INTRODUCTION.
EPIDEMIOLOGY AND ETIOLOGICAL FACTORS.
HISTORY OF DEVELOPMENT AND CLASSIFICATION.
PHARMACOKINETICS AND INNOVATION OF NEWER
AGENTS.
INTERFERENCE AND MECHANISM OF ACTION OF ACTION
ARRESTING IMMATURE CELL PROLIFERATION.
AGENTS WHICH POTENTIATE THE FUNCTION OF
CHEMOTHERAPEUTICAGENTS.
CLINICAL APPLICATION AS PRIMARY TREATMENT AND AS
ADJUVANT IN MALIGNANTLESIONS.
DRUGSENSITIVITY TO VARIOUS LESIONS AND
THERAPYREGIMES.
ROUTES OF ADMINISTRATION OF VARIOUS
CHEMOTHERAPEUTICAGENTS.
MARKERS USED TO INTERFERE WITH CELL GROWTH TO
STUDY THE PERFORMANCE OF THE DRUG.
TOXIC MANIFESTATIONS AND UNTOWARD REACTIONS
AND THEIR MANAGEMENT.
CONCLUSION.
INTRODUCTION
Malignancies of the head and neck region includes cancer of the
oral cavity; i.e., of the lip (International Classification of Diseases,
ninth revision (code140-ICD9:140), tongue (ICD9:141), and other
intra-oral sites (ICD9: 143-145). The salivary glands (ICD9:142) are
not normally included when describing oral cancer, i.e., of the
oropharynx (ICD9:146), nasopharynx (ICD9:147), and hypophaynx
(ICD9:148). Malignancies of these sites are generally clubbed together
as head and neck cancer, or mouth/pharyngeal cancer, or oropharyngeal cancer, or sometimes just oral cancer, because of the
common etiological/risk factors associated with these sites, with the
exception of nasopharyngeal cancers.17
Chemotherapy has its origin in the work of Paul Ehrilich who coined
the term in reference to the systemic treatment of both infection
diseases and neoplasia. Many of the Ehrlichs concepts regarding the
experimental evaluation of new therapies using murine or rat models
have survived to the present day and have provided a number of
of
chemotherapy.
the
experimental
basis
for
clinical
drugs
particularly
when
combined
with
radiotherapy.
- Development of the concepts of immunotherapy in man.
Disappointing results despite widespread application.14
Examples
Malignancies Used
Toxicities
1.Alkylating
Nitrogen
in
Lymphomas
agents
mustard
Chronic
Anemia
Chlorambucil
lymphoblastic
Thrombocytopenia
Ifosfamide
leukemia
Nausea
Melphalan
Sarcomas
vomiting
Thiotepa
Myeloma
Neurotoxicity
Cisplatin
Breast cancer
Alopecia
Carboplatin
Ovarian cancer
Head
and
Leucopenia
and
neck
II.Antimetabolite Methotrexate
cancer
Breast
5-Fluorouracil
gastrointestinal
Diarrhea
Ara-C
cancer
Leucopenia
Hydroxyurea
Fludarabine
leukemia
Thrombocytopenia
Chriocarcinoma
Alopecia
and Mucositis
Genitourinary
cancer
Head
and
neck
cancer
Lymphoma
III. Antibiotics
leukemia
anemia,
and
(Adriamycin)
thrombocytopenia
Daunorubicin
Gastrointestinal,
Mucositis
Mithramycin
lung,
Diarrhea
Mitomycin
Breast cancer
Skin disturbances
Bleomycin
Head
Mitoxantrone
cancers
Nausea
Sarcomas
vomiting
Lymphoma
Cardiac
and
neck Alopecia
and
and
pulmonary
toxicity
IV.
Plant Vincristine
alkaloids
V.Micellaneous
Testicular,
lung, Leukopenia
Vinblastine
VP-16
cancers
Thrombocytopenia
Taxol
Lymphoma
Alopecia
DTIC
Sarcomas
Nausea
Leucopenia
M-AMSA
Procarbazine
leukemia
Thrombocytopenia
Hexamethylme Hodgkin;s
Nausea
lamine
lymphoma
Bleeding
Asparaginase
Ovarian cancer
Acute
lymphoblastic
leukemia
The
terms. Dividing the curve allows for definition of the earlier portion as
the distribution phase of drug disposition, and of the later portion as
the elimination phase.
estimated
as
Cl
Vd.2
locally
advanced,
recurrent
metastatic
Head
andNeck
INTERFERENCE
AND
MECHANISM
OF
ACTION
time refers to the interval between mitoses. The faster that the cell
cycles, the faster the increase in the total number of cells. The growth
fraction refers to the subset of the population of cells which are
actually traversing the cell cycle. The larger the number of cycling
cells, the more cells will be produced. The rate of cell loss refers to the
number of cells that die or leave the cell loss population by migrating
to other tissue. In an adult organism where growth has ceased to exist,
there is a steady state produced where cell loss is equal to cell
production. Growth of both normal and neoplastic tissue occurs as a
results of an increase in the total cell number.1
Host-Tumor-Drug
Relationship
and
the
response
to
thymidine-labelling
index
(the
number
of
cells
synthesizing DNA).
- The shorter the doubling time at the onset of treatment, the
better the initial response to chemotherapy is likely to be.
Note that for both A and B rapidly proliferating cells are more
sensitive than slowly proliferating cells
Predominantly non-phase
dependent
Alkylating agents
Nitrosoureas
Anthracyclines
Imidazole carboxamide (DTIC)
Mitomycin C
Actinomycin D
Predominantly phase-dependent
Vinca alkaloids
Hydroxyurea
Cytosine arabinoside
Methotrexate
6-Mercaptopurine
6-Thioguanine
Procarbazine
Podophyllotoxins - VM26
- VPP 16-213
Drug metabolism
Most anti-cancer agents are metabolized in the body, usually to
products which are inactive having lower lipid solubility. These are
then excreted. In some instances, active metabolites are produced (e.g.
cyclophosphamide).
Drug absorption, distribution and excretion
EXCRETION
Biotransformation to
active or inactive
product(s)
Biotransformation
involving
hydroxylation,
Drug metabolism occurs chiefly in the liver but may also take
place in the plasma, gastro-intestinal tract, kidneys and lungs. For this
the urine and its toxicity may be markedly enhanced in patients with
renal failure.14
AGENT
WHICH
PONTENTIATE
THE
FUNCTION
OF
CHEMOTHERAPEUTIC AGENTS
Chemosensitization
Hypoxic cell Chemosensitizers
In the animal model the hypoxic cell sensitizers misonidazole
and SR-2508 enhance of the cytotoxicities of alkylating agents and
nitrosoureas. However, the optimal method of administration is not
known.
(hypoxic
cytotoxicity,
thiol
depletion,
and
active chemotherapeutic
The
However a
and 5-FU infusion than with any of the cisplatin and bleomycin
combinations. Also, the incidence of histological cure rate in those
clinical cure rate patients who underwent surgical resection is high
after cisplatin and 5-FU infusion than with any cisplatin and bleomycin
combinations. The side effects of these combinations are acceptable
and reversible.
From the clinical trails, patients achieving clinical cure rate to
the initial chemotherapy had significantly superior survival than those
patients with less than cure rate to the treatment regardless of the
subsequent definitive therapy. More important those cure rate patients
who were found to have no histological disease after surgical resection
have statistically superior survival when compared with those clinical
cure rate patients who had residual disease at surgery.
Oral cancers constitute about 10% and 6% of all cancer cases in
males and females respectively in India (ICMR 1989). Carcinoma of
buccal mucosa is more commonly seen among females than males with
a 3:1 incidence. About 80% of these tumors are locally advanced
(Stage III and IV) at the time of presentation, inspite of oral cavity
being easily accessible for examination and early identification.
Buccal mucosa is made up of stratified squamous epithelium
covering the internal surface of lips and cheeks. Pathologically buccal
mucosal cancers vary from verruccous exophytic indolent types with
well demarcated borders to deeply infiltrating ulcerative painful tumor
with poorly defined margins. More than 90% of these tumors are
squamous cell carcinomas and the remaining make up for minor
salivary gland tumors, melanoma, sarcoma etc., (Strong and Spiro
1987). Million and Cassissi (1984) reported that 95% of oral cancers
were squamous cell carcinomas.
The standard line of management of buccal mucosa cancer
depends on the extent of the disease. Radiotherapy or surgery is
advocated for early lesions (Stage I & II) and combination of both
practiced in advanced lesions (Stage III & IV) (Vanderwaal 1984). The
philosophy of combining surgery and radiotherapy in advanced lesions
is that surgery fails at the periphery and radiotherapy at the poorly
oxygenated center of the tumor.
As seen earlier, majority of the patients present with advanced
lesions and even combination of surgery and radiotherapy may not be
possible in most of the patients, as the tumors either will be
unresectable or the patient will not be fit to undergo surgery due to
associated medical conditions.
Over the years the results with surgery and radiotherapy has not
improved much and has reached a plateau (RTOG, 1980, Perez). The
locoregional recurrence with the above modality is as high as 60%
(Vikram, 1984; Kramer, 1985). The combined modality of surgery and
radiotherapy in advanced cases has given better results only when
surgery was very extensive and cosmetically inacceptable (Pinsolle,
1992).
In search of better results, good cosmesis and better quality of
life systemic chemotherapy has been incorporated into the treatment
modalities along with surgery or radiotherapy. Systemic chemotherapy
is usually accepted as standard treatment for palliation in patients with
recurrent and metastatic head and neck cancers who have failed the
definitive therapy. Recently with introduction of more active
after
surgery
and
before
radiotherapy
(Sandwich)
Sandwich method: Here chemotherapy is administered after
surgery and before delivering radiotherapy.
Various agents have been used either singly or in combination as
chemotherapy. The agents used are Methotrexate, bleomycin, 5flurouracil (5-Fu), vinblastine and cisplatinum. The commonly used
combinations being methotrexate and
5-Fluorouracil
(Tarpley 1975; Al Sarraf 197; Alan Coates 1984; Ervin 1987; Jaulerry
2.
The
planned
surgery
after
initial
successful
with
radiotherapy.
The
concept
of
combining
Methotreaxate
Hydroxyurea
5-Fluorouracil
Bleomycin
Cisplatin
Combined Agents
Bleomycin, vincristine, and methotrexate (BVM)
Bleomycin, and methotrexate
Bleomycin, Adriamycin,* and 5-FU
Bleomycin, and cytoxan
Bleomycin, cytoxan, and vincristine
Mitomycin-C, and 5-FU
Cisplatin, and 5-FU
5.
cisplatin)
post
definitive
treatments
of
surgery
and/or
The
the cisplastin/5-FU combination with the same dose and schedule but
have obtained overall response rates, usually in the range of 25% to
30%, with approximately 10% achieving a complete response.
Efforts have been made over the past several years to improve
the response rates of the cisplatin 5-FU combination. Some of this
research efforts has focused on (1) substituting the analogue
carboplatin for cisplatin, (2) modulating 5-FU with leucovorin, and (3)
dose escalating the cisplatin combined with the use of chemoprotectors
to try to prevent cisplatin-related toxicities.
Unfortuanately, these
cisplatin and bleomycin for two cycles prior to local treatment. In this
study, the combination of cisplatin and bleomycin as induction
chemotherapy yielded an overall objective response rate of 71%, with a
20% complete response rate. Subsequently, investigators at Wayne
State University combined cisplatin and infusional 5-FU for three
cycles prior to local treatment and reported an 88% overall response
rate, with 54% of the patients achieving a complete response.
Other investigators have also used the cisplatin and 5-FU
regimen for three courses prior to local therapy with less favorable
results. Parts of the disparity can be explained by patients selection
factors, because patients with N2 or greater disease have been noted to
obtain a complete response rate in the range of 20%.
The pilot
5-year survival has been reported in the range of 15% to 40% and for
Stage IV disease, it is only 0% to 30%.
Patients with nasopharyngeal carcinoma have a high likelihood
to developing distant metastasis, which seems to correlate with the
amount of cervical adenopathy.
In contrast,
Miscellaneous groups
A number of diverse histologic tumors present less commonly in
the head and neck area for which chemotherapy has been utilized.
These
include
sarcomas,
lymphomas,
esthesioneuroblastomas,
chemotherapy are similar to those seen for other sites and are largely
partial response.
Drug combinations
No.
No. with
evaluated
50%
regression
15
Methotrexate + vincristine
28
15(53%)
Dibromodulcitol + bleomycin
20
5(25%)
Adriamycin + bleomycin
MeCCNU + cyclophosphamide +
32
11(35%)
10
18
4(22%)
13
Methotrexate + bleomycin
Methotrexate+6-mercaptopurine +
procarbazine + chlorambucil + thiotepe + streptonigrin +
rufochromomycin + vinblastine
82
45(55%)
Dose Schedule
Evaluable
Responsea
Patients
Cyclophosphamid
8-10 mg/kg IV
56
2 CE, 35
improved
4 mg/kg/dy IV
4-60 mg/kg single
dose
150-300mg/dy;
15
2 improved
3 PR, 3
then 100-200
mg/day PO
2g in divided
doses for 8 days;
improved
2 excellent and
intrapleural
2 moderate
ranging from
responses
100mg daily PO to
8g IV loading dose
preceding PO
therapy
Cyclophosphamid
50-200 mg/day PO
e
30mg/kg IVP; then
10-15 mg//kg q1-2
Improved
wks
Cyclophosphamid
Various IV and PO
doses
Chlorambucil
0.2 mg/kg/day X
1 improved
34
1 CR, 4 PR
None
41
5 improved
84
1 CR, 4 PR, 20
42 days PO
Nitrogen mustard
5-FU
15mg/kg/day X 5
IV; then 7.1mg/kg
improved
1,000 mg/day X 5;
2 improved
17
3 improved
12
1 CR, 1 PR
4-8mg/kg/day X
14-42 days
5-FU
15-20 mg/kg/wk
Responsea
Evaluable
Patients
1 improved
10
3 improved
23
4 PR 7,
improved
Mitomycin C
50mg/kg/day X 6;
31
3 improved
12
76
11 PR
sidearm
infusion, continuous or intermittent
Intravenous push refers to directly administering the medication
into the intravenous cannula, through either an angiocath or a butterfly
needle. A piggyback method denotes there is a main line of
intravenous fluid connected into the intravenous cannula. The solution
to be piggybacked is connected, usually in the port closest to the
patient, into the main intravenous line. The sidearm method of
administration is the route of choice for chemotherapy with vesicant
properties. Again, a main line of intravenous fluid, freely flowing, is
connected into the intravenous cannula. The physician directly
administers the medication, slowly, into the part closest to the patient
while continually assessing the peripheral IV site for complications
and extravasation. This method, as could the piggyback method, allows
for further dilution of the chemotherapeutic agent with the main fluid.
The two solutions must be compatible. The infusion method may last
from several minutes (bolus infusions) to several days, 24 hours a day
(continuous infusions).
Selecting a Vein Assess veins in both arms and hands. Do not use
veins in compromised limbs/lower extremities
Appropriate
Choice of
Venipuncture Site
forearm
hand
forearm
Satisfactory Vein/Undesirable
hand
Location
small thins veins in hand; veins in
forearm not palpable or visible
Unsatisfactory Vein/Undesirable
Consider central
Location
small, fragile veins, which easily
venous line*
rupture, in hand/forearm
Unsatisfactory Vein/Undesirable
Location
veins in forearm/hand not palpable or
Consider central
venous line*
visible
*In some situations, central venous lines are inserted before the patient
is started on a chemotherapy protocol.
Dealing with the veinless patient
One of the most common dilemmas facing oncology nurses is
trying to administer chemotherapy to the veinless patient (described
by Lokich 1978). With the variety of central venous access devices,
both catheters and subcutaneous ports, this issue doesnt have to be a
problem.
1. In an attempt to dilate the veins, apply moist heat to the arms
for 5-10 minutes (Johnston Early, Cohen and White 1981).
2. Once the soaks are removed, work efficiently while the veins
are dilated.
3. Local vein manipulation may also aid dilation:
a. Appropriate use of a tourniquet or blood pressure cuff
to encourage pooling of venous blood.
b. Milking the veins from proximal to distal (elbow to
hand)
c. Gently striking the surface of the vein
4. Catheter selection is very important in this setting. The veins
may well be small and an appropriately sized needle will
decrease trauma.
5. Perform
the
actual
techniques
and
preparation
for
Issue
Solution
Administration Use antecubital
Rationale
Larger veins permit more rapid
site
fossa
drugs
Larger veins permit more rapid
circulation of potentially
Avoid antecubital
irritating drugs
Mobility of arm restricted
fossa
Risk of extravasation increased
due to patient mobility
Ealry infiltration and
extravasation difficult to assess
due to subcutaneous tissue
Repair of infiltration would be
difficult and debilitating for the
Needle size
patient
Potentially irritating drugs
21 scalp vein
needles)
veins
Smaller gauge needles less
25)
mechanical phlebitis
Slower infusion rate may
reduce side effects, i.e., nausea
Sequencing of
and vomiting
Administer vesicant Vascular integrity decreases
medications
first
Particular
Use sidearm
infiltrate or not
Freely running intravenous
intravenous
method
method
method of
administration
earlier
1987).
Patients
receiving
continuous
infusions
of
Mild
Pretreatment
with
10mg
prochloreperazie
Treatment
a) Stop oral intake
b) Diphenoxyate with Atropine (lomotil) 1 t.i.d. to .i.d. PO or
loperamide (Imodium) 2 to 4mg q.i.d. PO
c) Patients failing to respond to Lomotil have been reported by
Petrilli et al. to resolve the diarrhea in 24 hours by having the
somatostain analog (Sandostatin) at a dose of 150 g/hr IV.
Stomatitis: Causes =actinomycin D (Cosmogen), amethopeterin,
cyclophosphamide, cytosine arabinoside, daunorubicin, doxorubicin,
fluorouracil, FUDR, hydroxyurea, 6-mercaptopurine, mitomycin C,
and procarbazine fludarabine.
Treatment
a) Switch to soft bland foods; avoid citrus products
b) Viscous xylocaine swish before meals and PRN
c) Tyleno #3 1 to 2 tabs every 4 hours RN or stronger pain
medication
d) To prevent or reduce the severity of stomatitis with
fluorouracil, the patient should place ice chips in the mouth 5
minutes before receiving the IV dose of Fluorouracil and
continue the ice chips for 30 minutes after the injection
(Mahood et al., 1991).
CNS Toxicity:
a)
Peripheral
neuropathy
cisplatin,
carboplatin,
Actinomycin,
cyclophosphamide,
daunorubicin,
hexamethylmelamine,
6-mercaptopurine,
hydroxyurea,
mitomycin
C,
ifosfamide,
nitrogen
mustard,
Amethopterin,
bleomycin,
5-fluorouracil,
CONCLUSION
Despite
Clearly, for
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