massive tumor recurrence equivalent to advanced
T3 and T4 lesions
Location of recurrence in or around the central
nervous system
High doses- 6,000 to 6,500 cGy

73. Concurrent chemotherapy, external beam
radiation therapy alone, external beam
radiation therapy with brachytherapy, or
brachytherapy alone Caution- re-irradiating
alveolar ridge and floor of mouth
Brain & spinal cord must not be re-irradiated
Mostly used primarily for localized recurrent
nasopharyngeal carcinomas with T1 & T2
lesion
Incidence of late toxicity is greater

74. Dental care in theDental care in the
irradiated patients…irradiated patients…
Complete dental examination
Pre-irradiation dental care
Group I : Edentulous patients
Group II : Condition – poor
Group III : Fair
Group IV : Good
Dental care during radiation therapy

75. Fate of irradiated cells…Fate of irradiated cells…
Lethally injured
cells
Division delay
Non lethally
injured cells

76. Tissue reaction toTissue reaction to
radiation therapy…radiation therapy…
TISSUE
REACTION
TasteBone
Salivary
glands
Teeth
Oral
mucosa
Skin

78. Radiation caries

79. Sequelae of radiation therapySequelae of radiation therapy
ORN
Oral candidiasis
Xerostomia
Soft tissue fibrosis
Trismus
Obliterative endartritis
Slow/ non healing ulcers

80. ORN Oral candidiasis
Xerostomia Slow/ non healing ulcers

81. Causes Of Normal TissueCauses Of Normal Tissue
Complications…Complications…
Simple overdosage
Volume effect
Size of dose per fraction
Protraction of treatment
Radiation quality
Concomitant chemotherapy
Trauma
Nutritional status

82. Nutritional care of patientsNutritional care of patients
receiving radiotherapy…receiving radiotherapy…

83. CHEMOTHERAPYCHEMOTHERAPY

84. Contents…Contents…
Introduction
Historic Milestones
Classification
Basic Concepts- tumour
biology
Gompertzian growth
model
Cell cycle
Cell kill hypothesis
Principles of clinical
trials
Prognostic factors in
planning chemotherapy
Individual drugs
Chemotherapy
approaches
Chemoprevention
Intralesional & topical
chemotherapy
Complications
Conclusion
References

85. Introduction…Introduction…
Before 1970
During past 2 decades
There now are clearly defined parameters for
objective evaluation of response & survival
time & statistical guidelines for design of
clinical research trials to establish efficacy or
to show improvement compared with standard
therapies

86. Cisplatin- Rosenberg in 1968- spurred
clinical research efforts to test new
agents & combination chemotherapy
regimens for palliation
Several highly effective chemotherapy
regimens were identified
The goal was to improve survival time

87. Historical Milestones…Historical Milestones…
Exposure of military seamen to mustard gas in
WWII resulted in marrow and lymphoid
hypoplasia
1943 – Yale Cancer Center 1st used Nitrogen
Mustard to cure hematologic neoplasms
1946 – Sidney Farber observed folic acid had
proliferative effect on leukemic cell growth
Development of folic acid analogs to inhibit
folate metabolism

88. 1940– beginning of “antineoplastic
chemotherapy”
1950-1959- search of new agents
Better alkylating agents
Heidelberger- 5-Fu
1960-1969 [Wide spread interest]
Combination therapy evolved
New clinical trials
Cure of childhood leukemias
1970-1979 [decade of cure]
Multi drug therapies in solid tumours

89. Classification…Classification…
AGENT MECHANISM TOXICITY
Alkylators
Cyclophosphamide
Ifosfamide
DNA cross-linker Neutropenia, nausea, cystitis
Myelosuppression, confusion,
alopecia
Antimetabolities
Methotrexate
5-Fluorouracil
Binds dihydrofolate reductase
Inhibits thymidylate synthetase
Mucositis, myelosuppression,
diarrhoea
Antibiotics
Bleomycin
Adriamycin
Scission of DNA
DNA intercalator
Pulmonary fibrosis, rash, mucositis
Cardiotoxicity, myelosuppression,
alopecia
Vinca Alkaloids
Vincristine
Vinblastine
Mitotic arrest
Neurotoxicity, myelosuppression
alopecia
Miscellaneous
Cisplatin
Carboplatin
DNA intercalator
Nephrotoxicity, vomiting, ototoxicity,
neuropathy, myelosuppression
Taxanes
Paclitaxel
Docetaxel
Microtubule stabilizer
Myelosuppression, neuropathy
edema, neutropenia,

90. Gompertzian growth model..Gompertzian growth model..
Initial tumour growth- 1st
order, with
later growth being much slower
Smaller tumour
Medium size tumour
Large tumour
Growth rate &
growth fraction

91. Tumor GrowthTumor GrowthTumor GrowthTumor Growth
number ofnumber of
cancer cellscancer cells
diagnosticdiagnostic
thresholdthreshold
(1cm)(1cm)
timetime
undetectableundetectable
cancercancer
detectabledetectable
cancercancer
limit oflimit of
clinicalclinical
detectiondetection
hosthost
deathdeath
1010 1212
1010 99

92. Cell cycle…Cell cycle…

99. Principles of clinical trials…Principles of clinical trials…
Efficacy
To evaluate use of a particular T/t, clinicians
establish parameters
Object survival
Disease-free survival
Duration of response
Toxicity
Evaluation of chemotherapeutic agents occurs
in 3 phases
Phase I
Phase II
Phase III

100. T/t response Criteria
Complete
response
Cplt disappearance of all evidence of
tumor for at least 4 wk
Partial
response
Disease regression by at least 50% of
sum of product of the perpendicular
diameters of all measurable tumor for at
least 4 wks. No simultaneous ↑ in size of
any lesions or appearance of new
lesions
Minor
response
Regression by less than 50% of sum of
products of the perpendicular diameters
of all measurable lesions
Stable Disease No appreciable change
Progressive
disease
↑ size of any detectable lesions by at
least 25% or the appearance of new
lesions
Criteria for response

101. T/t response

102. CT scan will be more objective than physical
examination in gauging the degree of
response
A careful evaluation of response status is
critical for making a decision to continue a
regimen, to alter T/t or to discontinue it

103. Prognostic factors in planningPrognostic factors in planning
chemotherapy…chemotherapy…
Influence response, regardless of treatment
Nutritional state
Bulk of primary tumors
Extensive lymph node spread
Tumor site
Degree of tumor differentiation
Prior treatment status
Radiotherapy
Chemotherapy
Functional status of kidneys, liver, bone marrow,
heart & lungs
Motivation & compliance of pt
↓ Response rates

104. ZUBRID SCALES (0- 5) KARNOFSKY SCALE (0- 100)
0- Fully active, able to carry all predisease performance
without restrictions
100- Normal, no complaints, no evidence
of disease.
90- Able to carry normal activity; minor
signs or symptoms
1- Restricted in physical strenuous activity but ambulatory &
able to do work of light or sedentary nature, e.g. light
housework, office work
80- Normal activity with effort; some
signs or symptoms of disease
70- Cares for self; unable to do normal
activity or active work
2- Ambulatory & capable of all selfcare but unable to do any
work activities; up and about more than 50% of waking hours
60- Requires occasional assistance, but
is able to care for most needs
50- Requires considerable assistance and
frequent medical care.
3- Capable of only limited selfcare, confined to bet or chair
more than 50% of waking hours
40- Disabled, requires special care and
assistance.
30- Severely disabled, hospitalization
indicated; death no imminent.
4- Completely disabled. Cannot do any selfcare; totally
confined to bed or chair
20- Very sick, hospitalization and active
support treatment necessary.
10- Moribund, fatal process, progressing
rapidly.
5- Dead 0- Dead

105. Principles ofPrinciples of
Chemotherapy…Chemotherapy…
Chemotherapy for H&N cancer differs in 2
fundamental respects from regional T/t
Chemotherapy reaches tumors cells throughout the
body
Administered in widely varying treatment schedules
ranging from a brief single treatment course to
extended treatment programs
Goal

106. Concept underlying most
chemotherapy is cell kill hypothesis
Most effective- when given at max
tolerated dose & when administered
while tumor is still small
Sensitivity to chemotherapy varies
inversely with tumor burden

108. Methotrexate…Methotrexate…
Most widely used drug- standard
Folic acid analog that is S-phase specific
Cytotoxic effects - can be ↓ by
administration of reduced folates which
can be converted to tetrahydrofolate
Methotrexate + Leucovorin = ↑
therapeutic index

109. Mechanism of action

110. Im, iv, sc or oral routes- Weekly or
biweekly preferred schedule
Conventional dose of iv 40- 60 mg/ wk
Moderate dose - 250- 500 mg iv
High dose- 5 to 10 g iv
At this dose range- toxicity for pts with
normal renal function- limited to mild
stomatitis & myelosuppression
More severe, life-threatening reactions
consisting of confluent mucositis,
pancytopenia, liver function
abnormalities & exfoliate maculo-
papular rash occur rarely & require
intensive medical support
Leucovorin

111. Renal dysfunction may occur with high-dose
because of precipitation of drug, esp in acid
urine
Hydration & alkalinization of urine before &
after methotrexate administration can ↓ risk
Advantages
Relatively nontoxic
Inexpensive
Convenient
Response rates to conventional doses vary
b/w 8%- 50%, avg 30%
Weekly T/t, if tolerable, is superior to twice
monthly or monthly T/t

112. Cisplatin…Cisplatin…
Inorganic metal coordination complex
Drug behaves as a bi-functional alkylating
agent binding to DNA to cause inter-strand
and intra-strand cross-linking
Also binds to nuclear and cytoplasmic
proteins
Metabolic inactivation - resistance
Iv route
Requires hydration & diuresis
to prevent renal tubular
damage
80 to 120 mg every 3 or 4
weeks + mannitol diuresis

113. Toxic reaction
Renal dysfunction- ↑ in S creatinine or ↓ in creatinine
clearance
Nausea & vomiting
Ototoxicity
Neutropenia & thrombocytopenia
Bone marrow suppression
Hypomagnesaemia - renal wasting
Peripheral neuropathy
Response rate same as methotrexate
Advantages
Relatively rapid response
Given only once every 3 or 4 weeks

114. Carboplatin…Carboplatin…
MOA similar to cisplatin
Dose-limiting toxicity is
myelosuppression
Renal toxicity, ototoxicity &
neurotoxicity are rare & less
emetogenic potential
Can be administered in outpatient-
without need for hydration
Not as active as cisplatin- 24%
response rate
Reserved for pts with renal impairment
or preexisting peripheral neuropathy

115. Taxanes…Taxanes…
Act by stabilizing microtubules by binding to
B-subunit of tubulin, thereby inhibiting
microtubule de-polymerization, which results
in a cell cycle arrest at G
Response rates of approximately 30% to 40%
Paclitaxel- 135- 250 mg given over 3- 24 hrs
Docetaxel- 60- 100 mg by bolus injection every
3 wks
Toxicity
Neutropenia
Infection

116. Bleomycin…Bleomycin…
Anti-neoplastic antibiotic- binds to DNA &
produces DNA strand breaks by generating
oxygen free-radicals
Conventional dose- 10 to 20 units/m twice
weekly im or iv
Continuous 24-hr infusion over 5- 7 days at
a dose of 10 units/m each 24 hrs
Toxic effects
Fever or chills
Anaphylactic reaction
Alopecia

117. Skin toxicity- erythema, thickening &
hyper pigmentation
Stomatitis
Pulmonary toxicity
Pneumonitis
Dry cough
Rales
Pulmonary fibrosis
Hypoxia
PFT- ↓ carbon monoxide diffusion
capacity

118. 5-Fluorouracil…5-Fluorouracil…
Fluorinated pyrimidine similar to uracil
The conventional iv dose of 5-FU is 10- 15
mg/kg weekly
An alternate method of delivery is a loading
dose of 400 to 500 mg daily for 5 days,
followed by a weekly iv dose of 400- 500 mg
Not > 800 - single bolus
Therapeutic index- ↑ by giving it by
continuous infusion, which allows delivery of
up to 1 g for 5 days repeated every 3 or 4
weeks, without enhanced toxicity

120. Toxic reactions
Myelosuppression
Nausea, vomiting & diarrhea
Stomatitis
Alopecia
Hyper-pigmentation
Maculo-papular rashes

121. Cyclophosphamide…Cyclophosphamide…
Activated in the liver by microsomal enzymes
Cross-links DNA strands, preventing further
division
Orally or iv
Iv- as a single dose of 500 to 1500 mg
repeated every 3 or 4 weeks
Hydrate pts well before & after
Drugs that stimulate liver enzymes
(barbiturates) shd be avoided
Side effects
Bone marrow suppression
Nausea & vomiting

122. Alopecia
Ridging of nails
Azoospermia
Cessation of menses
Permanent infertility
Acute hemorrhagic cystitis
Haematuria
Fibrotic bladder
Bladder carcinoma

123. Metabolism OfMetabolism Of CyclophosphamideCyclophosphamide
CYCLOPHOSPHAMIDECYCLOPHOSPHAMIDE
4-OH CYCLOPHOSPHAMIDE4-OH CYCLOPHOSPHAMIDE
ALDOPHOSPHAMIDEALDOPHOSPHAMIDE
PHOSPHORAMIDEPHOSPHORAMIDE
MUSTARDMUSTARD
4-KETOCYCLOPHOSPHAMIDE4-KETOCYCLOPHOSPHAMIDE
CARBOXYPHOSPHAMIDECARBOXYPHOSPHAMIDE
ACROLEINACROLEIN
HEPATICHEPATIC
CYTOCHROMESCYTOCHROMES
P 450P 450
ACTIVATIONACTIVATION
CYTOTOXICITYCYTOTOXICITYTOXICITYTOXICITY
INACTIVATIONINACTIVATION
ALDEHYDEALDEHYDE
DEHYDROGENASEDEHYDROGENASE

124. Ifosfamide…Ifosfamide…
Structurally related to cyclophosphamide
DNA interstrand & intrastand cross-linking
that disrupts DNA replication
Activated by hepatic p-450 mixed- function
oxidase & its metabolites are excreted in urine
7 to 10 g- 5-day continuous
infusion or over 3 to 5 days in
equally divided doses
Repeated at 3/ 4 week intervals

125. Na mercaptoethane sulfonate (MESNA) is a
thiol compound that shd be administered
concomitantly with ifosfamide to limit
urothelial toxicity.
Total daily dose of MESNA.
Pts need to be well hydrated
Dose-limiting toxicity
Hemorrhagic cystitis
Myelosuppression
Nausea & vomiting
Hyponatremia
Central nervous system toxicities
Cerebellar dysfunction
Seizures,
Confusion

126. Adriamycin…Adriamycin…
Doxorubicin - anthracycline derivative
Intercalates b/w pairs in DNA to interfere with
nucleic acid synthesis
Iv 60 to 90 mg/m every 3 weeks.
Side effects
If infiltrates sc- severe necrosis of skin & sc tissue
Alopecia
Stomatitis
Nausea, vomiting & diarrhea
Neutropenia & thrombocytopenia
Cardiac toxicity

127. Vinca alkaloids…Vinca alkaloids…
Disrupts microtubular spindle
formation- mitotic arrest
Vinblastine- weekly at 5 mg
Toxic reactions
Myelosuppression
Alopecia
Myalgias
Vincristine - 1.0 to 1.5 mg/m once or
twice monthly
Toxic reactions
Peripheral neuropathy
Constipation
Alopecia
No myelosuppressive effects

128. Hydroxyurea…Hydroxyurea…
Inhibits RNA reductase, interfering with
conversion of RNA to DNA
Orally - 80 mg/kg every third day
Toxic responses
Neutropenia & thrombocytopenia
Nausea & diarrhea
Stomatitis
Maculo-papular rashes

129. SITES OF ACTION OF CYTOTOXICSITES OF ACTION OF CYTOTOXIC
AGENTSAGENTS
6-MERCAPTOPURINE
6-THIOGUANINE
METHOTREXATE
5-FLUOROURACIL
HYDROXYUREA
CYTARABINE
PURINE SYNTHESIS PYRIMIDINE SYNTHESIS
RIBONUCLEOTIDES
DEOXYRIBONUCLEOTIDES
DNA
RNA
PROTEINS
MICROTUBULESENZYMES
L-ASPARAGINASE
VINCA ALKALOIDS
TAXOIDS
ALKYLATING AGENTS
ANTIBIOTICS
ETOPOSIDE

130. Chemotherapy ApproachesChemotherapy Approaches
Palliative chemotherapy
Concomitant chemoradiotherapy
Intralesional chemotherapy
Combination therapy
Induction chemotherapy
Chemoprevention
Adjuvant chemotherapy
Topical chemotherapy

131. Palliative chemotherapy…Palliative chemotherapy…
Used in M/m of H&N cancers that are
recurrent, metastatic, unresectable &
considered incurable
Goal- ↑ QOL- ↓ pain, preserving or improving
organ function & preventing obstruction of
airway or esophagus
In some instances survival may be prolonged,
survival is not the 1º goal of palliative therapy

133. Single agent- Methotrexate therapy
Multiagent chemotherapy- cisplatin & FU has
demonstrated ↑ response rates (30% to 50%) &
may slightly prolong survival- ↑ toxic, ↓
convenient & ↑ expensive
New therapeutic regimens- taxanes, vinca
alkaloids in single & multi-agent trials

134. Induction Chemotherapy…Induction Chemotherapy…
Rationale for induction chemotherapy
↑ drug conc in tumor because of intact vascular
supply
↓ in tumor size- ↓ extent of surgery or make a
nonresectable tumor resectable
Eradication of micrometastatic disease
Can be given in ↑ doses & is better tolerated prior to
definitive locoregional therapy

135. Advantages
Delivery of drugs to best possible host in terms of
medical condition- ↑ compliance & better tolerance
to therapy
↓ tumor burden
Preservation of organ function
↓ metastatic seeds
Eliminate problems with poor vascularity that often
occur after surgery/ radiation
Disadvantages
Delay in potentially curative surgery or radiotherapy
Patients may refuse further T/t

136. One of the first uses- methotrexate with
leucovorin given twice before surgery
Cisplatin + 5 to 7 day continuous infusion of
bleomycin
Response rates of 71% to 76% with a 20%
complete response rate
Vinblastine, vincristine or methotrexate- 2
drug combination with similar results
An alternate & more effective regimen tested
in 1980s at Wayne State University is cisplatin
(100 mg/m + 5-day infusion of 5-FU (1 gm/ day
by continuous infusion)
93% overall response rate & 54% cplt
response rate (3 cycles were administered)

137. Induction chemotherapy with Fu & cisplatin
for stage III & IV Ca of larynx & hypopharynx
followed by definitive radiotherapy- preserve
organ function
Based on currently available information,
except for preservation of the larynx,
induction chemotherapy for H&N SCC shd be
limited to therapeutic trials & has no identified
place in standard H&N oncologic therapy

138. ConcomitantConcomitant
Chemoradiotherapy…Chemoradiotherapy…
Unresectable disease to improve local &
regional control
Mechanism for interaction b/w cytotoxic drugs
& radiation that results in additive or
synergistic phenomenon rests on several
mechanisms
Inhibition of DNA repair
Redistribution of cells in sensitive phases of the cell
cycle
Promoting oxygenation of anoxic tissues
The net effect is to improve cellular
cytotoxicity

139. Mechanisms
Spatial co-operation : radiation to control locoregional
disease & chemotherapy systemically to control
micrometastatic disease
Non-overlapping toxicity : chemotherapy &
radiotherapy have different mechanisms of toxicity,
which re additive to tumor but less to normal tissues
Chemotherapy ↓ ability of radiotherapy - damaged
tumor cells to repair
It has cytotoxic activity against radioresistant cells-
hypoxia
It has selective cytoprotective properties for normal
tissues- allowing ↑ radiation doses
Specific chemotherapeutic drugs such as fluorouracil,
cisplatin, and taxanes induce cell cycle arrest at the
G2 checkpoint, where the cell is most radiosensitive

140. Radiosensitizing property of chemotherapeutic agents
constitutes major rationale for concurrent
chemoradiotherapy

141. Single agent +
radiotherapy
Multiple agent +
radiotherapy
Concomitant
Chemoradiotherapy

142. Single agents & radiotherapySingle agents & radiotherapy
Methotrexate + radiotherapy
Methotrexate- S-phase block of cell cycle-
accumulation of cells in G I phase- ↑ radiosensitivity
Hydroxyurea + radiotherapy
Kills cells in S-phase & synchronizes cells into more
radiosensitive G, phase
Bleomycin + radiotherapy
Enhanced effects- interference with cellular repair
after irradiation
5-FU + radiotherapy
5-FU - active radiosensitizer for pts with H&N cancer

143. Mitomycin + radiotherapy
Mitomycin active alkylating species
Hypoxic cells within tumors have ↓ sensitivity to effects of
radiation- combined T/t improve therapeutic ratio
Cisplatin + radiotherapy
Hypoxic/ aerobic cell sensitization & inhibition of cellular
repair processes for sublethally damaged cells contribute
to effects observed in invitro systems
Hypoxia
reduces
Selectively toxic to
hypoxic cells

144. Multiple agents & radiotherapyMultiple agents & radiotherapy
Improved survival time- primary goal
Combining several drugs with radiation- acute toxicity-
trials designed with split course radiation- allow healthy
tissue recovery
Infusional 5-FU + cisplatin or hydroxyurea + concurrent
split-course single daily fraction radiation- promising
survival and response data but also severe toxicity
All reported trials of concomitant chemotherapy &
radiotherapy- ↑ acute radiation-induced toxicity,
primarily mucosal- dose ↓ & lengthy interruptions in
radiation without evidence of survival benefit- in
combining these 2 T/t modalities, it is essential that
toxicity not preclude use of chemotherapy & radiation
in optimal dose & schedule

145. Different approaches
↓
Most frequent used- standard radiotherapy or
hyper-fractionated radiotherapy with low-dose
chemotherapy as a radiosensitizing agent
↓
↑ toxicity, including mucositis & systemic
toxicity
↓
Manageable
↓
Concomitant chemoradiotherapy as the
standard of care for locally advanced
carcinomas of H&N cancer

146. Adjuvant Chemotherapy…Adjuvant Chemotherapy…
Adjuvant chemotherapy after primary surgery
has been shown to be effective
Advantages over neoadjuvant treatment
Surgery is not delayed
Neoadjuvant therapy can blur margins of disease
Neoadjuvant therapy- symptom abatement- pt
refusal to surgery
High- risk pts (those with extracapsular extension,
carcinoma in situ or close surgical margins)- benefit
from adjuvant chemotherapy with ↑ survival time &
local control

147. Subsequent to definitive locoregional therapy, adjuvant
chemotherapy has been given to control microscopic
residual disease & micrometastatic disease
Although there appears to be some ↓ in incidence of
distant metastases, adjuvant therapy has not been
demonstrated to improve survival
Vast majority of deaths related to H&N cancer are due
to local & regional failures & not due to disseminated
metastatic disease- adjuvant chemotherapy has not
been shown to have a role in M/m of Ca of H&N

148. Combination therapy…Combination therapy…

150. Organ preservation…Organ preservation…
Diagnosis at a late stage- often necessitate
extensive surgery
Loss of function- preservation of function -
major challenge
Laryngeal Ca- combined modality treatment,
neoadjuvant chemotherapy followed by
radiotherapy- better than surgery

151. Intra-aterial chemotherapy…Intra-aterial chemotherapy…
Surgery or radiotherapy
↓
Impaired drug delivery
↓
Poor response to chemotherapy
↓
To overcome
↓
Intra-arterial chemotherapy
↓
Tumor exposure to a high conc of drug
↓
Maximum cell kill

152. Factors
Drug conc, not time of exposure, is major
factor in cell killing
Drug shd be deactivated in systemic
circulation
There shd be a high tissue extraction
Drug shd not require activation in liver
Drawbacks- catheter-related
complications
Air & plaque emboli
Sepsis
Pt immobility during chemotherapy
administration
Overcome by
Use implantable
infusion pump

153. Intra-arterial cisplatin - effective in pts with
several solid tumors - 70% to 80% response
Response rate of 87% using intra-arterial 5FU,
methotrexate& bleomycin was reported by
Donegan and Harris
1 primary site for which intra-arterial
chemotherapy has been more extensively
studied is paranasal sinus cancer. Japanese
investigators have favored cannulation of
superficial temporal artery & infusion of 5-FU
integrated with surgery & radiotherapy

154. Chemoprevention…Chemoprevention…
Definition
Investigators studying various genomic, proliferation &
differentiation biomarkers have found alterations in
specific markers (keratin, involucrin, transglutaminase)
during process of abnormal squamous differentiation
These biomarkers may be useful as intermediate end
points in future chemoprevention trials
It includes strategies to prevent/ reverse carcinogenesis
before an invasive cancer develops or to prevent a 2nd
primary cancer in pts who had a previous cancer cured

155. It is particularly relevant to pts who are
curatively treated for an early stage H&N SCC-
field cancerization- Repeated exposure of
entire epithelial surface to carcinogens, such
as tobacco & alcohol, can lead to the
development of multiple sites of premalignant
& malignant change
Retinoids & carotenoids- prevent malignant
transformation- modify genomic expression at
the level of mRNA synthesis & regulate
transcription of specific genes

157. Intralesional chemotherapy…Intralesional chemotherapy…
Intralesional injection of vinblastine,
vincristine, or interferon- effective in local
control of epidemic Kaposi’s sarcoma
Can be used in combination with systemic
chemotherapy or radiotherapy
If necessary, lesions are
reinjected at 3-6 wk
intervals

158. Topical chemotherapy…Topical chemotherapy…
Actinic keratotic lesions- 5% fluorouracil
cream
Superficial basal cell carcinomas
Not effective for invasive lesions
Needless delay in definitive therapy

159. Complications…Complications…

161. Allergic Reactions…Allergic Reactions…
Hypersensitivity, anaphylaxis, drug reaction
Overactive or misdirected immune response
that results in local tissue injury or changes
throughout the body in response to a foreign
substance
Management
Epinephrine
Antihistamines
Corticosteroids

162. Nausea and vomiting…
Most distressing side-effects
Emesis is mediated mainly by several
neurotransmitters in GIT & CNS including
serotonin, dopamine, protachykinin 1 &
aminobutyric acid (GABA), which act directly/
indirectly on centre that controls emesis
located in medulla & on postrema of 4th
ventricle
The most highly emetogenic agent is cisplatin,
which at doses of 50 mg or more induces
nausea and vomiting in more than 90% of pts
who are not given prophylactic antiemetics

163. Emetogenic potential of chemotherapy
agents
High
>50 mg/m2 cisplatin
>500 mg/m2 dacarbazine
>1500 mg/m2 cyclophosphamide
Moderately high
<50 mg/m2 cisplatin
Area under curve 5 carboplatin
>1000 mg/m2 methotrexate
>60 mg/m2 doxorubicin
Moderate
>370 mg/m2 bolus fluorouracil
750 mg/m2 cyclophosphamide
250–1000 mg/m2 methotrexate
20–60 mg/m2 doxorubicin
80–120 mg/m2 intravenous etoposide

164. Current Rx
An antagonist of 5-hydroxytryptamine 3
receptors (5-HT3R) combined with oral
dexamethasone is used to prevent acute
emesis after use of high or moderately high
emetogenic agents
New antiemetic agent- Palonosetron- higher
binding affinity for 5-HT3R and a terminal
half-life of elimination at least 4 times
longer than any other antagonist

165. Diarrhoea…
Severe diarrhoea causes dehydration, renal
failure & thromboembolic events. Also,
diarrhoea combined with severe neutropenia
commonly leads to Gram-negative sepsis &
such complications have contributed to ↑
incidence of mortality within 60 days
Current treatment
Main aim shd be to ↓ volume of diarrhoea, treat
dehydration aggressively
antibiotics if symptoms persist or if there is
accompanying neutropenia
High-dose loperamide- an initial dose of 4 mg
followed by 2 mg every 2 h until there has been 12 h
without loose motions

166. Mucositis…
Mucositis & xerostomia are most common
oral complications of nonsurgical therapy of
cancer
Mucositis significantly affects quality of life
in terms of pain, ability to eat, swallow & talk
Indeed, symptoms are often of such severity
as to require an interruption of therapy or
lead to dose ↓ of cancer therapy or T/t delay
In presence of neutropenia, mucositis
predisposes to septicemia, bacteremia &
fungemia

168. Grading of chemotherapy-induced oral
mucositis according to the National Cancer
Institute of Canada
Grade O- No toxic effects
Grade 1- Painless ulcers, erythema, or mild
soreness in the absence of lesions
Grade 2- Painful erythema, oedema, or ulcers, but
eating and swallowing possible
Grade 3- Painful erythema, oedema, or ulcers that
prevent swallowing or lead to need for hydration
and parenteral or enteral nutritional support
Grade 4- Severe ulceration that requires
prophylatic intubation or leads to aspiration
pneumonia
Grade 5- Death from toxic effects

169. Rx
Antiinflammatory agents
Antimicrobial agents
Biologic response modifiers
Cytokines such as interleukin-1, interleukin-11,
TGF- 3, and keratinocyte growth factor
Thalidomide, an angiogenesis-inhibiting drug,
also acts against TNF.
Cytoprotective agents
primarily free radical scavengers or antioxidants
Methods to reduce exposure of the mucosa
to damaging agents

171. Bone marrow suppression…
Anemia
Erythropoietin (EPO): stimulates production of red
blood cells in the bone marrow
Administered SC or IV
Side effects: headache, hypertension, arthralgia (bone
or joint pain), diarrhea, nausea, fatigue
Neutropenia
G-CSF (granulocyte-colony-stimulating factor):
stimulates production of white blood cells in the
bone marrow
Administered SC or IV
Common side effect: bone pain
Do not give < 24 hrs before or after chemotherapy, or
within 12 hours of radiation
Thrombocytopenia
GM-CSF (granulocyte-magrophage-colony-
stimulating factor)
Stimulates neutrophils and platelets
Platelet transfusion to keep platelet count >20,000

172. Bleeding…
Drug induced myelosuppression- 14%
bleed
Thrombocytopenia – petechiae-soft
palate, lips, tongue, submucosal
hemorrhage

173. Infections…

174. Alopecia…

175. Conclusion…Conclusion…
Cancer of H&N- devastating group of
biologically diverse tumors
Mainstay T/t
Field of medical oncology is a relatively new
discipline
Metastatic or locally advanced disease that is
not amenable to curative therapy with surgery
or radiation
Previously undergone surgery & radiotherapy
Ca of larynx as part of primary
curative T/t when voice
preservation
Experimental protocols as 1º
therapy or combined with
radiotherapy for patients with a
high risk of relapse

176. References…References…
Maxillo Facial Surgery- Peter Ward Booth
DCNA head and neck tumor surgery Vol. 9 Aug 1997
Oral Radiology – Goaz and White
American cancer society atlas of clinical oncology cancer of
head and neck- Jatin P Shah
Radiotherapy of head and neck tumour - C.C. Wang.
Radiation oncology - William T. Moss, Brend / Hector.
Text book of radiotherapy - Fletcher
Malignant tumors of the mouth, jaws and salivary glands—JD
Langdon

177. References…References…
Scientific foundations of surgery - JAMES KYLE
Cancer- SCOTT BROWN
Chemotherapy for Head and Neck- William Ligget
Principles of Chemotherapy- Wiliam J. Primrose
Chemoradiotherapy: emerging treatment improvement
strategies - head & neck february 2003
Chemotherapy in the management of squamous-cell
carcinoma of head and neck-lancet oncol 2001; 2: 261–69

178. THANK YOUTHANK YOU