Chemotherapy.doc2 / orthodontic courses by Indian dental academy

CONTENTS

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 oro-

pharyngeal cancer, or sometimes just oral cancer, because of the

common etiological/risk factors associated with these sites, with the

exception of nasopharyngeal cancers.17

The standard line of management depends on the extent of the disease.

Radiotherapy or surgery in advocated for the early lesions and

combination of both is practiced in advanced lesion. (Vanderval1984).9

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 tumour. So combination of both help

in total cure.

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 cancer who have failed the

definitive therapy. Recently with the introduction of more active

chemotherapy agents and combination systemic chemotherapy, it is

being increasingly used before local therapy in previously untreated

and locally advanced head and neck cancer. (A1 Sarraf, 1988).

Today, the role of chemotherapy in the treatment of Head and

Neck Squamous Cell Carcinoma is being intensively reevaluated. The

possibility of inducing major tumour shrinkage with chemotherapy before

local treatments has led to the enthusiastic expectation that neoadjuvant

chemotherapy could have a major effect in improving survival rates in

patients with head and neck cancer. Conflicting data have been derived

from an analysis of some single-arm studies, whose results have been

compared with those obtained in historical control patients, treated with

local treatment alone. The last ten years have witnessed the changing role

of chemotherapy in patients with advanced head and neck Squamous cell

carcinomas. This is due in part to the introduction of better agents against

the disease and to the high over-all objective response and cure rates

produced by combination chemotherapy in patients with previously

untreated and advanced cancer.15

The aim of this library dissertation is to exhaustively review the

literature on chemotherapy from its historical and developmental

aspects, basic principles, its effectiveness in improving the cure rate

and also to enlighten upon the recent advances in the field of medical

oncology.

EPIDEMIOLOGY AND ETIOLOGICAL FACTORS

As see from Table, there is an enormous variation in the

incidence of mouth and pharyngeal cancer worldwide. The highest,

particularly those of South-East Asia. There are also, pockets of high

incidence rates in western populations, such as that of the Bas-Rhin in

France. Table 1.1 also shown that in males the incidence of cancer –

of the tongue varies from a high of 8.0 to a low of 0.4 per 100,000; of

the mouth varies from 12.4

to 0.5 per 100,000; of the oropharynx varies from 13.3 to 0.3 per

100,000; and hypopharynx varies from 15.0 to 0.1 per 100,000. Lip

cancer is particularly common in Australian and Canadian populations

with its incidence in males going up to 13.5 per 100,000. It is not so

common in the South-East and East Asian countries. For example, in

Japanese, Chinese, and Indian populations, its incidence is barely 0.2

per 100,000. The incidence of cancer of the mouth and pharynx is

universally higher in males than in females, except in some countries

of South-East and East Asian countries. For example, in Japanese,

Chinese, and Indian populations, its incidence is barely 0.2 per

100,000. The incidence of cancer of the mouth and pharynx is

universally higher in males than in females, except in some countries

of South-East Asia. In Bangalore (in Indian), for example, the

incidence of cancer of the mouth (ICD9:143-145) in males is lower, at

2.8 per 100,000, as compared to the incidence rate of 8.9 per 100,000

in females (PArkin et al., 1997).

Globally, almost haft-a-million cancers of the mouth and

pharynx (ICD9:140-149) are diagnosed every year, and three-fourths

of these are from the developing world (Parkin et al., 1993). A similar

picture emerges as regards deaths from these cancers. Currently, over

400,000 individuals die from this disease every year, and again, over

80 per cent of these deaths are from the developing world (Pisani et

al., 1993).

Thus, cancer of the head and neck region is an important cancer

globally. For the developing world it is certainly of great significance,

and ranks fourth in frequency. In males, however, it is the third most

common cancer, and in females it ranks fourth (Parkin et al., 1993).

In countries like India, it is in fact the leading cancer site as reported

by the various cancer registries in the country (Biennial Report, 1992).

However, in western countries also, cancer of the mouth and pharynx

is now gaining importance. There is evidence that the incidence of

and mortality rates due to this cancer has started to increase in recent

decades particularly in men (Johnson, 1991; Moller, 1989; Hakulinen

et al., 1986). Va Vacchia et al. (1997) has compared the mortality

rates of the cancer of the head and neck region (ICD9: 140-149) at two

different time periods for thirty-two European countries and found that

in males of age group 35 to 64 years the mortality rate in the early

1990s were two-to-eight- fold higher than that reported in the late

1950s, except in Finland. An increase in the risk of tongue was

particularly noted in young adult (Davis and Severson, 1987; Coleman

et al., 1993).

The ratios of high and low incidence rates reported world-wide

shown in Table 1.1, vary from twenty-five-fold to over a hundred-

fold. These high ratios indicate that a tremendous potential for

successful implementation of preventive strategies exists, once the

risk/protective factors have been identified. These are likely to be

more prevalent in males than in females in view of the pattern of

distribution of the disease in the two sexes.17

ETIOLOGY

The association of betal quid chewing with oral cancer was

observed in India as early as 1902 by Niblock and confirmed by Orr

(1933) in an excellent epidemiologic study. Niblock (1902) described

oral cancer in Madras and Travancore and attributed it to the habit of

chewing arecanut and betel leaf and often a lime rich paste with

tobacco. Orr (1933) in his study concluded that the use of shell lime

and Vadakkan or Jaffna tobacco along with a low vitamin content in

the diet due to tapico consumption, was primarily responsible for the

prevalence of oral cancer.

Sanghvi and his colleagues (1955) demonstrated for the first

time, the association of beedi smoking in addition to chewing with oral

cancer in a case-control study at the Tata Memoriral Hospital,

Mumbai, India.

Besides these risk factors, diet has been implicated in the

etiology of oral cancer (Notani 1987) also alcohol usage has been

shown to be an independent risk factor (Notani 1988).9

CHEMOTHERAPY, HISTORY OF DEVELOPEMENT AND

CLASSIFICATION

The word ‘chemotherapy’ can be defined as the use of chemical

compounds in the treatment of infection diseases, so as to destroy off

evolving parasites or organisms without damaging the host, tissues.

The use of the term to cover all drug, or synthetic drug, therapy

needlessly removes a distinction which is convenient to the clinician

and has the sanction of long usage. By convention the term is used to

include therapy of cancer.11

This method of treating cancer has been used in head and neck

tumours for palliation and in a curative role, both as integral part of a

planned regime involving surgery or radiotherapy or both, and on its

own. Certain tumors have been found to respond well to

chemotherapy and in management of these it is an accepted part of

total treatment. In the context of head and neck malignancies how ever

such tumours are rarities and it is the value of chemotherapy in the

common tumours such as squamous carcinoma and the salivary

tumours which is of real interest to the oral and maxillofacial

surgeon.18

History of drug Discovery

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 Ehrlich’s 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

important biologic insights that have been applied successfully to the

clinical setting. Gilman and Philips conducted the first clinical trial of

nitrogen mustard in patients with malignant lymphomas at Yale

university in 1947. The results, initially published in 1946, could be

said to mark the beginning of modern chemotherapy.13

HISTORICAL OUTLINE OF DEVELOPMENT OF CANCER

CHEMOTHERAPY

A. Period 1946-1960

- Development of single-drug chemotherapy mainly on

empirical basis.

- Establishment of critical criteria for the clinical development

of new drugs: criteria of response; toxicity; performance

status; optimum tolerated dose.

- First results from the treatment of leukemias and malignant

lymphomas. Generally poor results in the treatment of

advanced solid tumours.

B. PERIOD 1960-1970

- Development of knowledge of cell kinetics and application of

kinetic concepts to the design of chemotherapy schedules.

- Broadening of the experimental basis for clinical

chemotherapy.

- Introduction of pharmacokinetic concepts into clinical

chemotherapy.

- First developments in the field of combination chemotherapy.

- Introduction of the concept of the controlled randomized

clinical trials into clinical chemotherapy assessment.

- Further improvement of treatment results in leukemias and

lymphomas and significant progress in the results obtained in

the treatment of certain solid tumours.

C. PERIOD 1970 TILL DATE

- Development of the concept of the combined modality

approach; improved cooperation between the onco- surgeon,

radiotherapist and chemotherapist.

- First indication of definitive role for adjuvant chemotherapy.

- Recognition, in long-term survivors, of the late toxicities of

anti-cancer drugs particularly when combined with

radiotherapy.

- Development of the concepts of immunotherapy in man.

Disappointing results despite widespread application.14

Classification of chemotherapeutic agents 3

Major Classes Examples Malignancies Used

in

Toxicities

1.Alkylating

agents

Nitrogen

mustard

Chlorambucil

Ifosfamide

Melphalan

Thiotepa

Cisplatin

Carboplatin

Lymphomas

Chronic

lymphoblastic

leukemia

Sarcomas

Myeloma

Breast cancer

Ovarian cancer

Head and neck

cancer

Leucopenia

Anemia

Thrombocytopeni

a

Nausea and

vomiting

Neurotoxicity

Alopecia

II.Antimetabolite

s

Methotrexate

5-Fluorouracil

Ara-C

Hydroxyurea

Fludarabine

Breast and

gastrointestinal

cancer

Acute myeloblastic

leukemia

Chriocarcinoma

Genitourinary

cancer

Head and neck

cancer

Lymphoma

Mucositis

Diarrhea

Leucopenia

Anemia

Thrombocytopeni

a

Alopecia

III. Antibiotics Actinomycin-D Acute myeloblastic Leucopenia,

Doxorubin

(Adriamycin)

Daunorubicin

Mithramycin

Mitomycin

Bleomycin

Mitoxantrone

leukemia

Germ cell cancer

Gastrointestinal,

lung,

Breast cancer

Head and neck

cancers

Sarcomas

Lymphoma

anemia, and

thrombocytopenia

Mucositis

Diarrhea

Skin disturbances

Alopecia

Nausea and

vomiting

Cardiac and

pulmonary

toxicity

IV. Plant

alkaloids

Vincristine

Vinblastine

VP-16

Taxol

Testicular, lung,

breast and bladder

cancers

Lymphoma

Leukopenia

Anemia

Thrombocytopeni

a

Alopecia

Nausea

V.Micellaneous DTIC

M-AMSA

Procarbazine

Hexamethylme

lamine

Asparaginase

Sarcomas

Acute myeloblastic

leukemia

Hodgkin;s

lymphoma

Ovarian cancer

Acute

lymphoblastic

leukemia

Leucopenia

Anemia

Thrombocytopeni

a

Nausea

Bleeding

PHARMACOKINETICS AND INNOVATION OF NEWER

AGENTS

Pharmacokinetic of cancer chemotherapy

Because there are such narrow margins between effective and

toxic dosages for many antineoplastic agents, rational therapy should

be assisted by the ability to maintain drug concentrations in specified

therapeutic ranges. Thorough pharmacokinetic analyses have been

performed for a number of anticancer drugs in a variety of clinical

situations.

Modeling

The classical pharmacokinetic device for describing the disappearance

of drugs from plasma is the two-compartment open model. The

concept assumes that a drug is instantaneously injected and distributed

in Compartment 1(with concentration, C1, and volume, V1) and that all

elimination of the drug from the system occurs from this “central”

compartment. Immediately after injection the drug may distribute into

compartment 2(concentration, C2, and volume, V2) at a rate defined by

k12. Drug may move from Compartment 2 (the “peripheral”

compartment) at the rate k21 into the central compartment, thence to be

eliminated. The elimination rate is indicated as kel. Movement of drug

into and out of either compartment is a first-order process and the rate

constants k12, k21, and kel have dimensions of inverse time (e.g., min-1,

hr-1). A typical two-compartmental curve for plasma disappearance of

a drug is depicted in fig which plots concentrations on a logarithmic

ordinate and time on a linear abscissa. This smooth curve can be

divided into two discrete exponential terms. Ae-at and Be-t, indicated

by hatched lines. The concentration, C, at any time is the sum of these

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. Five parameters are commonly found in

pharmacokinetic descriptions of antineoplastic agents, and can be

calculated from the relationship, C= Aeot + Be-. The concentration at

the moment of injection, C0, is usually the peak concentration during

rapid intravenous bolus injections and equals the sum of the constants

A and B: C0 = A+B. The terminal elimination half life, t1/2, is

determined by the elimination rate constants, : t1/2 = 0.693/. The

initial volue of distribution of the drug, Vd, is related to the initial

(peak) concentration, Co, and the dose given: dose = Vd x Co, or Vd =

dose/Do (dimensional units of dose and Co must be similar, e.g., mg

and mg/ml or nmol and nmol/ml). The area under the plasma

concentration-time plot provides a measures of the exposure of the

body or of a particular tissue to a drug over a period of time. This

quantity, often referred to as the area under curve (AUC) or

concentration x time product (C x t) of a drug, is calculated by

integrating the equation C = Ae-nt + Be-. Because e-t approaches zero

at very late times of observation, this integral can be reduced to C x t

(or AUC)=A/ + B/. The C x t can be estimated equally well by the

trapezoidal rule. Finally, the clearance of a drug Cl =kel x V1. In

practice kel and V1 are difficult to determine and clearance values can

be estimated as Cl = x Vd.2

New Chemotherapy Agents

To date, the combination of cisplatin and 5-FU represents

standard polychemotherapy in association with RT in HN cancers.5

Recently, pre-clinical studies have demonstrated an enhanced activity

of RT with new cytotoxic agents such as taxol, which has

radiosensitizing properties and anti-cancer activity. A phase I study

was conducted with 24-hours paclitaxel infusion and simultaneous RT

in locally advanced, recurrent metastatic Head andNeck

malignancies. The dose limiting toxicity was febrile granulocytopenia

and the maximum tolerated dose of paclitaxel was 75 mg/m2. All the

patients with locally advanced disease demonstrated either a complete

or a partial response, and at a median follow-up of more than 1 year

only 9 per cent of patients had progressed (Seinberg et al., 1977). The

results were confirmed by an additional preliminary report in a study

using concurrently taxol at 60 mg/70 per cent showing complete

response. Mucositis was the main toxicity (Amrein et al., 1998). A

potentially synergistic activity between RT and gemicitabine has been

suggested in recent trials. A pilot study performed at the Institute of

Cancer Research, Genoa, Italy and Croce General Hospital, Cuneo,

Italy demonstrated a high response rate (90 per cent) in advanced,

inoperable Head and Neck cancer patients, treated with alternating RT

and a combination of gemcitabine and cisplatin (Benasso et al., 1997;

1998). A complete response was observed in 85 per cent of the

patients, of which more than 70 per cent are alive and disease-free

after a median follow-up of 1 year. However, modifications to the

schedule are mandatory in light of the heavy toxicity observed, but

the high anti-tumour activity obtained suggests further investigations

on the combination of RT and gemcitabine.17

INTERFERENCE AND MECHANISM OF ACTION

ARRESTING IMMATURE CELL PROLIFERATION

General

Chemotherapy is planned on the basis of observed differences

between normal and tumour cells in response to anti-tumour agents

used both as single and in combination. Part of the difference between

normal and neoplastic cells can be emphasized that cell kinetics cannot

explain all the consequences of tumour-cell exposure to a drug, since

these are also dependent upon pharmacokinetics, biochemistry and

tumour biology.

The proliferation of tumour cells is not entirely autonomous,

neither is it constant; it varies with the size of the tumour and is related

to its blood supply. Animal studies show that the characteristics of

tumour cell proliferation have an important influence on the response

to chemotherapy. Skipper (1971) has reviewed some of the principles

concerned and the following generalizations can be made for

experimental tumours.14|

The Cell Cycle

An understanding of cell-cycle kinetics is essential for the

proper use of the current generation of antineoplastic agents. Many of

the most potent cytotoxic agents act at specific phases of the cell cycle

and, therefore, have activity only against cells that are in the process

of division. Accordingly, human neoplasms that are currently most

susceptible to chemotherapeutic measure 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

follicles, and intestinal epithelium) are subject to damage by some of

these potent antineoplastic drugs, and such toxicity often limits the

usefulness of drugs. On the other hand, slow –growing tumors with a

small growth fraction (for example, carcinomas of the colon or lung)

are often unresponsive to cytotoxic drugs. Although difference in the

duration of the cell cycle occur between cells of various types, all cells

display a similar pattern during the division process. This cellcycle

may be characterized as follows : (1) there is a presynthetic phase

(G1); (2) the synthesis of DNA occurs (S); (3) an interval follows the

termination of DNA synthesis, the postsynthetic phase (G2); and (4)

mitosis (M) ensues – the G2 cell, containing a double complement of

DNA, divides into two daughter G1 cells. Each of theses cells may

immediately reenter the cell cycle or pass into a nonproliferative stage,

referred to as G0. The cells of certain specialized tissues may

differentiate into functional cells that are no longer capable of

division. On the other hand, many cells, especially those in slow-

growing tumors, may remain in the G0 state for prolonged periods,

only to be recruited into the division cycle again at a much later time.

Most antineoplastic agents act specifically on processes such as the

synthesis of DNA or of the mitotic spindle. Other block the synthesis

of DNA precursors or damage the integrity of DNA. While most of

the known anticancer drugs are G1 is the period between mitosis and

the beginning of DNA synthesis. Resting cells (cells that are not

preparing for cell division) are said to be in subphase of G1, G0. S is

the period of DNA synthesis; G2 the premitotic interval; and M the

period of mitosis. Example of cell-cycle-dependent anticancer drugs

are listed in blue below the phase in which they act. Drugs that are

cytotoxic for cells at any point in the cycle are called cycle – phase-

nonspecific drugs. (Modified from Pratt et al., 1994 with permission.)

most effective against actively proliferating cells, some (called – cell

cycle phase-specific, such as cytosine arabinoside and methotrexate)

affect cells only during the S phase or during mitosis (e.g., pactiaxel

and vinca alkalids) and will not kill nondividing cells. Damaged cells

that cross the G1/S boundary will undergo apoptosis, or programmed

cells death, if the p53 gene is intact and exerts its normal checkpoint

function. If the p53 gene is mutated and the diversion down the

apoptotic pathway does not take place, the damaged and potentially

mutated cells will proceed through S phase and emerge as a drug-

resistant population.8

All tissues are basically composed of three populations of cells.

The first of these consist of cells that are continuously traversing the

cell cycle. The second population is composed of cells that leave the

cell cycle after a certain number of divisions to differentiate and later

never to divide again, and die. In the third population group, the cells

remain dormant and leave the cell cycle temporarily to return when a

stimulus or other environmental conditions dictates their re-entry into

the cell cycle. An example of these populations is seen in the bone

marrow. The marrow is composed of a sub-set of cells which are

continuously traversing the cell cycle by dividing and producing more

blast cells from precursors.

The second population consists of cells such as granulocytes

which have differentiated and are destined to perform a specific

function, not undergo further mitosis, and finally to die. Cells in the

third population include stem cells which do not cycle until marrow

depletion causes them to re-enter the cell cycle and proliferate again.

In terms of tissue growth in both normal and abnormal

situations, 3 factors regulate the population: 1. The cell cycle and its

duration, 2. The growth fraction, 3. The rate of cell loss. The cell cycle

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

Chemotherapy. A number of pharmacokinetic parameters such as

activation, inactivation, binding to carrier proteins, excretion, and

delivery of drug have obvious impact in the clinical response to even

the most active agents. As well, the response to an agent given in an

appropriate schedule seems to depend heavily on the proliferative

status of tumor cell populations, which in turn seems to vary as a

function of tumor burden. Thus, understanding the host-tumor

relationship with the purpose of designing more effective schedules

might be profitable.

The early pioneering work of Skipper et al in the L1210

leukemia model led to their statement of the log-kill hypothesis in

1964. This holds that a constant fraction of the tumor cells will survive

a given level of effective therapy irrespective to the size of the tumor.

Thus, the greatest number of cells will be killed in large tumors, while

small tumors should be curable if the same level of therapy is

repeatedly applied until virtually every cell is killed.

In 1977 Norton and Simon suggested that tumor killing for a

given level of effective therapy varies with the growth rate of the

tumor. For L1210 or other tumors which follow logarithmic growth,

growth fraction (GF) is large and stays constant. Thus, growth rate

accelerates as the tumor grows, rendering large tumors sensitive. In

contrast, for Gompertzian tumor growth, which probably more

accurately describes human tumors, GF is large initially, but

progressively diminishes. Growth rate progressively increases reaching

its maximum at about 37% of total volume and subsequently

decreases, as decreased GF become significant. Consequently, large

tumors, as well as very small tumors, have low growth rates wand are

relatively resistant to effective treatment.16

- The doubling time of a tumour increases with the tumour

mass up to a critical point while the thymidine labeling index

decreases. The growth of most experimental tumours can be

described as Gompertzian (after the statistician who first

described the mathematics) rather than linear.

- The response to chemotherapy is reflected by the change in

the 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.

- As the tumour volume increases the disease becomes less

easy to eradicate by single modality therapy.

- Non-phase dependent agents are theoretically more effective

than phase-dependent agents against tumours with long times

and low thymidine-labelling indices.

Gompertzian growth curve

Animal tumours do not grow in a linear manner. As they become

larger the growth rate slow. Though few data are available for human

tumours, there are suggestions that the above generalizations may

apply to human cancer, and proliferation studies may come to be

helpful in the choice of chemotherapy and in predicting duration of

remission and survival.

Phase-specificity / Phase dependency of cytotoxic drugs

Phase dependent agents exert an increasingly toxic effect with

prolonged exposure of the cells to an effective concentration while in

the sensitive phase. This results from an accumulation of cells in that

phase (provided the drug does not prevent entry). Given over a short

period, even at high dose level, these agents are not very toxic. Cells

not in the sensitive phase, at the time of the brief exposure, will be

minimally affected.

The toxicity of cycle-dependent or non-phase-dependent drugs

for both malignant and normal cells depends on the drug concentration

and the duration of exposure. To achieve maximum effect it is

therefore logical to administer the drugs intermittently at the highest

dose. Some drugs interfere with progression from one phase of the cell

cycle to another. Cytosine arabinoside and hydroxyurea, for example,

inhibit the progression of G1 cells into S and therefore cells not is S are

protected. This protective effect can be overcome by giving the drug

intermittently at intervals that permit the non-S phase cells to enter S

during the drug-free period.

Note that for both A and B rapidly proliferating cells are more

sensitive than slowly proliferating cells

Classification of anti-tumour agents according to their effect on the

cell cycle

Predominantly non-phase

dependent

Predominantly phase-dependent

Alkylating agents Vinca alkaloids

Nitrosoureas Hydroxyurea

Anthracyclines Cytosine arabinoside

Imidazole carboxamide (DTIC) Methotrexate

Mitomycin C 6-Mercaptopurine

Actinomycin D 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

Anabolic activation is particularly important in the case of anti-

metabolites. The role of anabolic and catabolic activation and

deactivation is of great importance since it may form the basis of

selective activity in different cell types (normal and malignant).

Usually, drug metabolism occurs in two phases:

A. Biotransformation – involving hydroxylation,

oxidation, reduction or hydrolysis

B. Conjugation – e.g. with sulphate, acetyl or a

glucuronyl group.

Drug metabolism occurs chiefly in the liver but may also take

place in the plasma, gastro-intestinal tract, kidneys and lungs. For this

EXCRETION

Renal and extra-renalBiotransformation to

active or inactive product(s)

Free drug in plasma

ABSORPTION Plasma protein binding

Tissue binding (specific and non-specific) tumour

and normal tissues

reason, hepatic function is an important consideration in the choice of

dose of some anti-tumor agents. The anthracyclines (e.g. Adriamycin

and Daunorubicin) are excreted mainly in the bile and these drugs

produce enhanced toxicity in patients with hepatic failure or biliary

obstruction.

EXCRETION

Most anti-tumour agents are excreted in the bile and urine.

Drugs not bound to albumin are filtered by the glomerulus. The

proximal tubule possesses two pump systems which transport drugs

from plasma to urine, one for the secretary mechanism and probenecid

can be used to reduce the elimination of acidic drugs (e.g. penicillins

and, possibly, anti-cancer agents such as Methotrexate). Passive

reabsorption of lipid-soluble drugs and the non-ionized fraction of

drugs which are weak electrolytes takes place in the renal tubule.

Elimination of weak acids by the kidney is increased by alkalinizing

the urine. The reverse is true for weak bases. Active tubular

reabsorption of ions and various solutes can also take place in the

proximal tubule.

Excretion in tears, sweat, saliva and in the breath is relatively

unimportant but may be the cause of unusual toxicity such as the

conjunctivitis seen following the use of high dose Methotrexate.

Several host dependent factors have important influences on drug

absorption, distribution, metabolism and excretion. Illness which

affects renal and hepatic function, bone-marrow reserve or gastro-

intestinal function may well have a marked influence on the efficacy

and toxicity of a drug. Methotrexate, for example, is largely excreted in

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. Dose-response curves for the different sensitizers and

alkylating agents are needed to optimize efficacy and reduce toxicity.

A randomized trial using intravenous melphalan with or without

misonidazole in metastiatic non-small-cell lung cancer showed a

small, but statistically significant, improvement in response rate with

misonidazole. Other single-arm trials of misonidazole and alkylating

agents have been negative or inconclusive.

Perfluorochemicals as Chemosensitizers

Fluosol-DA and carbogen breathing increased the antitumor

efficacy of bleomycin and cyclophophamide in the animal model.

With cyclophosphamide when the Fluosol dose was increased from

0.1 to 0.3 ml and carbogen breathing extended from 6 hr the tumor

growth delay tripled. Similar effects were seen with bleomycin.

Chemosensitization by Vasocative Drugs

Several vasoactive drungs can selectively reduced blood flow

and increases the percent of hypoxic areas in experimental tumor

systems. By promoting hypoxia in the tumor, the cytotoxicity of

drugs which are active in hypoxic conditions is potentiated. When

hydralazine was given prior to or after the alkylating agents

melphalan, melphaln’s antitumour activity increased by a factor of 2

and 3, respectively. However, systemic toxicity was only increased by

a factor of 1.2. Additional animal studies have shown that hydralazine

cause a dose-dependent decrease in tumour energy metabolism

(measured by PNMR spectroscopy). PH, and perfusion pressure in

tumors. Despite these alternations in tumor metabolism, toxicity is

minimal in the treated animals. These data suggest that hydralazine

might be beneficial combined with therapy which is specifically toxic

by hypoxic cells (e.g., hyperthermia, mitomycin C, and perhaps after

alkylting agents). Verapamil and other calcium chemotherapeutic

agents also potentiate the efficacy of certain chemotherapeutic agents

by preventing drug efflux and altering tumor blood flow .

Agents That Are Toxic to Hypoxic Cells

The bioreductive alkylating agents mitomycin and porfiromycin

may target to hypoxic cells. In a randomized trial of radiation with or

without mitomycin in head and neck cancer, improved disease-free

survival was observed in the patients treated with mitomycin .

SR-4233 is a new benzotriazine which is 15-to 50-fold more

toxic to anoxic than to well-oxygenated human tumor cells in vitro.

However, the invivo results with SR-4233 were less impressive.

A new analog, SR-4482 is more toxic than SR-4233 in vitro, and

less toxic in vivo.Several important effects of the nitroimidazole

compounds (hypoxic cytotoxicity, thiol depletion, and

chemosensitization) are felt to be due to reduction of the parent

compound. The benzotriazines are activated by enzymatic reduction.

The differential activity of various reductases in normal and malignant

tissues may lead to the logical selection of the appropriate sensitizer in

this class.

NONHYPOXIC RADIATION SENTIZIERS

Halogenated pyrimidines

Bromodeoxyuridine (BUdR) and iododeoxyuridine (IUdR), are

halogenated pyrimidines, which were designed as thymidine analogs.

The initial hypothesis was that these drugs could be incorporated into

the DNA of actively dividing cells and act as radiosensitizers. Clinical

trails should attempt to achieve sustained plasma levels of 10m IUdR

for optimal radiosensitization.

Early clinical trials using the halogenated pyrimidines

demonstrated excessive normal tissue reactions without increased

antitumor efficacy in patients with head and neck cancer. Since the

halogenated pyrimidines are absorbed preferentially in actively

dividing cells, it is not surprising that severe mucosal toxicity was

encountered. Since BUdR is associated with photosensitivity, recent

interest has focused on IUdR. More encouraging results may be

observed in the Phase II trials combining halogenated pyrimidine with

radiotherapy for gliomas and sarcomas, since the irradiated,

surrounding normal tissues have lower mitotic rates .

Two clinical studies of continuous intrahepatic artery infusions

of IUdR have shown that human colon cancer cells absorb almost six

times the amount of IUdR compared with adjacent normal liver.

Regional infusion also decreases systemic IUdR leves 50-78% .

DNA repair inhibitors

Inhibitors of DNA repair may act as radiosensitizers. Inhibitors

of DNA replications which act by inhibiting DNA-dependent DNA

polymerases can decrease the radiation damage at the chromosome

level. However, the effectiveness of inhibiting both replication and

repair of DNA does not always correlate with clinical response. In

human cervical cancer cell lines, the DNA repair inhibitors reduced

radiation survival. Various DNA repair inhibitors have been studies in

the laboratory. Hydroxyurea reduced survival at both high and low

radiation doses. Beta-ARA-A and caffeine are more effective in

reducing all survival at low doses.

Nicotinamide

In several animal models nicotinamide has bee shown to

preferentially radiosensitize tumors, perhaps by reducing hypoxia.

The radiation enhancement ratio ranged from 1.2 to 1.7 in animal

tumors and 1/0 to 1.3 in normal tissues.

Platinum analog

Cis-plantinum is one of the most active chemotherapeutic

agents. However, its radiosensitizing properties have not been

exploited with fractionated radiation because cis-plantinum’s normal

tissue toxicity. The less toxic transiomer trans-platinum and other

platinum analogs interact with radition in vitro. Trans-platinum might

be an ideal sensitizer for most radiation fractionation schedules used

in clinical practice.

Thiol Depletors

As the thiol content in cells increases, most cells are protected

from the cytotoxicity of radition of alkylting agents. In vitro, thiol

depletion leads to radiosensitization. When BSO depletes cellular

glutathione in vitro, radiation injury increases. However, the presence

of other reducing agents (such as ascorbic acid or -tocophero) blunts

the sentizing effect of BSO in vivo. Lowering glutathione levels in

tumours might potentiate the effect of hypoxic radiosensitizers.

However, glutathione depletion’s major likely role will be in

chemosensitization.4

Chemoprevention

The most effective methods of preventing oral cancer are

avoidance of the major etiological factors, tobacco and alcohol.

However patients with premalignant conditions in the mouth have a

high risk of developing carcinoma, and patients successfully treated

for oral cancer have a high risk of developing seconds primary

neoplasms. Accordingly there is now a considerable interest in

measures to prevent the development of cancer in this high risk group,

including the use of chemical agents.

Retinoids

Vitamin A and related compounds have several properties which

suggests that they may be useful as chemopreventive agents in oral

squamous cell carcinoma. They are modulators of epithelial cell

differentiation, both in vitro and in vivo. They probably act by

regulating gene expression. Cell nuclei contain retinoic acid receptors

that mediate the biological effects of retinoids. The ligand for these

receptors is probably all-trans-retinoic acid, to which retinoids must be

metabolized to exert their biological effect. In experimental animals

vitamin A deficiency causes squamous metaplasia similar to that

induced by chemical carcinogens. It has been found that vitamin A

and related retinoids can reverse the metaplsia in vitamin A deficient

animals. They have also been shown to inhibit the growth of

squamous carcinoma cell lines in vitro.

There have been several studies of treatment of oral dysplastic

leukoplakia by retinoids. Hong et al. used isotretinoin in a dose of 1-2

mg/kg per day for 3 months in a placebo-controlled trail involving 44

patients. The drug produced major clinical responses in 67 per cent of

patients compared with 10 per cent who received placebo (P=0.0002)

and reversed the dysplastic change in 56 per cent. At this dosage

isotretinoin has appreciable toxicity, with peeling of the skin, chelitis,

facial erythema and hypertriglyceridaemia in about 75 percent of

patients, headaches and dyspepsia also occasionally occur. The

leukoplakic changes recur after stopping treatment. However a

subsequent study demonstrated that low dose maintenance treatment

(0.5 mg/kg) after the end of the 3 months of high dose therapy was

well tolerated and prevented recurrences.

Vitamin A in high dosage was shown to reverse premalignant

change in Indian betel chewers. Vitamin A is generally less loxic than

isotretinoin, but effective dose levels, i.e.300 000 IU per day, produce

similar if less severe side effects. In both of the above studies -

carotene was also tested as maintenance treatment because of its lower

either vitamin A or isotretinoin, probably because it is less easily

metabolised to the active ligand.

Experience with isotretinoin in the treatment of leukoplakia has

led to being tested as adjuvant treatment in patients with oral and

laryngeal carcinoma who were disease-free after primary treatment.

There was no influence on recurrence rates of the original tumours,

but there was a significant reduction in the incidence of second

primary tumours. This experience led to the setting up of larger

multicentre chemopreventive trails in cured head and neck cancer

patients, for examples the Euroscan trail using vitamin A.

Antioxidants

Agents with antioxidant properties can inhibit the effects of

many toxins including carcinogens. N-acetylcysteine, a precursor of

intracellular glutathione, inhibits the mutagenic effect of carcinogens

such as benzpvrene in vitro.10

CLINICAL APPLICATION AS PRIMARY TREATMENT AND

AS ADJUVANT IN MALIGNANT LESIONS

One of the most important factors in selecting chemotherapy is

the incidence of clinical and histological cure rate achieved by such

treatment. Present chemotherapy regimes do not produce cure rate in

all patients treated and considerable improvement is required in this

area. Also, it is very important to mention that after clinical cure rate is

achieved, the additional number of courses of chemotherapy

administered is critical in determining the frequency of histological

cure rate and duration of overall survival. A clinical cure rate occurring

after one course of chemotherapy, when additional courses of the same

chemotherapy are planned, is a more favorable prognostic factor than

clinical cure rate occurring at the end of the last planned course of

chemotherapy. It is important in evaluating chemotherapy as part of

multimodality treatment that in addition to the minimum number of

courses needed to achieve clinical cure rate.

The goals of including chemotherapy as part of the

multimodality treatment in patients with locally advanced head and

neck cancers are better overall survival and/or quality of life. When our

best chemotherapy is proven to be of value as part of multimodality

therapy, then the possibility of delaying or performing less extensive

surgery can be studied. The main purpose would be to lessen the

cosmetic and/or functional morbidity caused by radical surgical

procedures without jeopardizing the survival of the patients.

Induction (initial) chemotherapy

To investigate the effectiveness of chemotherapy as part of

multimodality treatment, the drugs must be administered before

definitive surgery and/or radiotherapy when gross and measurable

disease in present. As with most new therapies patients with more

advanced disease (stage III and IV) are usually selected for trials.

The use of chemotherapy as initial treatment started in the mid

1970s because of the increased local toxicities of simultaneously

administered chemotherapy and radiotherapy and lack of benefit of the

combined approach at that time.

Initially high dose methotrexate with leucovorin rescue as

utilized. In general, the overall response rate to this agent alone in

previously untreated patients with locally advanced disease was poor,

with no clinical cure rate and no evidence of improved survival of

these patients as compared with historical controls.

With the demonstration that cisplatin was effective as a single

agent in patients with recurrent cancer of the head and neck, many

trails were initiated with cisplatin containing combinations in patients

with previously untreated and locally advanced disease, summarizes

the overall results of trials with cisplatin alone or in combination with

other agent(s) that are known to be effective against head and neck

cancers. More than sixty such trials were reported up to 1985. All

except two trials were single arm pilot studies.

Because of patient heterogeneity and marked variation in the

doses and schedules of drug administration it is difficult to draw

conclusions. It does seem that cisplain combinations are superior to

cisplatin alone in achieving clinical cure rate and in overall response

rate. The most common agent(s) combined with cisplatin are

bleomycin alone or with other agents like methotrexate, vinblastine or

Oncovin. The overall clinical cure rate rate seems high with cisplatin

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

chemotherapy agents and combination systemic chemotherapy is being

increasingly used before local therapy in previously untreated and

locally advanced head and neck cancers (Al Sarraf 1988).

Systemic chemotherapy has been used in various forms as

detailed below.

Induction chemotherapy: This is other wise called as

neoadjuvant chemotherapy. This started being used from mid 1970’s

because of increased local toxicities seen with simultaneously

administered chemotherapy and radiotherapy and lack of benefit of

combined approach during 1960’s (Al Sarraf 1988). The drugs are

administered prior to start of definitive therapy. The rational for

neoadjuvant chemotherapy is that a) ability to deliver drug to untreated

tumors with intact vascularity, b) Better tolerance to chemotherapy, c)

to enhance the efficacy of planned definitive local therapy after

cytoreduction and eradication of sub clinical metastasis and d) for

better overall survival and quality of life.

Concurrent chemotherapy: The drugs are used simultaneously

with definitive therapy (Radio Therapy or Surgery).

Chemotherapy 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, 5-

flurouracil (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

1991) and Cisplatinum and 5-Fluorouracil (Singhal 1993). Ten years of

clinical trails have not yet identified the best chemotherapy regimen

to be combined with definitive treatment (Al Sarraf 1988).

Methotreaxate and –Fluorouracil has been used in combination in

advanced head and neck cancers as neoadjuvant chemotherapy agents

(Alan Coats 1984; Jacobs 1982; Pitman 1983; Mackintosh 1988) with

varying success.

Oral cancers are common tumors presenting in advanced stages.

The effect of treatment is easily assessable in oral cancers.

Neoadjuvant chemotherapy has shown its effectiveness in head and

neck cases. So we want to assess the effect of combined neoadjuvant

chemotherapy with definitive radiotherapy in carcinoma of buccal

mucosa.

In patients with previously untreated respectable and operable,

locally advanced head and neck cancer, the timing and sequence of

effective chemotherapy as part of multimodality treatment is important

and needs to be investigated. The following problems existed with

induction chemotherapy when given as the initial treatment in

combined modality therapy:

1. Patients refuse surgical resection or any further

therapy, especially those achieving the best response to

chemotherapy.

2. The planned surgery after initial successful

chemotherapy is not the same as that done in

previously untreated patients with identical tumors.

3. The results of surgery after three courses of

chemotherapy, even with achievement of up to a 50%

clinical cure rate, are no different than adequate

surgery without preoperative treatment.

4. Chemotherapy yields higher objective response rates in

patients with smaller tumor masses (stage III v stage

IV). Thus a higher effectiveness is expected of the

same chemotherapy when it is given to patients with

minimal residual disease after surgery (microscopic)

rather than gross bulky disease present before surgery.

Because of the above, a pilot study for patients with locally

advanced but respectable cancer in which three courses of cisplatin and

120 hour 5-FU infusion were given after surgery and before

radiotherapy. Following the demonstration of the feasibility of this

approach two pilot studies were activated by the RTOG in 1981, one

using induction chemotherapy followed by surgery and postoperative

radiotherapy in respectable patients, while the second uses the same

chemotherapy after surgery and before radiotherapy. The

side effects of chemotherapy were the same regardless of the sequence

of chemotherapy in relation to the definitive treatments. Survival

favored chemotherapy in the middle “sandwich”, in spite of more stage

IV patients and poorer performance status in this group. This led to a

phase II trail RTOG 83-22, Head and Neck Cancer Inter Group I-0034)

in which after surgical resection patients are stratified and randomized

to receive radiotherapy or three courses of cisplatin and 5-FU infusion

followed by radiotherapy.

Combined chemo-radiotherapy

Since the late 1960s several efforts were made to commune

chemotherapy with radiotherapy. The concept of combining

chemotherapy and radiation in the treatment of locally advanced

squamous cell carcinoma of the head and neck, particularly

unresectable or inoperable lesions, is attractive.

Many single agents or combinations of drugs were used with

radiotherapy . The most common single agents selected for combination

with irradiation were, hydroxyurea, methotrexate or bleomycin. The efficacy

of these agents combined with radiotherapy has not been established in

randomized oral cancer, which often results in interruption of therapy.

The search for better and safer agents to combine with radiotherapy

led to the administration of Cisplatin. Cisplatin is an active agent in

squamous cell cancers of the head and neck. It does not produce mucositis

of the oral cavity and should not interfere with the delivery of radiotherapy.

Cisplatin possesses properties of radiosensitization that have been observed

both in vitro and in vivo. It has been suggested that the cytotoxic activity of

cisplatin is independent of cellage, and that radiation enhancement is both

dose and cell cycle phase dependent.

The combination of cisplatin and radiotherapy produced high CR

rates when given preoperatively in resectable stage III head and neck

malignancy and IV head and neck cancer or as the total treatment in

unresectable and/or inoperable disease. Also, this combination is

being tested as postoperative treatment at Wayne State University in

Detroit.

Because of the high complete response rate obtained with the

combination of cisplatin and 5-FU, this two drug regimen was added

to radiotherapy, and resulted in improved local control. The

combination of the cisplatin and radiotherapy is being compared to

radiation alone in phase III randomize trails by ECOG, RTOG, and

SWOG.

We feel that chemo-radiotherapy may play an important role

in the treatment of patients with locally advanced head and neck

cancer and clinical investigation in this area continues.

Chemotherapeutic agents used concurrently with radiotherapy in

advanced cancers

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. Adrimycin (Adria Laboratories, Columbus, OH)

Chemotherapy After Radiotherapy

It has been reported that chemotherapy is most effective in

animal models when used for the eradication of small tumor masses.

Thus, chemotherapy administered after the definitive treatments of

surgery and/or radiotherapy may be efficacious in eradicating

minimal residual disease.

Randomized trails of single agent chemotherapy (methotrexate

or cisplatin) post definitive treatments of surgery and/or

radiotherapy were initiated in many cooperative groups. In the

NCI head and neck contract trial one of the experimental arms

required that six doses of cisplatin be administered following one

course of cisplatin plus bleomycin, surgery and postoperative

radiotherapy. Only about 10% of the patients finished the total six

courses while about 30% either progressed or died, or refused

therapy respectively. Chemotherapy postdefinitive treatment is an

important concept that needs further evaluation.15

DRUG SENSITIVITY TO VARIOUS LESIONS, THERAPY

REGIMES

Chemotherapy for recurrent or metastatic SCC H&N

When a patient relapses after extensive surgery or radiation

therapy, treatment options are limited. Traditionally, chemotherapy

has been used in this patient population, with chemotherapeutic single

agents and combination chemotherapy being evaluated for their

response as well as their impact on the patient’s quality of life. Four

drugs have been noted to have major activity in recurrent and

metastatic SCC H&N. They are (1) methotrexate, (2) cisplatin, (3)

belomycin, and (4) 5-fluorouracil. Other chemotherapeutic agents are

noted to have activity but are not as frequently used.

Methotrexate

Include in the antimetabolite class of agents, methotrexate exerts

its cytotoxic effect through inhibition of the enzyme dihydrofolate

reductase. This enzyme is responsible for maintaining the intercellular

pool of folates in reduced state, which is required for the synthesis of

the purine nucleotides.

For most oncologists, this is the standard chemotherapeutic

agents to which other single agents and combinations are compared.

The overall response rate using methotrexate as single agents

approximately 31%, with predominantly partial response seen and few

complete response noted. The initial dose is 40mg/m2, given

intravenously weekly until toxicity is noted, usually in the form of

mucositis or leucopenia. Various doses and schedules have been used,

including leucovorin as a bone marrow protector in the higher doses.

Nevertheless, pooled response rates are very similar between the

moderate and high doses of methotrexte, and toxicity plus cost are

more appreciable at the higher doses.

Cisplatin

Cisplatin is considered a heavy metal compound and is believed

to exert its activity by causing DNA cross-linking. This agent has been

extensively evaluated for patients with recurrent SCC H&N, with

single-agents activity in the range of 28%.

Cisplatin has been evaluated when given on a weekly basis,

every 3 weeks as an intravenous bolus, or by continuous infusion. All

schedules have shown similar response rates. The issue of dose

intensity has also been addressed, with dose-realted toxicity being a

limiting factor, particularly involving renal toxicity and neurotoxicity.

The typical dose used has been between 80 and 100mg/m2, with no

clear advantage see when higher doses are used. Cisplatin is usually

given every 3 to 4 weeks, with pre and post-hydration plus mannitol

infusion to protect renal function.

Bleomycin

Bleomycin is a mixture of glycopeptides considered in the class

of antibiotic considered in the class of antibiotic neoplastic agents with

activity in the G2 and mitotic phases of the cell cycle. It has been one

of the more frequently used agents for head and neck cancer and has a

single agent response rate of approximately 21%. Bleomycin has been

administered as a bolus or by continuous infusion, with equal activity

in both continuous infusion, with equal activity in both schedules but

with a suggestion of an improved toxicity profile when the continuous

infusion, with equal activity in both schedules but with a suggestion of

an improved toxicity profile when the continuous infusion schedule is

used.

The dose-limiting toxicity of bleomycin is its cumulative effect

on pulmonary function, making it difficult to administer after several

courses. The single-course dosage frequently used is 10 to 15 mg/m2

daily for 3 to 4 days every 3 to 4 weeks.

5-Fluorouracil

One of the most frequently used chemotherapeutic agents for

head and neck cancer, 5-FU is usually used in combination with

cisplatin. 5-FU is pyrimidine antimetabilite that is converted

intracellularly to fluorodeoxyuridine monophosphate (5-F-DUMP); a

potent inhibitor of thymidylate synthetase, thereby inhibiting DNA

synthesis.

Another way -5-FU mediates its activity is by forming

fluorouridine triphosphate (FUTP), which is incorporated into a

interferes with the function of RNA. Single-agent response rate with

5-FU is approximately 15%. 5-FU has been extensively used with

cisplatin because of preclinical synergy noted.

Recently, it has been observed that 5-FU can be potentiated

when used in conjunction with leucovorin, which is the reduced form

of folate. Leucovorin stabilizes the 5-FU and thymidylate synthetase

tenary complex. When 5-FU is administered as a bolus daily for 5

days, the dose-limiting side effect is predominalty bone marrow

suppression. If the schedule is altered to a continuous venous infusion

over 24 hours daily for 4 to 5 days, the limiting toxicity changes to

mucositis, diarrhea, and cutaneous erythema. Cardiac toxicity has also

been noted. The continuous infusion schedule was used in an effort to

reduce myelosuppression, but, indeed, it seems to have improved the

activity of this drug in SCC H&N. The dosage most frequently used

has been 800 to 1000 mg/m2 by continuous intravenous infusion for 72

to 96 hours.

Other single agents, not as widely used but with reported activity

in SCC H&N in the range of 15% to 36%, are the following: (1)

carboplatin, an analogue of cisplatin whose dose-limiting toxicity is

myelosuprresion, specifically thrombocytopenia (2) cyclophosphamide

and its analogue, ifosfamide, and hydroxyurea; (3) general classes of

drugs with limited single – agent activity, including the anthracylines

(doxorubicin), the vinca alkaloids, mitomycin, and the nitrosureas.

Combination chemotherapy for recurrent or metastatic SCC H&N

In the 1970s, the many trails using combination chemotherapy

for patients with recurrent or metastatic SCC H&N combined the

active single agents cisplatin, bleomycin, and methotrexate. The

response rates noted were encouraging, with the cisplatin-based

combination thought to be superior to the non-cisplatin-based

regimens.

In the 1980s, investigators at Wayne State University combined

cisplatin with 5-fluorouracil, both as a bolus and by continuous

intravenous infusion for 96 hours. The initial results were very

encouraging, with an objective response rate of 78% noted; more

importantly, a 29% complete response rate was obtained for patients

with recurrent and metastatic disease. Other investigators have used

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

efforts have failed to significantly improve the response rate of this

combination, and no overall improvements have been seen with these

approaches.

Eleven randomized trails have looked at comparing single

agents, such as cisplain, 5-FU, and methotrexate, versus combination

chemotherapy, including cisplatin and 5-FU, for patients with recurrent

or metastatic SCC H&N. Review of these studies reveals that,

although slightly higher response rates have been noted using

combination chemotherapy, this has not translated into an improved

disease-free or overall survival advantage. In addition, combination

chemotherapy has added toxicity and cost for the patient when

compared with single agents.

Although higher responses and, in particular, complete

responses, can be obtained with the use of cisplatin and 5-fluororuacil,

more toxicity is noted with this combination than with single agents.

Primary Chemotherapy

Primary chemotherapy refers to the use of chemotherapy, given

either before local therapy, concurrent, with radiation, or after local

treatment has been completed. The rationale for using chemotherapy

prior to local treatment is based on factors such as (1) an improved

patient performance status, (2) an intact vascular supply to the tumor

bed, and (3) the eradication of micrometastasis to prevent regional and

distant metastases.

Induction (Neoadjuvant)

The initial observation made was that response rates using single

agents, such as cisplatin, bleomycin, and methotrexate, were higher for

patients who had not received prior local therapy than for patients in

whom disease recurred. In the 1970s, Randolph et al combined

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

feasibility studies pointed to an improved overall and complete

response rate obtained with induction chemotherapy, without

compromising local therapy.

Concurrent Chemoradiation Therapy

Although there have been no new agents developed to add to the

response rate of combination chemotherapy for patients with locally

advanced, unresectable SCC H&N, the concurrent use of single agents,

such as bleomycin, 5-FU, methotrexate, hydroxy- urea, mitomycin-C,

and cisplatin, with radiation therapy has been investigated.

The rationale for combining these two modalities is based on

preclinical data suggesting the radiation-sensitizing effects of certain

chemotherapeutic agents. Also, combining these two modalities of

treatment simultaneously applies the concept of dose-intensity –

administering the largest amount of treatment per unit time in an effort

to over-come any inherent drug or radition resistance.

Adjuvant Chemotherapy

Chemotherapy given after local therapy has been tried with the

rationale of eradicating micrometastases and thereby possibly reducing

the local, regional and distant metastatic rate. Unfortunately, of the six

randomized trials using chemotherapy in this fashion, none has shown

a survival advantage. Nevertheless, one large study showed a

statistically significant decrease in distant metastases for patients

receiving chemotherapy after local therapy, even though overall

survival rates in both arms were not different.

Nasopharyngeal cancer

Standard treatment for nasopharyngeal carcinoma worldwide has

been radiation therapy because of this tumor’s known radiation

sensitivity and poor anatomic location, making surgical intervention

difficult. In fact, early-stage disease is well controlled with radiation

therapy alone, but in advanced stage disease, survival is considerably

less. For example, for Stage III disease using radiation therapy alone,

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 patients with bilateral neck

involvement, there is an established 80% chance for developing distant

metastases at a later date, usually involving the lung, liver, or bone.

Nasopharyngeal carcinoma is believed to be a chemosensitive

tumor; in fact, multiple single agents, such as cisplatin, 5-FU,

methotrexate, bleomycin, the vinca alkaloids, and doxorubicin, have

known activity in this disease. Various studies have reported rate, of

which less than 20% are complete responders, with the use of cisplatin

and non-cisplatin-based regimes for patients with recurrent or

metastatic nasopharyngeal carcinoma.

Salivary gland carcinoma

Salivary gland carcinomas make up approximately 5% to 10%

of all head and neck malignancies. These tumors demonstrate very

diverse anatomic, histologic, and biologic behaviour. Traditionally,

treatment for these tumours has been surgery with or without radiation

therapy. Chemotherapy has been reserved for patients with recurrent

and/or metastatic disease, and the benefits of chemotherapy have been

predominantly palliative for this group of patients. A number of single

agents have shown activity in this disease, but the most active and

frequently used are cisplatin, doxorubicin, 5-FU, cyclophosphamide,

and methotrexate.

Depending upon the histologic type of the tumor, methotrexate,

for example, has been shown to have a single-agent response rate of

approximately 36% in mucoepidermoid cancer, which is similar to the

activity seen for this agent in SCC H&N. However, for other

histologic types of salivary tumours, the response rate with

methotrexate is much lower, approximately 6%. In contrast,

doxorubicin is relatively inactive in mucoepidermoid carcinoma but is

active in other salivary gland histologic types. Single-agent cisplatin

has also been extensively used with a wide range of response rates

from 17% to 70%. Multiple combinations of the most active agents

have been tested, with the most frequent combination being cisplatin

and doxorubicin, with or without 5-FU or cyclophosphamide. The

responses with doxorubicin-based combinations have been in the range

of 35% to 100% with a median response of approximately 50%.

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,

neuroendocrine carcinomas, and Merkel cell carcinomas.

Sarcomas

Sarcomas can arise from either the bone or soft tissues in the

head and neck but are rare. When they d occur, the most common of

these tumors are the osteogenic sarcomas, malignant fibrous

hitiocytomas, rhabdomyosarcomas, fibrosarcomas, synovial sarcomas,

and angiosarcomas.

Surgery and radiation therapy remain the treatment of choice for

local disease, but depending upon the extent of disease, grade and

location, local and regional recurrences can be significant, with distant

metastases predominantly involving the lung, liver and bone.

Chemotherapy, particularly with doxorubicin-based regimens,

has been used and can provide palliation. Response rates with

chemotherapy are similar to those seen for other sites and are largely

partial response. For one particular subtype, rhabdomyosarcoma,

chemotherapy added to surgery and radiation therapy has been reported

to improve 5-year survival compared with that seen with surgery

and/radiation therapy alone.

Lymphomas Both Hodgkin’s and non-Hodgkin’s lymphomas can present in the head and neck area. When the disease is

localized to the head and neck, the treatment usually consists of radiation therapy only. However, this disease is frequently

found in multiple areas, and chemotherapy and radiation therapy are used with substantial success. The most commonly

used chemotherapeutic agents for the lymphomas are the alkylating agents (i.e., cyclophosphamide) in combination with

doxorubicin and vincristine. Prednisone is also incorporated into these regimens.

Drug combinations No.

evaluated

No. with

50%

regression

Methotrexate + bleomycin 4 2

15 8

Methotrexate + vincristine 28 15(53%)

Dibromodulcitol + bleomycin 20 5(25%)

Adriamycin + bleomycin 8 4

MeCCNU + cyclophosphamide + bleomycin + vincristine (COMB)

32 11(35%)

Methotreaxate + 5-fuorouracil + cyclophosphamide + vincristine (modified COMF)

10 8

Methotrexate + cyclophosphamide + vincristine+prednisone (Cooper’s regimen)

18 4(22%)

CCNU+HN-2+ adriamycin + bleomycin + vincristine (BACON)

13 7

Methotrexate+6-mercaptopurine + 82 45(55%)

procarbazine + chlorambucil + thio-tepe + streptonigrin + rufochromomycin + vinblastine

SINGLE AGENT ACTIVITY

Drug Dose Schedule Evaluable

Patients

Responsea

Cyclophosphamid

e

8-10 mg/kg IV 56 2 CE, 35

improved

4 mg/kg/dy IV

4-60 mg/kg single

dose

150-300mg/dy;

then 100-200

mg/day PO

15 2 improved

2g in divided

doses for 8 days;

then 100 mg/day

PO

6 3 PR, 3

improved

Cyclophosphamid

e

IV, PO, IP, or

intrapleural

ranging from

100mg daily PO to

8g IV loading dose

preceding PO

therapy

4 2 excellent and

2 moderate

responses

Cyclophosphamid 50-200 mg/day PO 1 Improved

e

30mg/kg IVP; then

10-15 mg//kg q1-2

wks

Cyclophosphamid

e

Various IV and PO

doses

4 1 improved

Chlorambucil 0.2 mg/kg/day X

42 days PO

34 1 CR, 4 PR

Nitrogen mustard Total dose, 0.5-0.8

mg/kg

2 None

0.6mg/kg in 3

divided doses

41 5 improved

5-FU 15mg/kg/day X 5

IV; then 7.1mg/kg

every other day

until toxicity.

Maximum loading

dose per day,

1,000 mg

84 1 CR, 4 PR, 20

improved

5-FU 1,000 mg/day X 5;

then 500mg every

other day until

toxicity

2 2 improved

5-FU 4-8mg/kg/day X

14-42 days

17 3 improved

5-FU 15-20 mg/kg/wk 12 1 CR, 1 PR

Evaluable

Patients

Responsea

1

10

1 improved

3 improved

23 4 PR 7,

improved

31 3 improved

12 0

76 11 PR

Mitomycin C 50mg/kg/day X 6;

then 50 mg/kg every

other day until

toxicity

4 0

aCR = Complete response; PR = Partial response (50% or more in

tumor measurements); Improved = Less than a PR not quantitated

ROUTE OF ADMINISTRATION OF VARIOUS

CHEMOTHERAPEUTIC AGENTS

The administration of chemotherapy has not always been as it is

today. As recently as the 1950s, the physician administered the

medications and the nurse was left to care for any side effects (Lind

and Bush 1987). The first chemotherapy drug. A nitrogen mustard

(mechlorethamine), was discovered in the 1940’s and in comparison to

other areas of medicine, the field of oncology was still in its infancy.

As the number of available drugs increased and the technology of

chemotherapy administration became more complex.

ROUTES OF ADMINISTRATION

The goal of chemotherapy administration is to optimize drug

availability. In an attempt to deliver drugs in high concentrations to

areas of greatest clinical need and to improve the antitumor effects,

many diverse routes of drug administration have been developed

(Haskel 1980). The current routes of administration include:

intrathecal (IT)

intra-arterial (IA)

intracavitary (IC)

subcutaneous (SQ)

intramuscular (IM)

topical (TOP)

oral (PO)

intravenous (IV)

The following three routes of administration allow for high drug

concentrations in the disease area while minimizing the systemic

concentrations, and thus the side effects:

intrathecal

intra-arterial

intracavitary

Administering chemotherapy intrathecally allows the drugs to

reach the central nervous system to prevent or treat local disease. The

majority of chemotherapy agents do not cross the blood-brain barrier,

so they must be delivered directly into the cerebrospinal fluid. This is

accomplished by either:1) a lumbar puncture or 2)utilizing an

indwelling subcutaneous cerebrospinal fluid reservoir, such as the

Ommaya reservoir (Heyer-Schulte del Caribe, Anasco PR). The

benefits and risks to the patient must be determined before either

method of administration is chosen. To put it concisely, include: 1)

having a lumbar puncture performed for each treatment (weighing the

pain and potential complications that procedure involves) or 2) the

potential complications of surgically inserting and Ommaya reservoir,

but utilizing a consistent port for each treatment. The Ommaya

reservoir is a mushroom-shaped, reusable, self-sealing, silicone port

which is connected to a catheter placed in the ventricle (Figure ). The

reservoir is accessed by inserting a hypodermic needle, usually a small-

gauged butterfly needle with an attached three-way stopcock and

syringe, directly into the dome. During the procedure an amount of

cerebrospinal fluid, equal to the amount of medication to be injected, is

removed. The medication is injected into the reservoir and, once the

needle is removed, the domed reservoir is manually compressed and

released to mix the medication with the cerebrospinal fluid (Brown

1987). This procedure is usually performed by a physician using strict

aseptic technique.

Cerebrospinal fluid reservoir and mode of use

Intra-arterial infusions treat an isolated organ or inoperable

tumor. The chemotherapy agents are administered through a catheter

inserted into an artery usually in the liver, head, neck, or brain. The

celiac artery is used to treat the liver, the external carotid artery for the

head and neck area, and the internal carotid artery for brain tumors

(Johnston and Pratt 1981). The catheters are inserted into the artery

surgically with general anesthesia or using angiographic catheterization

and a local anesthetic. The catheters are then connected to either an

implanted or portable pump. There are two impantable pumps

currently being used: the Infusaid pump (Shiley Infisaid Inc, Norwood,

MA), and the Medtronic pump (Medtronic, Minneapolis). The

Autosyringe Division, Hooksett, NH), is an example of a portable

systems used for intra-arterial infusions.

Portable infusion pump

Three other modes of drug administration are used less

frequently:

subcutaneous

intramuscular

topical

Many of the antineoplastic agents are irritating or damaging to

body tissue, so it is inadvisable to give a subcutaneous or intramuscular

injection of these agents. Some drugs that can be given by the

subcutaneous route are cytosine arabinoside (ARA-C) and the

interferons, while bleomycin and methotrexate can be given

intramuscularly. L-asparaginase is one drug that may be given either

by the subcutaneous or intramuscular route. Topical administration has

limited usefulness with only mechlorethamine and 5-fluorouracil

cream having this method as one of their routes of administration,

(Dorr and Fritz 1980). Occasionally, a specific protocol or drug may be

administered using one of the methods.

The last two routes of chemotherapy administration are the most

common:

Oral

Intravenous

The oral route is usually preferred but absorption can be

unpredictable. Several factors must be considered before choosing the

oral route: patency and functioning of the GI tract, presence of nausea,

vomiting, or dysphagia, the patient’s state of consciousness, the

patient’s willingness to comply to the schedule, and the availability of

the medication in oral form.

The intravenous (IV) route of administration is the most

common method used to deliver chemotherapy. It allows absorption of

the drug thus providing predictable blood levels (Brown 1987).

Intravenous drugs may be administered through a peripheral access, a

vein in the patient’s arm or hand, or through a central venous access

device, such as a silicone, silastic catherter, or an implanted infusion

port. The three major adviser reactions to the intravenous route of

administration are: phlebitis, venous flare, and extravasation

(Troutman 1985).

There are four methods of intravenous administrations:

push (IVP)

piggyback (IVB)

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

Criteria for Vein Selection Appropriate

Choice of

Venipuncture Site

Ideal Vein/Best Location forearm

Large, soft resilient veins in forearm,

hand

Ideal Vein/Undesirable Location

Large, soft, resilient veins in

hand/antecubital fossa; small, thin

veins in forearm

hand

Satisfactory Vein/Best Location

Small, thin veins in forearm/hand forearm

Satisfactory Vein/Undesirable

Location

hand

small thins veins in hand; veins in

forearm not palpable or visible

Unsatisfactory Vein/Undesirable

Location

Consider central

venous line*

small, fragile veins, which easily

rupture, in hand/forearm

Unsatisfactory Vein/Undesirable

Location

Consider central

venous line*

veins in forearm/hand not palpable or

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 doesn’t 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

venipuncture according to the institution’s policies and

procedures.

Controversial Issues in Chemotherapy Administration

Issue Solution Rationale

Administration

site

Use antecubital

fossa

Larger veins permit more rapid

infusion and administration of

drugs

Larger veins permit more rapid

circulation of potentially

irritating drugs

Avoid antecubital

fossa

Mobility of arm restricted

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

patient

Needle size Larger gauge (#19-

21 scalp vein

Potentially irritating drugs

reach circulation sooner, with

needles) less irritation to peripheral

veins

Small gauge (#23-

25)

Smaller gauge needles less

likely to puncture wall of vein;

less scar tissue at insertion site;

and less pain on insertion

Increased blood flow around

needle increases dilution of the

drug

Reduced incidence of

mechanical phlebitis

Slower infusion rate – may

reduce side effects, i.e., nausea

and vomiting

Sequencing of

medications

Administer vesicant

first

Vascular integrity decreases

over time, i.e., more stable and

less irritated at the beginning of

treatment

Initial assessment of vein

patency is most accurate

Irritating agents may cause

venous spasm and pain

Administer vesicant

last

Vesicants are irritating, may

increase vein fragility, and

cause spasm at onset of drug

administration. The nurse must

assess whether the spasm and

complaint of pain is an

infiltrate or not

Particular

intravenous

method of

administration

Use sidearm

method

Freely running intravenous

lines allow for dilution of drugs

Use direct IV push

method

Integrity of the vein can be

more easily assessed

Extravasation can be noted

earlier

DRUG DELIVERY SYSTEMS

One of the fastest growing areas in the oncology setting today is

the area of drug delivery systems – catheters, implantable ports, and

infusion pumps. By the time this book is published, numerous new

products will be available that were only a thought at the time the

authors were formulating this section.

Previously, a venous access device was only indicated when the

patient had unsatisfactory veins for further cancer therapy. Now there

are several indications for early placement of a venous access device

(Simon 1987). Patients receiving continuous infusions of

chemotherapy, nutritional supplements, or antibiotics either at home or

in the hospital are also ideal candidates for such devices.

Two central venous access devices will be discussed in this

section: silastic right atrial catheters and implantable venous access

ports (VAP).

Growth factors

Transforming growth factor-1 (TGF-1) is a potent cytokine

that affects growth inhibition of various cells and stimulates

extracellular matrix production and angiogenesis. Loss of TGF-

receptor type II (TGF- RII) expression has been related to tumor

progression.

Advances in molecular biology and genetics have provided new

insights into the carcinogenesis and behavior of malignant tumors of

the salivary glands. The WHO system provides a consistent taxonomy

for tumors of the salivary glands, which may facilitate sharing of our

experience with these relatively rare tumors. Clinical parameters such

as advanced stage, high grade, nodal metastasis, positive margins, and

perineural spread characterize patients with aggressive and potentially

lethal tumors. The relatively high rate of failure to control the disease

in these patients indicates the need for improvement in adjuvant

therapy.6

Treatment of nausea and vomiting

A. Mild – Pretreatment with 10mg prochloreperazie

(Compazine) orally or parenterally before therapy, and one or two

doses every 4 to 6 hours posttherapy is usually sufficient.

B. Moderate – retreatment with 10mg prochloreperazine PO or

parenterally, 10mg dexamethazone (decadron) IV, and 0.3mg/kg

ondansetron (Zofran) IV. At end of chemotherapy, 0.15mg/kg

ondansetron. Then, 10mg prochlorperazine every 6 hours as needed.

Ondancetron can also be given as a single injection of 30mg once a

day.

C. Severe – Same as for moderate, but with addition of 0.5mg

lorazepam IV before treatment. The lorazepam and ompazine are

repeated in 3 hours, then taken every 6 hours by mouth at home. On

occasion, 10 to 20mg metoclopramide (raglan) orally can be helpful.

In patients with severe, rather refractory nausea and emesis,

continuous infusion ondansetro (1mg/hr) has been very helpful. Such

treatment can be associated with headache.

Ondansetron has recently become available in an oral form

which is quite effective.

Diarrhea: Causes = amethopterin, fluorouracil (especially with folinic

acid), FUDR, 6-mercaptopurine, mitotane, and somatostatin.

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,

hexamethlmelamine, procarbazine, vinblastine, vincristine, and VP 16.

b) Change in consciouness – amethopterine, L-asparaginase,

cytosine arabinoside, ifosfamide, interferon, mitotane, ad procarbazine.

c) Seizures – cisplatin, interferon, hydroyurea, procarbazine, and

vincristine.

d) Cerebellar ataxia – cisplatin, fluorouracil, and Ara-c.

e) Ototoxicity – carboplatin.

f) Retinopathy – tamoxifen.

Pulmonary Fibrosis or pulmonary interstitial disease. Causes =

amethopterine, BCNU, bleomycin, CCNU, methyl CCNU, cytosine

arabinoside, and myleran.

Treatment: This is often unsatisfactory. Large doses of steroids have

been felt to be beneficial by some.

Alopecia: Actinomycin, cyclophosphamide, daunorubicin,

doxorubicin, fluorouracil, interfereon alpha 2, mitoxanthrone, and

VP16.

Liver dysfunction: Amethopterin, androgens, BCNU, CCNU, methyl

CCNU, cyctosine arabinoside, DTIC, 6-mercaptopurine, mithramycin,

and 6-thioguanine.

Treatment: Stop agent or decrease dose,.

Skin ulceration with extravasation: Actinomycin D, daunorubicin,

doxorubicin, nitrogen mustard, vinblastine, and vincristine.

Treatment: Stop agent. Elevate arm. Intermittent ice packs for 8 to

12hrs.If extravasation severe, consider infiltrating area with saline and

injecting with hyaluronidase.

Marrow Toxicity: Actinomycin D, amethoptein, BCNU, carboplatin,

CCNu, methyl CCNu, chlorambucil, cisplatin, cyclophosphamide,

cytosine arabinoside, daunorubicin, doxorubicin, DTIC, fludarabone,

5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,

interferon, 6-mercaptopurine, mitomycin C, nitrogen mustard,

novatrone, procarbazine, streptozotocin, 6-thioguanine, vinblastine,

and VP-216.

Treatment: Stop or reduce doses, use hematopoetic growth factors.

Renal toxicity: Amethopterin, BCNU, carboplatin, CCNU, methyl

CCNU, cisplatin, mitomycin C, nephrotoxocity, and streptozotocin.

Treatment: Stop medication or reduce dosage.

Anaphylaxis: L-Asparaginase, bleomycin, and VP-16.

Treatment: Epinephrine, steroids

Cardiac injury: Cyclophosphamide, daunorubicin, doxorubicin, 5-

fluorouracil, and novantrone.

Treatment: Stop drug. Supportive care with diuretics, digitalis (not

very effective). Limit total dosage of medications (e.g., 450mg/m2

doxorubicin).

Dermatitis: Amethopterin, bleomycin, 5-fluorouracil,

hexamethylmelamine, hydroxyurea, mitotane, and procarbazine.

Treatment: (1) Stop drug

(2) 25-50mg benadryl PO every 6 hours for itching.

(3} Topical agents for itching, and glucocorticoid creams

or ointments.

Fever: Bleomycin, cytosine arabinoside, interferon, mithramycin,

mitomycin C, and mitotone.

Treatment: (1) Stop drug

(2) Premedicate with acetaminophen

Syndrome inappropriate antidiuretic hormone: Cyclophosphamdie,

vinblastine, vincristine.

Treatment: (1) Stop medication

(2) Fluid restriction.7

CONCLUSION

Despite 20 years of active investigation, the role of

chemotherapy for head neck malignancies remains largely undefied

and continues to be an area for active investigation. Clearly, for

patients with recurrent and metastatic disease, palliation can be

achieve, with single agents methotrexate being the standard for SCC

H&N.

Primary chemotherapy still remains largely experimental, except

for patients with advanced respectable SCC H&N, new combinations

that can achieve greater than 50% complete response rtes with

acceptable toxicity remain the goal. The concurrent use of

chemotherapy and radiation appears promising with survival

advantages noted for patients with unrespectable SCC H&N. Organ

preservation without compromising survival has been noted for

advanced laryngeal primaries and is now under active investigation for

other sites of disease in the head and neck. The use of intra-arterial

chemotherapy may play a role in this regard, particularly for patients

with maxillary sinus tumors.

The area with the most promise is chemo-prevention, with the

retinoids showing an impact on reducing second primary aerodigestive

tract tumors. New chemopreventive agents and analogues are

currently being developed, with combined chemopreventive agent

trails forthcoming. Continued emphasis must concurrently be placed

on smoking cessation along with these trials.The most effective way of

reducing mortality and morbidity from oral cancer is early diagnosis

followed by adequate treatment.20

BIBLIOGRAPHY

1. Alton Brantely B.: Biology of tumours and Head and Neck

cancer chemotherapy. Laryngoscope.91:1181-1187, 1986.

2. Charles E. Riggs, John P. Bennett: Principles of cancer

chemotherapy.530-531.

3. Alan Mitchell Kramer: The role of chemotherapy in head and

neck malignancy: Oral and maxillofacial Surgery Clinics of

North America. 5: 303-314, 1993.

4. Donna J. Glover: Radiation therapy and chemotherapy

protectors and sensitizers. 634-638,1989.

5. Dorr, Von Hoff: Cancer Chemotherapy hand book. II

Edition.

6. Eugene N. Myers, James Y. Suen: Cancer of the head and

neck. Fourth Edition.504-506,2004.

7. Foley vose, Armitage: Concurrent Therapy in Cancer. 385-

387,1980.

8. Goodman & Gilman : Chemotherapy of Neoplastic

diseases.1230-1232.

9. Kimio: Chemotherapy and oral malignancies, 2000.

10.Langer, J.D., J.M. Henk: Malignant tumors of the mouth,

Jaw, and salivary glands.131-132.

11.Lawrence, D.R., P.N. Bennet: Clinical pharmacology. Fifth

Edition.p-191.

12.Margaret Barton, Gial M. Wilker: Cancer chemotherapy. A

Nursing approach.397-416.

13.Martin D. Abeloff, James O. Armitage: Clinical Oncology.

Third Edition. 301-302.