Monitoring of Suspected Adverse Drug Reactions in Oncology Unit ...

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701 

_____________________________________________________________Thesis Abstract 

Monitoring of Suspected Adverse Drug Reactions in Oncology Unit of 

an Urban Multispeciality Teaching Hospital 

Amartya De* 

BCDA College of Pharmacy &Technology, Hridaypur, Barasat, Kolkata – 700127, W.B., India 

________________________________________________________________________________________________ 

* Address for correspondence: amartyap.col30@rediffmail.com 

ABSTRACT 

Adverse drug reactions (ADRs) are a global problem and substantially add to the cost of healthcare. 

They are likely to be encountered more frequently in hospital in-patient settings where patients receive 

multiple drugs. Anticancer drugs are prone to cause ADRs and there is dearth of pharmacovigilance data 

on such drugs in the Indian context. Therefore the present study was planned to monitor suspected ADRs 

in the oncology unit of a tertiary care teaching hospital, in a focused manner, and to understand the 

strengths and limitations of cross-sectional observational pharmacovigilance activity for anticancer drugs. 

A total of 509 drugs were incriminated, with 507 being administered by intravenous route. The most 

frequently incriminated drugs (those accounting for more than 5% of the total count of 509) were 

cisplatin, 5-fluorouracil, cyclophosphamide, paclitaxel, carboplatin and doxorubicin, in that order. Of the 

296 events, 9.83% were severe and 5.76% were serious. However, there were no fatal or life-threatening 

events. Causality assessment showed a certain association for 1.84% of the events, probable or likely 

association for 85.28% and possible association for 12.88%. There was no event less convincing than 

possible. The frequency of ADRs, easy identification of acute treatment-emergent events and the 

cooperation offered by patients in the clinical surroundings were the strengths of this method of 

monitoring for suspected ADRs. On the other hand, the limitations were the inability to identify ADRs that 

require serial clinical or laboratory monitoring and the lack of scope for picking up chronic or delayed 

ADRs. 

Key Words: Pharmacovigilance, adverse drug reactions, Iatrogenesis, drug safety. 

INTRODUCTION 

As per the World Health Organization (WHO), an adverse drug reaction (ADR) is ‘Any response to a 

drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, 

diagnosis, or therapy of disease, or for the modification of physiological function’ [WHO, 1972]. This 

definition therefore excludes effects of wrong drug, medication errors e.g. overdose, and defective drug i.e. 

product not conforming to specifications. 

An adverse event, on the other hand, is any undesirable experience associated with the use of a medical 

product in a patient. This definition includes reactions from medications as well as events occurring due to 

prescribing, preparation, dispensing, or administration errors. It could also include therapeutic failures. 

Since adverse drug reaction implies that the drug itself is the cause of a particular undesirable event, an 

adverse event becomes a reaction only if a causal relation with the suspect drug can be reasonably 

established. 

There are several ways of classifying adverse reactions, but the simplest possibly is to separate them 

into Types A and B as proposed by Rawlins and Thompson in 1977. Type A reactions are qualitatively 

normal but augmented responses to drugs, such as bradycardia with beta-adrenoreceptor blockers or 

hypoglycemia with sulfonylurea antidiabetic drugs. Many Type A reactions are due to a property of the 

drug which is unrelated to its primary therapeutic effect, such as galactorrhea with domperidone and dry 

month with phenothiazines. Type A reactions are usually predictable from the pharmacology of a drug, 

they are generally dose dependent and although, they are relatively common, they do not generally cause 

serious illness. Type B reactions in contrast, are bizarre effects that are unpredictable on the basis of a 

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drug’s known pharmacology. Examples include hemolysis with methyldopa, or thrombocytopenia with 

angiotensin converting enzyme inhibitors. Continuous post-marketing surveillance is often required before 

many Type B reactions can be identified. They are generally due to hypersensitivity or identified 

‘idiosyncratic’ mechanisms. 

Adverse drug reactions (ADRs) are not so silent threat to the health of a nation. During the last decade it 

has been demonstrated by a number of studies that medicine induced morbidity and mortality is one of the 

major public health problems. With the quantal leap in the number of drugs being marketed it is becoming 

increasingly important to monitor ADRs. Worldwide, efforts are ongoing to identify ADRs, monitor drug 

use and improve prescribing habits of practitioners to ultimately make use of medicines safer. 

It has been estimated that ADRs are 4th to 6th largest cause of mortality in the USA [Lazarou J et al, 

1998]. They contribute to the death of several thousands patients each year, and many more suffers from 

their ADRs [Kelly WN, 2001; Somberg JC, 1998]. The percentage of hospital patients suffering ADRs, in 

some surveys, is more than 10% e.g. Switzerland 17%, France 14.7%, etc.[Vervloet D & Durham S, 1998]. 

ADRs often impose a high financial burden on healthcare due to hospitalization of patients with drug 

related problems. Some countries spend up to 15 to 20% of their hospital budget dealing with drug 

complications [Gautier S, 2003]. 

Unfortunately, there is very limited information available on ADRs in a developing country like India. 

Knowledge about ADR monitoring and reporting is lacking among health professionals in India. The 

reasons may be multiple – not sure about causality, considered too trivial or common to report, not aware 

of the procedure to report, not aware of whom to report. The problem is aggravated by lack of adequate 

enforcement of legislation, large number of substandard and counterfeit products circulating in the market, 

and lack of access to independent sources of drug information. Thus, one may expect that the burden of 

ADRs, both medically and financially, is worse than in the developed countries. 

In this scenario, the Government of India has launched a National Pharmacovigilance Programme 

(NPVP) in November, 2004 [Bavdekar SB & Karande S, 2006]. The programme mission is to sensitize 

medical professionals to the concept and practice of ADR reporting. The operation has countrywide 

coverage through 2 zonal, 5 regional and several peripheral centers. Data is collected in the form of 

spontaneous ADR reports generated by physicians, either as treatment emergent symptoms complained of 

by the patient or signs detected during clinical examination. In addition to untoward medical events, any 

abnormal laboratory finding occurring during administration of the drug is also captured. However, reports 

collected are not necessarily causally related to the drug with certainty. 

Against this backdrop, the current project work was conceived to monitor suspected ADRs with 

anticancer drugs, a therapeutic category prone to ADRs, in a focused manner and contribute to the overall 

knowledge base regarding ADRs in the country. The work was carried out in collaboration with an institute 

already engaged in ADR monitoring as part of the NPVP. 

Terminology of adverse drug reactions [Vervloet D & Durham S, 1998] 

As mentioned in the introduction, an adverse reaction to a drug has been defined as any noxious or 

unintended reaction to a drug that is administered in standard doses by the proper route for the purpose of 

prophylaxis, diagnosis, or treatment. Some drug reactions may occur in every one, whereas others occur 

only in susceptible patients. 

Some other relevant terminology in vogue in this connection is: 

 

 

 

 

 

Drug overdose : Toxic reactions linked to excess dose or impaired excretion or to both. 

Drug side effect : Unintended, usually undesirable, pharmacological effect at recommended doses. 

Drug intolerance : Reactions that occur only in susceptible subjects; a low threshold to the normal 

pharmacological action of a drug. 

Drug idiosyncrasy : A genetically determined, qualitatively abnormal reaction to a drug related usually 

to a metabolic or enzyme deficiency. 

Drug allergy : An immunologically mediated reaction, characterized by specificity and transferability 

by antibodies or lymphocytes, and recurrence on re-exposure. 



 

 

Pseudoallergic reactions : A reaction with the same clinical manifestation as an allergic reaction but 

lacking immunological specificity. 

Drug interactions : Influence of a drug on the effectiveness or toxicity of another drug. 

Magnitude of the problem of adverse drug reactions[Gough S, 2005; Impicciatore P, et al, 2001; 

Vervloet D & Durham S, 1998; Knowles S, et al, 1997; Einarson TR, 1993] 

Many studies have attempted to determine the incidence or frequency of ADRs both in hospital and in 

community. The estimates of incidence observed in these studies vary widely and these probably reflect 

differences in the methods used to detect and report ADRs. It is also apparent that a higher yield of adverse 

reactions is found when investigators undertake both detection and monitoring themselves, rather than 

relying on others to notify them of potential cases. Most studies have found that around 5% of hospital 

admissions are attributable to ADRs, that 10 to 20% of patients will experience an adverse reaction during 

their stay in hospital, and that as a result, the length of stay may be increased in upto 50% of these patients. 

Drug related deaths have been reported to occur in 0.1% of medical in-patients and in 0.01% of surgical 

patients. In general practice, the incidence of adverse reactions is reported to be around 2%, although 

studies in hospital out-patients have suggested that the incidence of ADRs may be as high as 30%. Despite 

the problems involved in accurately determining the incidence of ADRs, it is generally accepted that they 

increase hospital admission rates, increase morbidity and mortality and thus significantly increase health 

care costs. A further problem is the fact that drug induced disease is rarely specific and almost invariably 

mimics naturally occurring disease. Few ADRs are associated with diagnostic clinical or laboratory 

findings which demarcate them from the features of a spontaneous disease. Moreover, many of the 

subjective effects frequently attributed to drugs (such as headache, nausea, and dizziness) occur commonly 

in otherwise healthy individuals taking no medication. 

Classification of adverse drug reactions [Khong TK & Singer DR, 2002; Meyboom RH, 1999] 

By onset of event 

 

 

 

By severity 

 

 

 

Acute : Within 60 minutes. 

Sub-acute : 1 to 24 hours. 

Latent : after 72 hours. 

Mild : Bothersome but requires no change in therapy or intervention. 

Moderate : Requires change in therapy, additional treatment, hospitalization, etc. 

Severe : Disabling or life threatening. 

General classification 

 

Type A : Reactions that are extension of usual pharmacological effect; often predictable and dose 

dependent; responsible for at least two thirds of ADRs. 

e.g. Propranolol and heart block, anticholinergics and dry mouth. 

 

 

 

Type B : Idiosyncratic or immunologic reactions; uncommon and unpredictable; less dosedependent. 

e.g. Chloramphenicol and aplastic anemia. 

Type C : Associated with long-term use; involves dose accumulation. 

e.g. Phenacetin and interstitial nephritis; antimalarials and ocular toxicity. 

Type D : Delayed effect (dose independent) carcinogenicity, immunosuppression, teratogenicity 



e.g. Fetal hydantoin syndrome and phenytoin. 

Types of allergic reactions [Guglielmi L, et al, 2006; Gruchalla R, 2000] 

Type I Immediate, anaphylactic. 

e.g. Anaphylaxis with penicillins. 

 

 

 

Type II : Antibody (IgG, IgM) dependent cellular toxicity. 

e.g. Methyldopa and hemolytic anemia. 

Type III : Serum sickness type; mediated by deposition of antigen antibody complex. 

e.g. Procainamide and drug-induced lupus. 

Type IV : Delayed hypersensitivity type. 

e.g. Contact dermatitis. 

Serious adverse drug reaction [Knowles S & Shapiro L, 1997] 

Any adverse experience that results in one of the following outcomes: death, a life-threatening 

experience, in-patient hospitalization or prolongation of existing hospitalization, a persistent or significant 

disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in 

death, be life-threatening or require hospitalization may be considered as serious adverse event when, based 

upon appropriate medical judgment, they may jeopardize the subject and may require intervention to 

prevent one of the outcomes listed. 

Delayed adverse effects of drugs 

A number of adverse effects may only become apparent after long-term treatment, such as the relatively 

harmless melanin deposits in the lens and cornea that are seen after years of phenothiazine treatment (and 

which should be distinguished from pigmentary retinopathy). Other examples include the development of 

vaginal carcinoma in the daughters of women given diethylstilbestrol during pregnancy for the treatment of 

threatened abortion; and immunosuppressives and chemotherapeutic agents which can induce malignancies 

that may not be apparent until years after treatment has been given. 

Adverse effects associated with drug withdrawal 

Some drugs cause symptoms when treatment is stopped abruptly, for example the benzodiazepine 

withdrawal syndrome, rebound hypertension following discontinuation of antihypertensives such as 

clonidine, and the acute adrenal insufficiency that may be precipitated by the abrupt withdrawal of 

corticosteroids. These are all Type A reactions. 

Common therapeutic groups causing adverse drug reactions 

These are as follows: 

• Antibiotics 

• Antineoplastics 

• Anticoagulants 

• Antiarrythmics 

• Oral hypoglycemics 

• Antihypertensives 

• Non-steroidal anti-inflammatory drugs (NSAIDs) / Analgesics 



• Diagnostic agents 

• CNS drugs 

It has been estimated that the above types account for 69% of fatal ADRs. 

Body systems commonly involved in adverse drug reactions 

These are as follows: 

• Hematologic 

• Central nervous system 

• Dermatologic (Allergic reactions in particular) 

• Metabolic 

• Cardiovascular 

• Gastrointestinal 

• Renal/Genitourinary 

• Respiratory 

Detection and monitoring of adverse drug reactions 

[Gough S, 2005; Atuah KN, et al, 2004; Klepper MJ, 2004; Bates DW, et al, 2003; Arnaiz JA, et al, 

2001; Evans JM and MacDonald TM, 1999; Meyboom RH, 1997; Wood L and Martinez C, 1994] 

By the time a drug is marketed it will usually have been given to an average of 2500 people, and it is 

likely that clinical trials will have picked up the most common ADRs. 

It is unlikely that Type B reactions with an incidence of 1 in 500 or less, will have been identified by 

the time a drug becomes available for widespread use. It is only after much wider use that rare reactions, or 

those which occur predominantly in certain subgroups within the populations, such as the elderly, are 

detected, and it is therefore essential to monitor safety once a drug has been marketed. 

Pharmacovigilance is defined as the science and activities relating to the detection, assessment, 

understanding and prevention of adverse effects or any other possible drug-related problems’ [WHO, 

2006]. Various strategies of pharmacovigilance include: 

Case reports and case series 

The publication of single case reports, or case series, of ADRs in the medical literature is an important 

means of detecting new and serious reactions, particularly Type B reactions. Case reports have, in the past, 

been vital in alerting the medical profession to several serious adverse reactions. Examples include 

oculomucocutaneous syndrome associated with practolol, and halothane induced hepatitis. 

Case-control studies 

Case control studies compare drug usage in a group of patients with a particular disease with use 

amongst a matched control group who are similar in potentially confounding factors, but who do not have 

the disease. Examples of associations that have been established by case control studies are Reye’s 

syndrome and aspirin, and the relationship between maternal diethylstilbestrol ingestion and vaginal 

adenocarcinoma in female offspring. 

The case control method is an effective means for confirming whether or not a drug causes a given 

reaction once a suspicion has been raised. 

Cohort studies 

Cohort studies are prospective studies which study the fate of a large group of patients taking a 

particular drug. Cohort studies include ad hoc investigations set up to investigate specific problems (often 

sponsored by pharmaceutical companies), prescription event monitoring and a variety of record linkage 

schemes. 



Spontaneous reporting schemes 

The thalidomide tragedy led to the institution, in many countries, of national schemes for voluntary 

collection of adverse drug reaction reports, of which the UK Committee on Safety of Medicines adverse 

reactions reporting scheme (outlined later) is one. Spontaneous reporting schemes cannot provide estimates 

of risk because the true number of cases is invariably under estimated and the denominator is not known. 

To be successful, reports should be made despite uncertainty about a causal relationship, irrespective of 

whether or not the reaction is well recognized and regardless of other drugs having been giving 

concurrently. 

The development of pharmacist reporting of adverse drug reactions 

[van Grootheest AC and de Jong-van den Berg, 2005; Major E, 2002; Davis S, et al, 1999; Lee A, et al, 

1997] 

Adverse reactions cause considerable morbidity and mortality and have a significant impact on health 

care costs. Reports suggest that ADRs are responsible for 5% of all hospital admissions, with between 0.1 

and 0.3% of hospital patients suffering fatal ADRs. 

Following the thalidomide disaster in 1961, the Committee on Safety of Medicines was formed and the 

‘Yellow Card Scheme’ was introduced in the UK in 1964. The scheme is a spontaneous reporting system 

(based on yellow colored cards on which suspected ADRs are to be reported by health professionals) that 

was developed to act as an early warning system for the identification of ADRs. It is intended to provide 

information on the safely of a medicine throughout its lifespan. The success of the scheme is dependent 

upon the vigilance of health professionals. The yellow card scheme solicits reports on all serious reactions 

to all medicines licensed in the UK, as well as all reports on new ‘inverted black triangle’ medicines 

regardless of the seriousness of the reaction. A black triangle status is assigned to all new medicines and are 

described as being intensively monitored while this classification continues. The black triangle status 

remains in place until the safety/efficacy ratio that was established in premarketing clinical trials is 

adequately assessed. This period can be as short as two years but sometimes can last for upto five years. 

The British ‘Yellow card system’ is one of the most successful spontaneous ADR reporting systems in 

the world today. In the early 1990s, the number of reports received by the CSM was falling, particularly in 

the hospital setting. A pilot study to evaluate the potential contribution of hospital pharmacists was 

conducted in the Northern Region and showed a 45% overall increase in ADR reporting, with a 54% 

increase in the reporting of serious drug reactions. Hospital pharmacists became recognized contributors to 

the Yellow Card Scheme on 1 April 1997. In the first year of the scheme, hospital pharmacists reported a 

higher proportion of serious ADRs then doctors did, but fewer for black triangle drugs. Reporting was 

facilitated in hospitals where education on the scheme was provided, where there was a designated ADR 

Pharmacist and where there was a written procedure for reporting ADRs. 

From 1997 to 2002, the total number of reports submitted by pharmacists was 8,395, accounting for 

8.5% of the total UK reports for that period. There is, however, still reluctance to reporting which needs to 

be addressed through education and increasing awareness and ownership of the scheme. 

Prevention of adverse drug reactions – role of the patient [van Grootheest K and de Jong-van den Berg 

L, 2004; van Grootheest K et al, 2003; Egberts GPG, et al, 1996] 

The prevention of ADRs should be a collective responsibility of the pharmaceutical industry, the doctor 

and the patient. Patients themselves can play a significant role in the prevention of adverse reactions. In 

particular, ensuring a high level of compliance with medication instructions can maximize therapeutic 

effects and avoid or minimize the possible occurrence of potentially adverse reactions. Inadequate 

compliance can lead to toxicity or treatment failure (this is clearly exemplified in anticonvulsant, 

anticoagulant and immunosuppressive therapy) and consequently to increased treatment costs and / or 

possible fatal outcome for the patient. Patients should also reject the belief that there is a “Pill for every ill” 

and avoid indiscriminate self-medication and doctor hopping. 

Causality assessment of adverse drug reactions 

[Diemont WL, 2005; Merle L, et al, 2005; Brown SD Jr and Landry FJ, 2001] 

The establishment of a causal relationship between specific drug and a clinical event is a fundamental 

problem in pharmacovigilance. Firstly, ADRs frequently mimic other disease and secondly many of the 

symptoms attributed to ADRs occur commonly in healthy individuals who are not taking any medication. 

There is some evidence that patients themselves are capable of correctly distinguishing probable ADRs, 



from other types of adverse clinical event. When a patient is prescribed a new drug he should also be given 

information on possible ADRs, including how to recognize them, and what to do if one occurs. For 

instance, patients taking warfarin should know that if they notice unusual bruising or black stools, they 

should seek medical help at once. 

When a suspected adverse reaction has occurred it may be helpful to try to assess whether it is 

definitely, probably or possibly due to the drug. The Naranjo’s adverse drug reactions probability scale 

criteria [Naranjo CA, et al, 1992] has been extensively used for this purpose. This is based on ten questions 

each of which can be answered as ‘Yes’, ‘No’ or ‘Don’t know’ and the responses are scored as follows: 

1) Are there previous conclusive reports on this reaction? 

Yes [+1] No [0] Don’t know [0] 

2) Did the ADR appear after the suspected drug was administered? 

Yes [+2] No [-1] Don’t know [0] 

3) Did the ADR improve when the drug was discontinued? 


4) Did the ADR appear with re-challenge? 

Yes [+2] No [-1] Don’t know [0] 

5) Are there alternative causes for the ADR? 

Yes [-1] No [+2] Don’t know [0] 

6) Did the reaction appear when placebo was given? 

Yes [-1] No [+1] Don’t know [0] 

7) Was the drug detected in blood at toxic levels? 


8) Was the reaction more severe when the dose was increased, or less severe when the dose was 

decreased? 


9) Did the patient have a similar reaction to the same or similar drug in any previous exposure? 


10) Was the ADR confirmed by any objective evidence? 


The scores may range between –4 to +13 and the causality is assessed to be Definite if composite score is > 

9, Probable if between 5 to 8, Possible if between 1 to 4 and Unlikely if < 0. 

In our study, we have utilized the World Health Organization-Uppsala Monitoring Centre criteria for 

standardized case causality assessment, details of which have been provided in Annex 2. 

Review of major groups of anticancer drugs and their toxicities 

[Chu E et al, 2007; Brunton LL et al, 2006; Shepherd GM, 2003; Skeel TR, 1999] 

Nitrogen mustards and other alkylating agents (covalent DNA binding drugs) 

All of the alkylating agents form strong electrophiles through the formation of carbonium ion 

intermediates. This results in the formation of covalent linkages by alykylation of various nucleophile 

moieties. The chemotherapeutic and cytotoxic effects are directly related to the alkylation of DNA mainly 

through the 7 nitrogen atom of guanine although other moieties are also alkylated. The formation of one 

covalent bond with nucleophiles can result in mutagenesis or teratogenesis but the formation of two of 

these bonds through cross-linking can produce cytotoxicity. Bifunctional alkylating agents (those 



containing two reactive chloroethyl side chains) can undergo a second cyclization of the second side chain 

and form a covalent bond with another nucleophilic group. The second group could be a 7-nitrogen of 

another guanine or some other nucleophilic moiety. These bifunctional alkylating agents such as nitrogen 

mustard react with another nucleophilic moiety resulting in the cross-linking of two nucleic acid chains or 

the linking of a nucleic acid to a protein. This type of alteration could cause a major disruption in nucleic 

acid function. Cytotoxicity of bifunctional alkylators correlates very closely with interstrand cross- linkage 

of DNA. The ultimate cause of cell death related to DNA damage in not known. Some of the cellular 

responses produced include cell-cycle arrest, DNA repair and apoptosis or programmed cell death. The 

nucleophilic groups of proteins, RNA and many other molecules can also be subject to attack by the 

alkylating agents, although the exact result of these interactions is not known. 

The alkylating agents are generally considered to be cell cycle phase nonspecific. They also are known 

to be most cytotoxic to rapidly proliferating cells. Thus although DNA alkylation can occur anytime in the 

cell cycle, the biological consequences are most severe when this occurs during DNA synthesis. This is 

because cells exposed to the alkylating agents earlier, such as in G 1 phase, would have enough time to 

repair some of the DNA damage before the next DNA synthesis phase. Non-proliferating cells would have 

an even greater period for DNA repair to occur before irreversible damage occurs. Thus the alkylating 

agents are proliferation dependent but cell-cycle phase nonspecific. 

All of the nitrogen mustards are chemically unstable but they vary greatly in their degree of instability 

ranging from the highly unstable mechlorethamine to the highly stable chlorambucil and 

cyclophosphamide. The original alkylating agents such as mechlorethamine were very unstable and had 

to be administered rapidly to avoid breakdown. This, mechlorethamine must be given into a running 

intravenous (IV) infusion. 

Most of the current clinically useful alkylating agents have structural modifications that have produced 

stable compounds that can be given orally as well as parenterally. For example, cyclophosphamide can be 

administered orally or parenterally. However cyclophosphamide is unique in that it must be converted to an 

active form by liver microsomal enzymes. Cyclophosphamide was originally designed so that it would be 

preferentially activated in tumor tissue which is believed to contain high levels of enzymes that would 

convert it to an active form. Although selectivity is now known not to be achieved, the drug undergoes 

metabolic activation in the liver catalyzed by the cytochrome P 450 microsomal enzymes. One of the 

metabolites formed is believed to be active a s a cytotoxic agent while another metabolite, acrolein, is 

believed responsible for the cystitis produced by cyclophosphamide. Ifosphamide is a structural analog of 

cyclophosphamide. It is metabolized by the cytochrome P 450 system and it undergoes the same metabolic 

conversions as does cyclophosphamide. However, a smaller proportion of ifosphamide is converted to 

cytotoxic compounds and larger doses are used clinically as compared to cyclophosphamide. 

Therapeutic uses: 

The nitrogen mustards can be used for treatment of a variety of tumors ranging from leukemias to solid 

tumors. Mechlorethamine is used mainly to treat Hodgkin's disease (MOPP regimen). Chlorambucil is 

used almost exclusively in the treatment of chronic lymphocytic leukemia (CLL). Occasionally it has been 

used to treat certain lymphomas. Melphalan has been used principally to treat multiple myeloma. The most 

commonly used alkylating agent is cyclophosphamide. It is an extremely versatile agent used in Hodgkin's 

disease and other lymphomas. In addition it is useful to treat acute lymphocytic leukemia (ALL) and a 

variety of solid tumors. It can be given in a variety of ways and dosages unlike many of the other nitrogen 

mustards. The indications for ifosphamide are similar to cyclophosphamide. It is used almost exclusively 

with mesna, a compound that inactivates the alkylating activity and helps prevent the cystitis associated 

with this drug. 

Toxicity: 

The dose limiting toxicity of all the nitrogen mustards is bone marrow depression. This is usually of a 

delayed nature. It is important to monitor leukocyte and platelet counts carefully during therapy with these 

drugs. All of the nitrogen mustards produce acute nausea and vomiting, and with some, such as 

mechlorethamine, the effect is quite severe. Cyclophosphamide frequently causes alopecia and a 

hemorrhagic cystitis. As mentioned above, this cystitis is attributed to formation of acrolein during the 

metabolism of cyclophosphamide. Its incidence can be reduced by ensuring good fluid intake and frequent 

voiding and can be prevented by coadministration of sulfhydryl scavenging compounds such as N- 

acetylcysteine or mesna. High dose cyclophosphamide is generally not used without mesna. 



Mechlorethamine, but not the other nitrogen mustards, will produce a severe necrosis if extravasated on 

the skin during administration. If extravasation occurs, the area should be infiltrated with isotonic sodium 

thiosulfite which reacts with the electrophilic drug derivatives. 

Busulfan has few pharmacological effects other than myelosuppression. This property is important in 

both its therapeutic use and toxicity. Busulfan is an atypical alkylating agent, although it is converted to a 

bifunctional alkylator. Its action is limited mainly to the myeloid cells. It is useful for the treatment of 

chronic myelocytic leukemia (CML) during the chronic phase of this disease. Its toxicity is mainly on the 

bone marrow where it is toxic mainly to the granulocytes. At high doses it does affect platelets and red 

blood cells and in some patients a severe pancytopenia will result. Also at high doses pulmonary fibrosis 

can occur. 

The nitrosourea class of alkylating agents appear to function as bifunctional alkylating agents but differ 

in both pharmacological and toxicological properties from the other alkylating agents. The nitrosoureas are 

converted non-enzymatically into a carbonium ion and an isothiocyanate molecule. The carbonium ion acts 

as a typical alkylating agent and is probably responsible for the cytotoxic action of the nitrosoureas. The 

isothiocyanate may interact with proteins and account for some of the toxic effects of these drugs. Of the 

nitrosoureas used currently, carmustine must be administered parenterally while lomustine and semustine 

can be given orally. All of them have short plasma half-lives. All of the nitrosoureas are very lipophilic and 

have very good penetration into brain tissue. This allows good therapeutic utility in various CNS 

neoplasms. They are used mainly for the treatment of Hodgkin's disease, meningeal leukemia and brain 

tumors. Occasionally they are used in the treatment of solid tumors such as lung, gastrointestinal and breast 

carcinomas in combination with other anticancer agents. The usual dose limiting toxicity is a delayed bone 

marrow suppression. They also produce acute nausea and vomiting. Carmustine can produce an unusual 

interstitial pulmonary fibrosis. 

Several other alkylating agents have been available over the years. Most of them are quite toxic and 

have been used only in special circumstances. Among them are dacarbazine, hydroxymethylmelamine, 

thiotepa and mitomycin C. Dacarbazine is probably the most widely used of the miscellaneous agents. It 

functions as a methylating agent after metabolic activation in the liver. It is employed in combination 

regimens for the treatment of malignant melanomas, Hodgkin’s disease and adult sarcomas. 

Antimetabolites 

Antimetabolites are structural analogs of naturally occurring compounds. They interfere with the 

production of nucleic acids, working through a variety of mechanisms including competition for binding 

sites on enzymes and incorporation into nucleic acids. Their are three categories of antimetabolites – 

antifolates, purine analogs and pyrimidine antimetabolites. 

The importance of folates in tumor cell growth was demonstrated in 1948 by Farber and colleagues 

when aminopterin was shown to produce remissions in leukemia. Antifolates produced both the first 

striking remissions in leukemia and the first cure of a solid tumor, choriocarcinoma. Although aminopterin 

was the first clinically useful folate, methotrexate was soon introduced in therapy and it has become the 

major folate used in cancer therapy. Trimetrexate is a recent introduction. 

Folic acid is an essential growth factor from which is derived a series of tetrahydrofolate cofactors that 

provide single carbon groups for the synthesis of RNA and DNA precursors such as thymidylate and 

purines. Folic acid must be reduced in two successive steps by the enzyme dihydrofolate reductase (DHFR) 

before it can function as a coenzyme. The fully reduced form is the one that picks up and delivers single 

carbon units in various metabolic processes. DHFR is the primary target of action of most folate analogs 

such as methotrexate. Inhibition of this enzyme leads to toxicity through partial depletion of cofactors 

required for the synthesis of purines and thymidylate. Methotrexate is a strong inhibitor of DHFR. It has a 

high affinity for the tumor cell enzyme blocking the formation of tetrahydrofolate needed for thymidylate 

and purine synthesis. Cell death probably results from inhibition of DNA synthesis. As with most 

antimetabolites methotrexate is only partially selective for tumor cells and is toxic to all rapidly dividing 

normal cells such as those of the gastrointestinal epithelium and bone marrow. 

Several factors influence the effectiveness of methotrexate treatment. Included among them are factors 

that concentrate the drug intracellularly such as transport and conversion to the higher molecular weight 

polyglutamates that are preferentially retained within the cell. Also important are changes in the amount 

and structure DHFR. Changes in the latter will influence methotrexate binding and determine how well the 

drug is able to inhibit nucleotide synthesis. The major mechanisms of resistance are decreased drug uptake, 



amplification of DHFR gene and thus an increase in the target enzyme, mutations in the DHFR gene, and 

decreased ability to form methotrexate polyglutamate inside cells. 

Methotrexate can be administered by several different routes including chronic oral, intermittent oral or 

high-dose intravenous and intrathecal. Its absorption from the gastrointestinal tract depends on the dose, 

with large doses being only partially absorbed while low doses are efficiently absorbed. These differences 

are most likely due to dependence on a saturable folate carrier. At high doses methotrexate is most likely 

taken up by passive diffusion. Only a small percentage crosses into the cerebrospinal fluid (CSF), thus 

necessitating intrathecal administration for the treatment of tumor cells in the CNS. Approximately 50% of 

the methotrexate is bound to plasma proteins thus there is the distinct possibility of drug interactions with 

drugs that are also significantly bound to plasma proteins. Metabolism is usually minimal although after 

administration in high dose 7-hydroxymethotrexate is formed which is potentially nephrotoxic. Elimination 

is primarily renal and there is a clear relationship between serum levels of the drug and toxicity. 

Methotrexate is useful for the treatment of several different tumors. It is the drug of choice for 

gestational choriocarcinoma and related trophoblastic tumors of women where cures are obtained in a 

substantial number of cases. In this cancer, it is usually used in combination with dactinomycin. In the 

treatment of ALL in children, it is used for the maintenance of remissions. It is however of limited value for 

adult leukemias. It has also been used for the treatment and prevention of leukemic meningitis where it is 

given by intrathecal administration. Finally, high dose methotrexate along with leucovorin rescue is used 

for the treatment of osteogenic sarcoma and leukemias and lymphomas. 

The primary toxic effects are against the rapidly dividing cells of the bone marrow and gastrointestinal 

epithelium. The severity of the clinical effects depends largely on the duration of exposure to inhibitory 

levels of the drug. All of the stem-cell types of the marrow can be affected to produce leukopenia, 

thrombocytopenia and with long-term administration, anemia. Methotrexate therapy must therefore be 

modified according to the patient’s hematological status and leukocyte and platelet counts must be 

carefully monitored. Mucositis is one of the earliest signs of toxicity and its appearance indicates that the 

dose must be reduced or other serious toxicities will occur. If diarrhea and ulcerative stomatitis occur, 

therapy with the drug must be stopped. Methotrexate causes kidney damage which is a frequent 

complication of high dose therapy. Crystalline deposits of methotrexate and methotrexate derived materials 

have been found in the renal tubules which seems to account for most of the nephrotoxicity. Alkalinizing 

the urine to increase the solubility and ensuring good urine flow minimizes most of the nephrotoxicity due 

to high-dose methotrexate. Both low and high dose therapy can cause hepatotoxicity. High dose therapy 

results in elevated liver enzymes and low dose therapy produces a different type of hepatotoxicity which 

includes cirrhosis. Methotrexate can cause a reversible pulmonary syndrome which has been observed 

primarily in children undergoing maintenance therapy. Intrathecal and high-dose administration is 

accompanied by several types of neurotoxicity. These range from acute manifestations to long-term 

delayed toxicity in the form of encephalopathy. Nausea and anorexia frequently occur as acute side effects 

of methotrexate therapy. 

High dose methotrexate-rescue therapy: This involves administration of methotrexate at high doses along 

with leucovorin to rescue host tissues from the effects of the intense methotrexate therapy. The leucovorin 

provides the normal tissues with the reduced folate leucovorin which circumvents the inhibition of DHFR. 

The protection seems to be selective in that it does not alter the antitumor effect of methotrexate. 

Apparently, only the host cells are able to utilize the leucovorin. A more recent explanation is that of 

differential reactivation of DHFR in host and tumor cells. Beneficial effects have been observed in patients 

with osteosarcoma as well acute leukemia. 

The two major anticancer drugs in the purine antimetabolite category are 6-mercaptopurine (6-MP) 

and 6-thioguanine (6-TG). These drugs are analogs of hypoxanthine and guanine, respectively. Several 

other purine analogs are also now commercially available. Among these compounds are not only anticancer 

drugs but immunosuppressive agents (e.g. azathioprine) and antiviral compounds (e.g. aciclovir, 

ganciclovir). The antipurines can both inhibit nucleotide and nucleic acid synthesis and be incorporated into 

nucleic acid. Sometimes they can do both. 

Thiopurines work at multiple sites. They must first be converted into the nucleotide form in order to be 

active. This conversion is catalyzed by phosphoribosyltransferase enzymes. The nucleotide forms inhibit 

the first committed step in the de novo purine synthesis pathway, that catalyzed by phosphoribosyl 

pyrophosphate amidotransferase, and the key step in guanine nucleotide biosynthesis, catalyzed by inositol 



monophosphate (IMP) dehydrogenase. This latter site is the branch point where IMP is channeled towards 

either guanine nucleotide synthesis or adenine nucleotide synthesis. The mononucleotide derivatives are 

ultimately converted to triphosphates which can be incorporated into RNA and DNA. 

6-MP is an analog of hypoxanthine and thus can't be incorporated directly into DNA but must first be 

converted into a TG analog (thio-IMP to thio-GMP). Both drugs are thus incorporated as the same form. 

Although RNA incorporation can be significant most studies indicate that the biological effects of the drugs 

are due to incorporation into DNA. In humans receiving thiopurine therapy, increased alkaline phosphatase 

activity seems to be a major cause of resistance. This enzyme catalyzes the breakdown of the nucleotide 

form and could protect tumor cells by antagonizing the accumulation of thiopurine nucleotides. As would 

be expected there is cross-resistance between these two purine analogs. 

After oral ingestion, absorption of 6-MP is incomplete and variable, but it is still routinely given this 

way. It is widely distributed in the body with the exception of the CNS where little drug is found. As far as 

metabolism is concerned, 6-MP is methylated on the sulfhydryl group with subsequent oxidation of the 

methylated derivatives. In addition it is oxidized to thiouric acid by xanthine oxidase. This pathway is 

blocked by allopurinol. Therefore, if it used along with allopurinol the dosage of 6-MP must be reduced 

otherwise toxicity will be increased. 6-TG is also given orally although its oral absorption is slow. Unlike 

6-MP it is metabolized mainly to inorganic sulfate. There is no formation of thiouric acid with 6-TG. 

Unlike 6-MP, it can be used in combination with allopurinol without the dosage being reduced. 

Both drugs are used primarily in the treatment of leukemias. Response rates are higher in children than 

adults. 6-MP is used in the maintenance therapy of ALL and 6-TG in the treatment of acute nonlymphocytic 

leukemia. 

Toxicity: 

Bone marrow depression is dose limiting with both drugs. The maximum effect on the blood count may 

be delayed and it is important to discontinue these drugs temporarily if there is an abnormally large fall in 

the leukocyte count or abnormal depression in the bone marrow. Other major toxicities include nausea and 

vomiting and stomatitis. Hepatotoxicity is seen as jaundice in about 33% of patients treated with 6-MP. As 

mentioned above, 6-MP is a substrate for xanthine oxidase which converts it to 6-thiouric acid by 

oxidation. This appears to be an important route for inactivation of the drug. Allopurinol, a drug used to 

prevent the hyperuricemia and uricosuria that often follow marked cell kill consequent to leukemia therapy, 

inhibits this conversion. When 6-MP and allopurinol are used together, the dose of 6-MP is usually 

lowered. 6-TG is not extensively deaminated and only a small amount is converted to 6-thiouric acid. 

Therefore, no reduction in dosage is necessary with allopurinol. 

Chlorodeoxyadenosine and pentostatin are two newly introduced purine analogs which have good 

activity against certain types of leukemia. The presence of a halogen in the adenine ring of several purine 

analogs led to a group of compounds which resisted metabolic degradation by deamination. 2- 

chlorodeoxyadenosine (CdA) showed the greatest activity of these compounds. It was found to be an 

inhibitor of ribonucleotide reductase and consequently DNA synthesis. It also inhibited DNA strand 

elongation after incorporation into the DNA. It has been found to be very useful in the treatment of indolent 

B-cell lymphocytic leukemias such as hairy cell leukemia and chronic lymphocytic leukemia (CLL). Many 

of these have been resistant to other therapies. Additional studies have shown that this drug may be 

promising in lymphomas, and acute and chronic granulocytic leukemias also. The dose limiting toxicity is 

mild bone marrow depression. 

Pentostatin (2'-deoxycoformycin) is a natural product isolated from bacteria. It binds tightly to and 

inhibits the enzyme adenosine deaminase. Lack of this enzyme has been implicated in some 

immunodeficiency syndromes. It has significant activity in patients with B-cell CLL. Toxicities are varied 

and somewhat unpredictable. Lymphopenia is often encountered leading to infections. Acute renal failure 

and neurological toxicities are less common but have been reported to be life-threatening. 

Regarding, pyrimidine antagonists, there are several different compounds in this group but the principal 

members are the fluoropyrimidines and cytosine arabinoside. The most important fluoropyrimidines are 5- 

fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd or floxuridine). They are direct inhibitors of 

thymidylate synthetase, the key enzyme in thymidylate synthesis. Methotrexate in contrast is an indirect 

inhibitor of this enzyme through inhibition of DHFR. These agents produce multiple biochemical lesions 

all of which have the potential to be cytotoxic. 5-FU must first be converted to the nucleotide form to be 



active as a cytotoxic agent. The nucleotide (5'-FUMP) can be formed by several different pathways. FUMP 

can be incorporated into RNA and also can be converted to the deoxynucleotide (FdUMP). This latter 

reaction is crucial to the cytotoxic effects of 5-FU. FdUMP may also be formed by the direct conversion of 

FdUrd by thymidine kinase. FdUMP inhibits the enzyme thymidylate synthetase which leads to deletion of 

thymidine triphosphate (TTP), a necessary constituent of DNA. Ordinarily, thymidylate synthetase 

catalyzed the methylation of dUMP in a multistep process. When FdUMP is utilized, the process becomes 

inhibited at an intermediate step. A complex between the enzyme, the pseudosubstrate and the folate 

cofactor is formed. The complex dissociates very slowly and is sufficiently stable so that the enzyme no 

longer can catalyze the reaction. DNA synthesis is inhibited until the drug is removed and new enzyme 

synthesis occurs. Since FdUrd is converted to FdUMP directly in one step it is a more potent inhibitor of 

TMP synthetase than is 5-FU. It is often effective in the nanomolar concentration range. On the other hand 

5-FU will require micromolar concentrations to be effective and at such concentrations other active 

metabolites are formed, such as FUTP, which can become incorporated into RNA in place of UTP. 

Incorporation into RNA has resulted in observed effects on the function of both rRNA and mRNA. 

Although incorporation into RNA is much higher than incorporation into DNA, recent studies have shown 

this to occur also. However, the biological consequences of this are not known. It is most probable that the 

cytotoxic action of these drugs is not the same in all cell lines and that this heterogeneity is the basis for the 

wide variability in response to 5-FU. 

The oral absorption of 5-FU is erratic, so it is usually given parenterally either by IV bolus or by 

continuous infusion (IV or arterial). Administration by continuous infusion overcomes the problem of rapid 

disappearance of 5-FU from the circulation. Since these drugs work best if they are present during the S 

phase of the cell cycle their short time in the circulation would ordinarily present a problem as the plasma 

levels would greatly fluctuate. Protocols using continuous infusion were developed to overcome this 

potential problem. Metabolic degradation occurs particularly in the liver. 5-FU readily enters the CSF. 

5-FU is used to treat several common solid tumors. It produces partial responses in up to about 1/3 of 

patients with metastatic carcinomas of the breast and the gastrointestinal tract. Topically it has been used 

for the treatment of basal cell carcinomas and premalignant skin keratoses. 5-FU is used in many different 

combinations in order to enhance its activity. Some involve combination with other cytotoxic agents like 

methotrexate while others involve combination with agents that by themselves lack toxicity but modulate 

the cytotoxic effects of FU. Combination with leucovorin has been very successful as the leucovorin 

enhances formation of the ternary complex. Floxuridine is primarily used by continuous infusion into the 

hepatic artery for treatment of metastatic colon cancer. 

Toxicity: 

The toxicities of these two drugs are similar and somewhat dependent on the mode of administration. 

Anorexia and nausea are among the earliest toxicities seen. These are followed by stomatitis and diarrhea 

which are indicative of a sufficient dose being given. The frequency of effects varies with the treatment 

schedule employed. Stomatitis and diarrhea are the most common dose-limiting toxicities when continuous 

infusions are used. The major toxicity resulting from a bolus dose is bone marrow depression. This is 

manifested by leukopenia and somewhat less often by thrombocytopenia and anemia. The lowest blood 

counts occur at one to two weeks. Skin toxicity manifested by alopecia, thinning of the skin, nail changes, 

dermatitis and photosensitivity can also occur. 5-FU also produces an acute cerebellar syndrome in less 

than 1% of patients. This includes ataxia, nystagmus, slurred speech and dizziness. 

Cytosine arabinoside (cytarabine or ara-C) is an analog of 2'-deoxycytidine with the 2'-hydroxyl in a 

position trans to the 3'-hydroxyl of the sugar. The bases of polyarabinosides cannot stack normally as do 

the bases of polydeoxynucleotides. 

Ara-C is first converted to the monophosphate nucleotide (AraCMP) by deoxycytidine kinase. The 

monophosphate can then react with appropriate kinases to form the di- and triphosphate nucleotides. 

AraCTP is believed to be the key active component. Its accumulation causes potent inhibition of DNA 

synthesis in many cells. This nucleotide is a competitive inhibitor of DNA polymerases. Also, the 

triphosphate is a substrate for DNA polymerases and it is incorporated into the DNA. It apparently causes 

inhibition of DNA chain elongation when ara-C in incorporated at the terminal position of a growing DNA 

chain. Unlike most of the antimetabolites the effects of ara-C are directed almost exclusively towards DNA 

and it has little or no effect on RNA synthesis or function. The relative biological impact of DNA synthesis 



inhibition versus incorporation into DNA has been studied for several years now. The evidence indicates 

that synthesis inhibition is secondary to analog incorporation. However, the precise cause of cellular death 

by ara-C is not known. 

Cytarabine is very poorly absorbed after oral administration in humans. It is routinely given IV by 

continuous infusion, sometimes in high dose regimens. Intrathecal administration is also used for 

meningeal leukemia and lymphoma. Ara-C reaches the CNS reasonable well with CSF levels as high as 

40% of the plasma levels. It has a very short plasma half-life due to cytidine deaminase activity in liver and 

elsewhere, and its metabolites are renally excreted. Metabolism accounts for 70-90% of the Ara-C 

eliminated with most of the drug being excreted as ara-U. 

Ara-C is used primarily for the treatment of acute myeloid leukemia (AML) due to its potent 

myelosuppressive action. It is the single most effective agent for induction of remission in this disease and 

it is used primarily in combination with daunorubicin. It has occasionally been used to treat ALL and, in 

high doses, it has been used for non-Hodgkin’s lymphoma and CML. It is not active against solid tumors. 

Toxicity: 

The principal toxicity is bone marrow depression manifested as granulocytopenia and 

thrombocytopenia. Other toxicities include oral ulceration, nausea, vomiting and diarrhea, and peripheral 

neurotoxicity with high doses. Extra caution is needed when hepatic function is decreased. 

Fludarabine is a new nucleoside analog that has modifications in both the base and sugar moieties. 

Like ara-C it is metabolized to the nucleotide triphosphate by sequential action of several kinases. It then 

interferes with DNA synthesis by DNA polymerase inhibition and by incorporation into nascent DNA. 

Unlike ara-C this compound is much more likely to act as a chain terminator. It also apparently acts as an 

inhibitor of the proofreading exonuclease activity of DNA polymerase epsilon. Fludarabine has been shown 

to be very effective against CLL. It gives a response rate exceeding 80% in previously untreated patients. 

Moderate to severe myelosuppression occurs at therapeutic doses, while neurologic toxicity occurs 

especially at higher doses. 

Antitumor antibiotics (non-covalent DNA-binding drugs) 

These drugs interact with DNA in a variety of different ways including intercalation, DNA strand 

breakage and inhibition of the enzyme topoisomerase II. Most of these compounds have been isolated from 

natural sources and are antibiotics. However, they lack the specificity of clinically used antimicrobial 

antibiotics and thus produce significant toxicity. 

Actinomycin D (Dactinomycin) is the only actinomycin used clinically. This compound contains a 

phenoxasone ring and two cyclic pentapeptides as part of its structure. The phenoxasone ring is the 

chromophore moiety which imparts a red color to the drug. 

At low concentrations dactinomycin inhibits DNA directed RNA synthesis and at higher concentrations 

DNA synthesis is also inhibited. All types of RNA are affected, but ribosomal RNA is more sensitive. 

Dactinomycin binds to double stranded DNA, permitting RNA chain initiation but blocking chain 

elongation. Binding to the DNA depends on the presence of guanine. X-ray crystallography studies show 

that in the dactinomycin-DNA complex the phenoxasone ring lies between two deoxyguanosine molecules 

and strong hydrogen bonds connect the 2-amino group of guanine and the threonine residues in the 

polypeptide side chains of the drug. There is a very tight binding of the drug with the DNA and thus a very 

slow dissociation. This apparently reflects the intermolecular hydrogen bonds. Apparently the tight binding 

of the dactinomycin prevents unwinding of the DNA to facilitate its interaction with RNA polymerase. This 

prevents the synthesis of RNA by the DNA dependent RNA polymerase and this blockade is responsible 

for the cytotoxic effect. The exact mechanism of the cytotoxicity is not clear but in some cells apoptosis is 

initiated. Dactinomycin is cytotoxic to cells in any phase of the cell cycle and it is probably equally toxic to 

exponentially growing cells and stationary cells. 

Dactinomycin is usually given IV and can cause severe local necrosis if extravasation occurs. 

Therefore, it should be administered into the tubing of a rapidly flowing IV infusion. The plasma half-life is 

very short, but tissue half-life is long (48 h) due to DNA binding. Only a small amount of the drug is 

known to be metabolized. Urinary and fecal excretion of the drug is prolonged. In humans it does not 

appear to enter into the CNS . 



Dactinomycin is used mainly in the treatment of pediatric solid tumors (e.g. Wilm's tumor, 

rhabdomyosarcoma). It is also an alternative drug for choriocarcinoma when methotrexate can't be used 

because of resistance. The treatment of several solid tumors utilizes combination therapy with 

dactinomycin and radiotherapy. There seems to be an improved antitumor effect when the two are used in 

combination. 

Toxicity: 

The primary and dose limiting toxicity of dactinomycin is bone marrow depression. The leukocyte 

count and usually the platelet count are depressed with a trough after one to two weeks. Also nausea, 

vomiting, malaise, ulceration of the oral mucosa and gastrointestinal tract and acneiform eruptions of the 

skin occur. The nausea, vomiting and malaise begin several hours after treatment and last for as long as a 

day. If given to a patient who has had radiation treatment, a ‘recall’ effect may be observed i.e. when the 

drug is administered, the patient may develop a reaction in normal appearing tissue that was included in the 

field of radiation. 

The anthracycline antibiotics, like doxorubicin, daunorubicin, idarubicin and epirubicin, are among 

the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid 

tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemias. They all 

contain a four-membered anthracycline nucleus attached to a sugar molecule. Daunorubicin and 

doxorubicin are identical except for the presence of a hydrogen or hydroxyl at the 14 position of the 

anthracycline ring. Idarubicin is 4-demethoxy-daunorubicin. This minor structural modification at position 

4 of the chromophore ring makes the drug more lipophilic giving it a longer half-life. 

The anthracyclines all bind to double-stranded DNA. In human chromosome preparations treated with 

anthracyclines the bound drug is observed as well-defined, orange-red fluorescent bands. This interaction 

with DNA is by intercalation. If the structure of the anthracyclines is modified so that the binding to DNA 

is altered their is usually a decrease or loss of antitumor activity. However, the pathways leading to 

cytotoxicity are not all that clear. Inhibition of DNA and RNA synthesis is not though to be critical for 

cytotoxicity as it only occurs at high drug concentration. 

Breakage of the DNA strand can occur. This is believed to be mediated either by the enzyme DNA 

Topoisomerase II or by the formation of free radicals. Inhibition of the enzyme topoisomerase II, for 

example, can lead to a series of reactions leading to double strand breaks in the DNA. Temporary doublestrand 

breaks are induced by topoisomerase II in the course of its normal catalytic cycle, by formation of a 

cleavable complex. Disruption of this complex, which results in a permanent double-strand break, occurs 

infrequently in the absence of drugs. Inhibitors of topoisomerase II cause the cleavable complex to persist, 

thereby increasing the probability that the cleavable complex will be converted to an irreversible doublestrand 

break. Anthracyclines can also cause the formation of reactive oxygen species that then cause 

predominantly single-strand breakage. The anthracycline chromophore contains a hydroxyquinone, which 

is a well-described iron chelating structure. The drug-iron-DNA complex catalyzes the transfer of electrons 

from glutathione to oxygen, resulting in the formation of active oxygen species. 

All three anthracyclines are administered IV since the glycosidic bond would be split in the 

gastrointestinal tract making these drugs inactive if given orally. The anthracyclines are very irritating to 

tissue on extravasation. Thus, they are usually given into the tubing of a rapidly flowing IV infusion. These 

drugs are rapidly cleared from the plasma. The metabolic pathways of the anthracyclines are very similar. 

They are eliminated by metabolic conversion to a variety of less active or inactive metabolites by liver 

enzymes. A major pathway is conversion to the alcohols daunorubicinol and doxorubicinol which also have 

cytotoxic activity like their parents. This reduction is catalyzed by cytoplasmic NADPH-dependent 

reductase. Daunorubicin is a better substrate for this enzyme than is doxorubicin; thus after a few hours the 

alcohol is the principal circulating form of this drug while with doxorubicin the parent drug is the principal 

circulating form. Glycosidases also act on the parent drugs as well as the metabolites. Since the 

anthracyclines are detoxified in the liver, patients with impaired hepatic function risk severe toxicity and 

the dosage must be reduced. 

Daunorubicin has limited use. It is employed in treatment of ALL and AML. Doxorubicin has a much 

broader range of use. It is most active against solid tumors, particularly breast cancer. Other solid tumors 

against which it has good activity are ovary, bladder, and lung carcinomas. It is also active in the treatment 

of Non-Hodgkin's lymphoma and Hodgkin's disease. Idarubicin appears to be as effective as daunorubicin 

in combination treatment of AML with perhaps more efficacy in patients less than 60 years old. 



Toxicity: 

The toxic effects of the anthracyclines are similar. They frequently cause nausea and vomiting and 

patients may experience anorexia and diarrhea. The drugs and their metabolites may color the urine red for 

one or two days after administration. Bone marrow depression is dose-limiting and occurs in 60%-80% of 

patients. This is seen primarily as leukopenia which reaches a low point at approximately one to two weeks. 

Thrombocytopenia and anemia may also occur but is not as severe. Stomatitis is dose related and may be 

severe. Alopecia also occurs in most patients but reverses when therapy is stopped. The anthracyclines 

potentiate the effects of radiation and enhancement of radiation reactions and radiation recall effects on 

normal tissues have been seen. 

Cardiac toxicity is a peculiar adverse effect observed in both adults and children. Two types of reactions 

are observed: a) early, transient electrocardiographic changes, and b) a delayed progressive 

cardiomyopathy. Acute changes in the ECG, including tachycardia, extrasystolic contractions, and ST-T 

wave alterations, may occur in the week following drug administration. Arrhythmias generally reverse 

within a few hours, and the ST segment and T-wave abnormalities usually reverse in 1 or 2 weeks after a 

single dose. Pathological studies of patients who have died of congestive heart failure show a decrease in 

the number of cardiac muscle cells and signs of degeneration in the remaining cells. It is thought that the 

sarcoplasmic reticulum is the critical site of anthracycline induced damage within the myocardial cell. The 

cardiomyopathy is usually fatal. 

There is now a great deal of evidence that the myocardial damage produced by these drugs is due to 

production of reactive oxygen species, in particular the hydroxyl radical. These radicals are generated from 

redox cycling of the anthracycline quinone, which can undergo one electron reduction to the semiquinone 

or two electron reduction to the corresponding dihydroquinone derivative. The semiquinone reacts rapidly 

with oxygen to generate superoxide anion. Superoxide anion can dismutate to peroxide, which reacts with a 

number of species to produce hydroxyl ion. The heart may be especially prone to anthracycline toxicity 

because it contains lower levels of critical detoxifying enzymes (e.g. catalase and superoxide dismutase) 

than other organs such as the liver. It has been shown that doxorubicin administration leads to lipid 

peroxidation in cardiac tissue and that this process can be blocked by free radical scavengers such as alphatocopherol. 

However, free radical scavengers were found to be unsuccessful at controlling cardiac toxicity 

in humans. More successful in humans were agents that acted as iron chelators, the rational being that 

anthracycline induced lipid peroxidation required iron. Dexrazoxane has recently been approved to prevent 

anthracycline induced cardiac toxicity. 

Anthracenediones like mitoxantrone are analogs of the anthracyclines. They lack the sugar moiety of 

the anthracyclines but retain the planar polycyclic aromatic ring structure that permits intercalation into 

DNA . They have shown impressive clinical activity but appear to cause less cardiac toxicity, most likely 

because they cannot produce quinone type free radicals. 

Mitoxantrone interacts with DNA by a high-affinity intercalation. It also produces a lower affinity 

binding as a result of electrostatic interactions. Intercalation of mitoxantrone into DNA interferes with the 

strand-reunion reaction of topoisomerase II, resulting in production of protein-linked double-strand DNA 

breaks. Although mitoxantrone is cytotoxic to cells throughout the cell cycle , cells in late S phase are more 

sensitive. Tumor cells resistant to mitoxantrone may show cross resistance to other natural products. 

The drug is given by IV infusion. It undergoes extensive binding to several different tissues and has 

been detected in tissues of patients who died several weeks to several months after receiving the last dose. 

Mitoxantrone has a much narrower range of therapeutic activity than the anthracyclines. It is used mainly 

for treatment of the leukemias (mainly AML) and lymphomas as well as advanced breast cancer. 

Toxicity: 

The primary acute toxicity is nausea and vomiting which is mild to moderate and occurs in about 40% 

of patients. It causes less nausea and vomiting and alopecia than does doxorubicin. Its major toxicities are 

bone marrow depression and mucositis. The bone marrow depression is of a delayed nature with the lowest 

counts being seen at one to two weeks. Patients should be warned of a possible blue-green coloration of the 

sclerae and nails as well as the urine. 

The bleomycins are a group of antitumor agents isolated from Streptomyces verticillus. The drug 

employed clinically is a mixture of compounds of complex structure containing about 70% bleomycin A 2 . 

Bleomycin is a metal binding water soluble glycopeptide antibiotic. Bleomycins have attracted interest 



because of their significant anticancer activity against certain solid tumors as well as the fact that they are 

minimally toxic to the bone marrow unlike most other anticancer agents. 

Bleomycin has been found to profoundly inhibit DNA synthesis while RNA and protein synthesis are 

much less affected. Bleomycin usually produces a block in the early G 2 phase of the cell cycle. The 

cytotoxic activity results from the ability to cause fragmentation of DNA. Single strand breaks occur 

predominantly but double strand breaks can also occur. Damage to the DNA correlates with the cytotoxic 

effect of the drug. Bleomycin has two major domains in its structure. One portion interacts with DNA and 

one binds iron. Both iron and oxygen are required for bleomycin to degrade DNA. The drug binds Fe ++ and 

binds DNA by intercalation between GT or GC bases, and acts as a ferrous oxidase (Fe ++ to Fe +++ ) resulting 

in production of oxygen free radicals that cleave DNA. 

Bleomycin is given parenterally, by IV or intramuscular (IM) routes. After administration relatively 

high concentrations of the drug are found in the skin and lungs. These organs are major sites of bleomycin 

toxicity. The primary route of excretion is renal and renal failure increases risk of toxicity. As much as twothirds 

of the drug is excreted in the urine within 24 hours. Bleomycin is rapidly inactivated by a tissue 

enzyme, bleomycin hydrolase, which cleaves the amide bond of the aminoalanine moiety. Its activity is 

higher in drug-resistant tumors. Particularly low levels of the drug inactivating enzyme are found in skin 

and lung, and consequently high levels of biologically active drug are found in these two tissues. 

Bleomycin is highly active against squamous cell tumors of the head, neck and lungs. It is also highly 

effective against germ cell tumors of the testis and ovary. It is often used to treat testicular carcinomas 

along with cisplatin and vinblastine. It is also active against Hodgkin's disease and other lymphomas where 

it is often included in the ABVD regimen. 

Toxicity: 

Bleomycin is marrow sparing and is not immunosuppressive and is therefore a useful compound to use 

in combination drug protocols. In the usual doses, the gastrointestinal tract , liver, kidneys and CNS are 

also not affected. Despite these advantages bleomycin is quite toxic – the most common toxicity involves 

the skin and mucous membranes. Oral mucositis is dose related and common in the more aggressive 

regimens. Alopecia occurs in about 10 - 20% of patients. Toxic reactions of the skin include 

hyperpigmentation, sclerotic changes with collagen infiltration, edema and erythema of the hands and feet. 

These cutaneous changes are reversible when the drug is discontinued. Pulmonary toxicity is dose-limiting 

and the most severe toxicity associated with use of bleomycin. Symptoms include dyspnea, tachypnea, and 

a nonproductive cough. Fine rales are heard at the base of the lungs and radiography often shows a patchy 

basilar infiltrate and in some cases fibrosis. The overall incidence of pulmonary toxicity is about 10% with 

fatalities occurring in about 1% of patients. There is an increasing incidence when the total dose of 

bleomycin goes above 400 units. It occurs more commonly in patients with compromised renal function 

and when the drug is used with cisplatin which is itself nephrotoxic. Extreme caution is employed in 

anyone having pre-existing pulmonary disease. 

Other toxicities of bleomycin include nausea, vomiting, anorexia, drug-induced fever and chills. These 

effects are usually seen within the first few hours of bleomycin therapy. About 1% of lymphoma patients 

develop allergic reactions similar to anaphylaxis. For this reason, lymphoma patients are given 2 units or 

less for the first 2 doses. If no acute reactions occur, the regular dosage schedule may be followed. 

Plicamycin (mithramycin) is an antibiotic derived from Streptomyces plicatus. It is part of a group of drugs 

referred to as chromomycin antibiotics. It is rarely used in cancer chemotherapy because of its toxicity. Its 

use is now limited to the treatment of hypercalcemia associated with malignancy where it is used in lower 

dosage than that used for the treatment of tumors. 

Platinum coordination compounds 

Cisplatin and carboplatin are among a number of platinum coordination complexes with antitumor 

activity. Recently oxaliplatin was put on the market. 

The platinum compounds are DNA cross-linking agents similar to but not identical to the alkylating 

agents. They exchange chloride ions for nucleophilic groups of various kinds. Both the cis and trans 

isomers do this but the trans isomer is known to be biologically inactive for reasons not completely 

understood. To possess antitumor activity a platinum compound must have two relatively labile cis- 



oriented cleaving groups. The principal sites of reaction are the N7 atoms of guanine and adenine. The 

main interaction is formation of intrastrand cross-links between the drug and neighboring guanines. 

Intrastrand cross-linking has been shown to correlate with clinical response to cisplatin therapy. DNAprotein 

cross-linking also occurs but this does not correlate with cytotoxicity. Cross-resistance between the 

two groups of drugs is usually not seen indicating that the mechanisms of action are not identical. The types 

of cross-linking with DNA may differ between the platinum compounds and the typical alkylating agents. 

Both cisplatin and carboplatin must be given parenterally, usually by IV injection. Cisplatin is given IV 

and by local introduction into the bladder and into the peritoneal space. After IV infusion it has a plasma 

half-life of about a half hour. This is followed by a period of slow decline. Cisplatin binds extensively to 

plasma protein. Carboplatin generates a reactive species much more slowly than with cisplatin. Thus its 

pharmacokinetic and toxicologic characteristics are different. Its plasma half-life is several fold longer that 

cisplatin. 

Cisplatin is one of the most frequently used anticancer drugs. It is an effective component of several 

different combination drug protocols used to treat a variety of solid tumors. Carboplatin was introduced in 

the hope that it could reduce the toxic potential of cisplatin. These drugs are used in the treatment of 

testicular cancer (with bleomycin and vinblastine), bladder cancer, head and neck cancer (with bleomycin 

and 5-FU), ovarian cancer (with cyclophosphamide or doxorubicin) and lung cancer (with etoposide). 

Cisplatin has been found to be the most active single agent against most of these tumors. 

Toxicity: 

The dose limiting toxicity of cisplatin is nephrotoxicity. This effect is dose related and is manifested by 

a decrease in creatinine clearance and electrolyte imbalances particularly hypomagnesemia. The 

nephrotoxicity is initiated by a decrease in proximal tubular function. Several approaches can reduce the 

nephrotoxicity. This includes the use of diuretics and hydration. Thiol containing compounds such as 

thiosulfate have also been shown to prevent the nephrotoxicity and may allow increased dosage of the 

cisplatin. 

Other toxic effects associated with this drug include bone marrow depression, severe nausea and 

vomiting, anaphylactic reactions and peripheral neuropathy. The degree of bone marrow depression is 

usually moderate. Nausea and vomiting occur in virtually all patients receiving cisplatin and this usually 

occurs within a short period of time. Cisplatin also causes a neurotoxicity that most commonly is seen as a 

peripheral neuropathy with sensations of numbness in the hands, feet, arms, and legs. In most cases 

stoppage of the drug allows the symptoms to disappear. 

With carboplatin the dose limiting toxicity is bone marrow depression. Other toxic effects include 

moderate nausea and vomiting and a low potential for ototoxicity and peripheral neuropathy. 

Microtubule inhibitors 

Microtubules are protein polymers that are responsible for various aspects of cellular shape and 

movement. The major component of microtubules is the polymer tubulin, a protein containing two nonidentical 

subunits (alpha and beta). These drugs act by affecting the equilibrium between free tubulin 

dimers and assembled polymers. 

The vinca alkaloids, vincristine, vinblastine and vindesine, are large complex molecules produced by 

the leaves of the periwinkle plant (vindesine is actually a semisynthetic vinca alkaloid). There are slight 

structural differences between the different vinca alkaloids but significant differences in therapeutic uses 

and toxicity. 

They are cell cycle phase specific agents and block cells in mitosis. Their biological activity is 

explained by specific binding to tubulin. Upon binding to vinca alkaloids, tubulin dimers are unable to 

aggregate to form microtubules. This effectively decreases the pool of free tubulin dimers available for 

microtubule assembly, resulting in a shift of the equilibrium toward disassembly. Formation of 

paracrystalline aggregates by vinca-bound tubulin dimers shifts the equilibrium even further toward 

disassembly and microtubule shrinkage. They block mitosis with metaphase arrest. Resistance can be due 

to alterations in tubulin structure resulting in changes in drug binding to the tubulin. 

The absorption of the vinca alkaloids is unpredictable and they are therefore usually given by IV 

infusion. They are very irritating to tissues. They are rapidly cleared from the plasma and excreted 

predominantly by the liver by a combination of hepatic metabolism and biliary excretion. Caution should 

be used with decreased hepatic function. Many vinca metabolites have been found in humans and animals. 



It is believed that a number of these are active cytotoxic agents and that the pharmacological effects of 

these drugs are still felt long after the parent drug is gone. Vincristine is eliminated much more slowly than 

the other two vinca alkaloids. 

Despite close similarity in structure the different vinca alkaloids have quite different therapeutic uses. 

Vincristine is used mainly in combination therapy for the induction of remission in childhood acute 

leukemias. Vincristine together with prednisone is the main therapy for induction of ALL. Complete 

remissions are obtained in 80 to 90% of patients. It is also used for the treatment of Hodgkin's and non- 

Hodgkin's lymphoma where it is part of several complex protocols. Here again vincristine therapy is very 

successful. On the other hand the most important clinical use of vinblastine is for metastatic testicular 

tumors where it is combined with bleomycin and cisplatin. Beneficial responses have also been obtained in 

the treatment of Hodgkin's and non-Hodgkin's lymphoma. In Hodgkin’s disease it has been used in place of 

vincristine providing similar antitumor activity with less neurotoxicity. Vindesine, the newest of the vinca 

alkaloids, has significant activity in the treatment of acute leukemia, blast crisis of CML and Hodgkin’s and 

non-Hodgkin’s lymphomas. 

Toxicity: 

Like the therapeutic uses the toxicities of these drugs is different. The dose limiting toxicity of 

vincristine is mainly peripheral neuropathy and other neurological toxicities. The most common symptom 

is a depressed Achilles tendon reflex which is usually followed by paresthesias in the extremities. 

Autonomic neuropathy often occurs early in the course of therapy resulting in abdominal pain, 

constipation, paralytic ileus, urinary retention and orthostatic hypotension. Unlike most antineoplastic 

agents, vincristine usually does not cause significant bone marrow suppression. Therefore it is often found 

in combination therapies with other drugs that are myelosuppressive. Gastrointestinal symptoms are also 

common with this vinca alkaloid. 

Unlike vincristine the other vinca alkaloids produce mainly bone marrow depression. Myelosuppression 

(primarily neutropenia) is the major toxicity of vinblastine while lymphopenia is the dose limiting toxicity 

of vindesine but neurotoxicity also occurs frequently. The neurotoxicity produced by these drugs is similar 

to vincristine but less common and less severe. 

Paclitaxel and docetaxel are taxane derivatives. Paclitaxel was first isolated from the bark of the Pacific 

Yew tree (Taxus brevifolia). Docetaxel is a more potent analog that is produced semisynthetically. 

In contrast to other microtubule antagonists, the taxanes disrupt the equilibrium between free tubulin 

and microtubules by shifting it in the direction of assembly, rather than disassembly. As a result, taxol 

treatment causes both the stabilization of microtubules and the formation of abnormal bundles of 

microtubules. The binding site for taxol is apparently distinct from the binding sites for colchicine, 

vinblastine and podophyllotoxin. 

Paclitaxel is usually given IV, preferably in 24 hour infusions, in order to prevent certain severe 

hypersensitivity reactions from occurring. Taxol binds extensively to plasma proteins. It undergoes 

significant cytochrome P 450 enzyme mediated hepatic metabolism to hydroxylated metabolites and this is 

believed to be the major mechanism of elimination. 

Taxanes have significant activity against ovarian cancer, breast cancer, carcinoma of the lung and head 

and neck carcinoma. Response rates in these cancers are fairly high. 

Toxicity: 

The major toxicity of these drugs is bone marrow depression with neutropenia the common doselimiting 

toxicity. Hypersensitivity reactions are also common. They are characterized by dyspnea, urticaria 

and hypotension. It is not clear at this time whether they are due to the vehicle in which taxol is given or the 

drug itself. Avoidance of bolus injections and short infusions can minimize this toxicity as can pretreatment 

with steroids or antihistamines. Mucositis is also common and is manifested as ulcers of the mouth and 

throat. Taxol also causes some reversible neurotoxicities, most often numbness and paresthesias in the 

hands and feet. 

Chromatin function inhibitors 

These constitute a class of drugs that owe their antitumor effects to disruption of chromosomal 

dynamics. Chromosomes are complex structures which undergo many changes in conformation and 



intracellular position during the cell cycle. Drugs that interfere with the proteins responsible for these 

changes are selectively toxic to proliferating cells. 

The topoisomerase inhibitor epipodophyllotoxins, etoposide (VP-16) and teniposide (VM-26), are 

semisynthetic glycosidic derivatives of podophyllotoxin, a natural compound produced in the roots of the 

May Apple (Podophyllum peltatum) plant. 

DNA in eukaryotic cells must be packed very efficiently to be able to fit into the nucleus. As a result, 

chromosomal DNA is twisted extensively and the activities of enzymes called topoisomerases are needed 

to permit selected regions of DNA to become sufficiently untangled and relaxed to allow transcription, 

replication, and other essential functions to proceed. To do this topoisomerases have the ability to break 

DNA strands and then to reseal these breaks after the topological changes have occurred. The clinically 

useful drugs in this class are inhibitors of topoisomerase II as they break both strands of DNA. The two 

drugs work similarly although teniposide is taken up by cells more rapidly and retained to a greater extent 

than etoposide. This may be because teniposide is more lipophilic than etoposide. These drugs form 

complexes with the topoisomerase II enzyme. This complex produces inhibition of the enzyme along with 

production of double stranded breaks in the DNA. Removal of the drug results in a rapid return of normal 

topoisomerase function. Arrest of cells occurs during the G 2 phase of the cell cycle. Early studies with these 

drugs led investigators to believe that their action was due to inhibition of microtubules. Although these 

drugs bind to tubulin they have no effect on microtubular function or structure at therapeutic 

concentrations. 

They are usually given IV as oral administration usually results in variable absorption. Approximately 

30-50% of etoposide is recovered as unchanged drug. Almost all of this is found in the urine with a small 

amount excreted in the bile. As much as 20% is recovered as metabolites. Both drugs are extensively bound 

to plasma proteins. 

Etoposide has shown activity against a variety of tumor types. Its greatest effectiveness is in the 

treatment of testicular tumors where it is effective against tumors resistant to treatment with other drugs. It 

is most effective when combined with bleomycin and cisplatin. Etoposide also has an important role in the 

treatment of small cell lung carcinomas where it is often combined with cisplatin. Teniposide appears to be 

effective for the treatment of ALL and childhood neuroblastomas as well as brain tumors in adults. 

Toxicity: 

The principal dose-limiting toxicity of these drugs is bone marrow depression, primarily leukopenia and 

thrombocytopenia. Nausea and diarrhea are common but not severe. Mucositis can be severe at higher 

doses. Other toxic effects seen include fever, chills, erythema. Allergic reactions have been noted in some 

patients. 

The camptothecins are a new class of chemotherapeutic agents with a novel mechanism of action 

targeting the nuclear enzyme topoisomerase I. The parent compound was isolated from the bark of a 

Chinese tree. This drug and its derivatives are inhibitors of topoisomerase I. Camptothecin itself is poorly 

soluble and causes significant toxicity. Several more soluble and less toxic derivatives are now available. 

One derivative with a lot of promise is irinotecan. It is one of the most active compounds available for the 

treatment of non-small cell lung cancer. Leukopenia and diarrhea are the most severe toxicities seen. 

Nausea and vomiting are common but manageable. Topotecan is a more recent introduction. 

Other anticancer drugs 

L-asparaginase was developed after it was noted that guinea pig serum suppressed the growth of 

lymphosarcomas in mice. The active serum component was found to be L-asparaginase, an enzyme that 

hydrolyzes L-asparagine to L-aspartate. The enzyme is effective because a few neoplastic cells have low 

levels of asparagine synthetase activity and require L-asparagine for growth. The use of L-asparaginase in 

cancer chemotherapy is limited to ALL to induce remission. Resistance rapidly develops to in most cancer 

cells. 

Hydroxyurea inhibits DNA synthesis. Specifically, it inhibits ribonucleotide reductase to block 

deoxyribonucleotide formation and DNA synthesis. This enzyme is closely related to proliferative status in 

cancer cells. It is involved in the de novo synthesis of all the precursors used in DNA synthesis. It converts 

ribonucleotide diphosphates to deoxyribonucleotides. Hydroxyurea is an S phase specific drug. Resistance 

is due to changes in the ribonucleotide reductase. The drug is well absorbed from the gastrointestinal tract 



and is routinely given orally. It is mostly eliminated through the kidney and should be used with caution in 

patients with compromised renal function. Hydroxyurea is used primarily in the treatment of 

myeloproliferative disorders including CML, polycythemia vera and essential thrombocytosis. It has also 

been used in a variety of solid tumors including carcinomas of the head and neck and those of the 

genitourinary system. Mild nausea and vomiting are experienced by most patients who receive 

hydroxyurea. The major dose-limiting toxicity is bone marrow depression mainly seen as leukopenia. This 

is reversible when the drug is discontinued. With large amounts of the drug stomatitis and gastrointestinal 

ulceration may occur. 

Tamoxifen is a competitive inhibitor of estradiol binding to the estrogen receptor. It acts as a complete 

antagonist in some systems and as an antagonist with partial agonist activity in other systems. By binding 

to the receptor it competes with the binding of endogenous estradiol and its major therapeutic effect reflects 

this antiestrogenic mechanism. It induces a change in the three-dimensional shape of the receptor inhibiting 

its binding to the estrogen response element on DNA. It is administered orally. It is metabolized by the 

cytochrome P 450 system to at least 6 metabolites some of which possess estrogen binding activity. These 

metabolites are conjugated principally as glucuronides and excreted in the bile. The metabolites have very 

long half-lives because of extensive protein binding in the plasma and efficient reuptake from the intestinal 

tract. Tamoxifen is used in the treatment of metastatic breast cancer. It is used alone for palliation of 

advanced breast cancer in women with estrogen receptor-positive tumors, and it is used for adjuvant 

therapy in certain types of early stage disease depending on the patient’s age, receptor status of the tumor 

and degree of nodal involvement. It may also have benefit as a preventive agent for breast cancer especially 

in women with risk factors. Tamoxifen is very well tolerated. The most frequent side effect is acute nausea 

and vomiting. This usually disappears after a few weeks and it can be reduced by taking the drug with 

meals. More chronic effects include hot flushes, transient and mild thrombocytopenia and leukopenia, 

vaginal bleeding, skin rashes, hypercalcemia, retinopathy and corneal opacities with high dose long-term 

therapy. 

Anastrozole is a selective non-steroidal aromatase inhibitor (aromatase is a P 450 enzyme that catalyzes 

various steps in the conversion of androgen to estrogen). It is used for the treatment of postmenopausal 

women with advanced breast cancer that has progressed during treatment with tamoxifen. 

PLAN OF WORK 

Study design and setting 

Cross-sectional observational study with subjects recruited from the in-patient facility of the medical 

oncology department of a tertiary care teaching hospital. 

Study time frame 

The study commenced in October, 2006 with preparatory work. The observation period was from mid- 

December, 2006 till mid-March, 2007. Data analysis and report preparation was done in the remaining 

period till mid-April, 2007. 

For the individual patient, the observation would be at a single time point only. 

Methods 

Initially, patients receiving cytotoxic anticancer drugs as part of their therapeutic regimens were 

screened from out-patient or in-patient departments by the attending clinicians. The screened patients were 

interviewed (i.e. a thorough clinical history taken), clinically examined as necessary, with the help of the 

attending clinicians and medical and laboratory records reviewed for those admitted. 

For capturing the data, rather than designing a Case Report Form de novo, the Suspected ADR 

Reporting Form of the National Pharmacovigilance Programme itself was used since this provides a 

standardized format. A copy has been provided in Annex 1. The form allows data to be organized in four 



sections – A. Patient information B. Suspected adverse reaction C. Suspected medications D. Reporter 

details. 

The data captured on the form was transferred to a computer database maintained at the Department of 

Pharmacology, Institute of Postgraduate Medical Education & Research (IPGME&R), Kolkata, which is 

one of the designated peripheral centers of the national programme. This database is in Microsoft Access. 

The data was subsequently analyzed through simple descriptive statistics. 

Causality assessment was done following the WHO-Uppsala Monitoring Centre standardized case 

causality assessment criteria [Olsson S, 1998; The Uppsala Monitoring Centre, 2005]. According to this 

WHO-UMC system, the causality terms may be certain, probable/likely, possible, unlikely, 

conditional/unclassified, unassessable/unclassified. 

RESULTS & DISCUSSION 

The current pharmacovigilance study screened suspected ADRs in patients of various malignancies 

admitted to in-patient unit of the Department of Radiotherapy (Oncology) of Medical College Hospital, 

Kolkata for anticancer chemotherapy. Of 300 reports collected, these 295 records were deemed to be 

evaluable. Rest were rejected for data inconsistencies. 

These 295 records were gathered over a period of 32 actual field-work days spread over 3 months, namely 

mid-Dec, 2006 to mid-March, 2007. The data pertains to 163 patients, out of 165 screened – this gives a 

98.79% incidence of adverse events in cancer patients hospitalized for receiving anticancer chemotherapy. 

During this period, the unit from which records were obtained had an average admission rate of 5.78 

patients per working day. 

The study population comprised 72 females (44.17%), the rest were males, except in one case were the 

gender data was inadvertently not recorded. The age and medication count profile of the patients are 

presented in Table 1. 

Table 1 

Age and medication count profile of 163 patients receiving anticancer chemotherapy and 

complaining of at least one adverse event. 

Mean Median Minimum Maximum IQR SD 

Age [years] 45.2 45 9 85 18.0 13.63 

No of anticancer drugs per 

patient associated with ADRs 

No of anticancer drugs per 

patient not associated with 

ADRs 

Total number of anticancer 

drugs received by a patient 

Abbreviations: IQR = Interquartile range; SD = Standard deviation 

1.67 2 1 2 1.0 0.472 

0.69 1 0 2 1.0 0.634 

2.36 2 1 4 1.0 0.574 

The patients were admitted for a multitude of malignancies as depicted in Table 2. Table 3 depicts the 

frequency of use of individual anticancer drugs that were suspected to be responsible for one or more 

adverse events in these 163 subjects. In 81 of the 295 adverse event instances (27.46%), only one 

anticancer drug was incriminated. In the rest 2 drugs were incriminated. In no case was more than 2 

incriminated to be possibly responsible for the same event. Of the 509 incriminated drugs, only in 2 

instances (0.39%) the route of administration was oral. In all the rest, suspected medications were 

administered by the intravenous route – either bolus dosing or as intravenous infusion. 



Table 2 

Disease profile (type / site of malignancy) of the 163 patients receiving anticancer chemotherapy and 

complaining of at least one adverse event. 

Type / site of malignancy Count Percentage 

1. Carcinoma breast 32 19.63 

2. Carcinoma lung 29 17.79 

3. Carcinoma ovary 19 11.66 

4. Carcinoma cervix 14 8.59 

5. Carcinoma rectum 11 6.75 

6. Carcinoma nose / nasopharynx / paranasal sinuses 6 3.68 

7. Carcinoma colon 5 3.07 

8. Carcinoma larynx 5 3.07 

9. Carcinoma tongue / oral cavity 5 3.07 

10. Soft tissue sarcoma 4 2.45 

11. Carcinoma gall bladder 3 1.84 

12. Carcinoma stomach 3 1.84 

13. Osteosarcoma 3 1.84 

14. Rhabdomyosarcoma 3 1.84 

15. Carcinoma esophagus 2 1.23 

16. Carcinoma penis 2 1.23 

17. Testicular tumor 2 1.23 

18. Carcinoma tonsil 2 1.23 

19. Carcinoma vulva 2 1.23 

20. Hodgkin's lymphoma 2 1.23 

21. Carcinoma bladder 1 0.61 

22. Carcinoma maxilla 1 0.61 

23. Carcinoma neck 1 0.61 

24. Carcinoma prostate 1 0.61 

25. Gestational trophoblastic disease 1 0.61 

26. Mediastinal seminoma 1 0.61 

27. Non-Hodgkin's lymphoma 1 0.61 

28. Periampullary carcinoma pancreas 1 0.61 

29. Squamous cell carcinoma 1 0.61 



TOTAL 163 100.00 

Table 3 

Medications responsible for causing at least one adverse event in the study population with the 

frequency of their involvement. 

Suspected medication involved Count Percentage 

1. Cisplatin 128 25.15 

2. 5-fluorouracil 88 17.29 

3. Cyclophosphamide 68 13.36 

4. Paclitaxel 48 9.43 

5. Carboplatin 35 6.88 

6. Doxorubicin 28 5.50 

7. Etoposide 25 4.91 

8. Ifosphamide 19 3.73 

9. Bleomycin 16 3.14 

10. Vincristine 12 2.36 

11. Oxaliplatin 11 2.16 

12. Docetaxel 10 1.96 

13. Gemcitabine 7 1.38 

14. Methotrexate 7 1.38 

15. Leucovorin 3 0.59 

16. Actinomycin-D 2 0.39 

17. Estramustine 2 0.39 

TOTAL 509 100.00 

The frequency of adverse events has been tabulated in table 4. As can be seen, nausea, with or without 

vomiting, was by far the most frequent adverse event (50.51%), accounting for just over half of the 

documented events. The next most frequent were acidity, with or without heartburn (16.27%) and pruritus, 



with or without skin rash (9.49%). Hair loss, severe enough to be distressing to the patient, was 

encountered in 3.05% cases. Milder instances of hair loss were ignored. Patients complained of 

constipation in 2.71% cases. Events encountered in less than 1% instance were chest pain, fever, gum 

bleeding, headache and insomnia. 



Table 4 

Adverse event profile encountered in the study population with the frequency of individual events. 

Event Count Percentage 

1. Abdominal pain (cramps), diarrhea 1 0.34 

2. Abdominal pain (cramps) 1 0.34 

3. Abdominal pain 2 0.68 

4. Acidity 43 14.58 

5. Acidity, heartburn 4 1.36 

6. Acidity, oral ulceration 1 0.34 

7. Anorexia, constipation 1 0.34 

8. Anorexia 5 1.69 

9. Blepharospasm 3 1.02 

10. Chest pain, vomiting 1 0.34 

11. Constipation 8 2.71 

12. Fever 1 0.34 

13. Fever, chills 1 0.34 

14. Fever, headache 2 0.68 

15. Gastrointestinal discomfort 15 5.08 

16. GI ulceration 2 0.68 

17. Gum bleeding 2 0.68 

18. Hair loss (distressing) 9 3.05 

19. Headache, vomiting 1 0.34 

20. Headache 2 0.68 

21. Insomnia 2 0.68 

22. Nausea 1 0.34 

23. Nausea, vomiting, anorexia 3 1.02 

24. Nausea, vomiting, diarrhea 1 0.34 

25. Nausea, vomiting 144 48.81 

26. Oral ulceration, stomatitis 4 1.36 

27. Oral ulceration 5 1.69 

28. Pruritus, skin rash 17 5.76 

29. Pruritus 11 3.73 

30. Stomatitis, diarrhea 1 0.34 

31. Stomatitis 1 0.34 

TOTAL 295 100.00 

Regarding the severity profile of the ADRs encountered, the data has been tabulated in Table 5. This 

severity grading relates to the clinically judged severity of treatment-emergent events in individual cases, 

and not to any scoring system or standardized criteria for severity grading for toxicity. A total of 29 of the 

295 recorded events (9.83%) were severe. As already noted, hair loss events were recorded only if severe 

enough to be distressing to the patients, which in almost all cases meant complete scalp alopecia. Milder 

hair loss was universal and was ignored. Although nausea and vomiting was the most frequent adverse 

event recorded, it was severe in only 7 of the 149 cases. 



Table 5 

Profile of severe adverse events encountered in the study population with the frequency of individual 

events. 

Event 

Count 

Percentage of all 

severe events 


2. Acidity 1 3.45 


4. Hair loss 9 31.03 




8. Pruritus 3 10.34 


TOTAL 29 100.00 

Serious adverse events 

Adverse events are regarded as serious if they are fatal, life-threatening, cause significant disability or 

incapacitation, cause or prolong hospitalization, or require intervention to prevent any of these outcomes. 

Congenital anomalies also fall in this category. In our study, there were no fatal or life-threatening events, 

but all the 7 instances of severe nausea vomiting, the 5 instances of severe pruritus with or without skin 

rash, the 4 instances of severe stomatitis with oral ulceration, and the single instance of severe abdominal 

cramps with diarrhea were considered as serious as they were disabling and required intervention to prevent 

perpetuation. Thus the incidence of serious ADRs was 17 out of 295 i.e. 5.76%. 

Causality status 

This was assessed, as already stated, as per the WHO-UMC standardized case causality assessment 

criteria. The causality profile obtained is depicted in Table 6. 

Table 6 

Causality status profile of the adverse events as per WHO-UMC system. 

Event 

Count 

Percentage of all 

adverse events 

1. Certain 3 1.84 

2. Probable / Likely 139 85.28 

3. Possible 21 12.88 

4. Unlikely 0 

5. Conditional / Unclassified 0 

6. Unassessable / Unclassified 0 

TOTAL 295 100.00 



Adverse event profile of individual drugs 

Finally, in Tables 7 to 9, we have presented the adverse reaction profile to each of the three anticancer 

drugs for which the number of suspected adverse reactions recorded is more than 10% of the total 295 

events – namely cisplatin, 5-fluorouracil and cyclophosphamide. 

Table 7 

Profile of adverse events encountered when cisplatin was one of the suspect medications. 



2. Acidity 20 15.63 



5. Bleeding gum 1 0.78 





10. Hair loss 2 1.56 

11. Insomnia 2 1.56 





TOTAL 128 100.00 

Table 8 

Profile of adverse events encountered when 5-fluorouracil was one of the suspect medications. 




3. Acidity 14 15.91 



6. Blepharospasm 1 1.14 




10. Gum bleeding 2 2.27 

11. Hair loss 3 3.41 









TOTAL 88 100.00 

Table 9 

Profile of adverse events encountered when cyclophosphamide was one of the suspect medications. 




3. Acidity 10 14.71 


5. Acidity, oral ulceration 1 1.47 




9. Hair loss 3 4.41 







TOTAL 68 100.00 

In the course of this study, the following strengths and limitations of cross-sectional pharmacovigilance 

activity in a hospital oncology unit came to the fore: 

Strengths 

 

 

 

Adverse events are encountered with considerable frequency. 

Acute treatment-emergent adverse events are easily identified. 

Patients are more motivated to cooperate with the reporter which helps in the completeness and 

accuracy of the data collected. 

Limitations 

 

 

Inability to identify ADRs that require serial monitoring. 

Inability to identify ADRs that require supporting serial laboratory tests for detection. 



 

No scope for picking up chronic or delayed ADRs. 

DISCUSSION 

ADRs significantly diminish quality of life, increase hospitalizations, prolong hospital stay and increase 

mortality [Pirmohamed M, et al, 2004]. The financial cost of ADRs to health care systems is enormous. 

There are several recent trends that are likely to expose more people to ADRs. For example, new drugs are 

being approved for marketing more quickly and without adequate long-term safety studies, supranational 

marketing is making drugs available to many more people at an early stage, and removal of restrictions on 

availability is leading to some medicines being used more widely by patients for self-medication. 

Monitoring of ADRs or pharmacovigilance is a new and evolving science [WHO, 2006]. Although 

various strategies and systems are being used worldwide, in general, most suffer from problems of 

underdetection and / or underreporting. Therefore the exact incidence (either population- or prescriptionbased) 

of specific ADRs is unknown. Information about ADRs from the pharmaceutical industry and 

regulatory authorities is usually not accessible to the public. Health professionals’ motivation for 

pharmacovigilance is low, there is little encouragement for them to be involved in the process. Patients 

receive inadequate and poorly understandable information about ADRs. Reports directly from patients, the 

individuals who actually suffer the consequences of ADRs, are often not conveyed by health professionals 

to established monitoring centers or to the regulatory authority. Added to this, is the difficulty in causality 

analysis of ADRs which often discourages health professionals from reporting [Karch FE & Lasagna L, 

1975]. 

In this context, it was felt that focusing on pharmacovigilance is the need of the hour [WHO, 2004]. The 

field of cancer chemotherapy was selected because this is one therapeutic area where ADRs are likely to 

occur frequently, if not universally [Iyer L & Ratain MJ, 1998]. Surprisingly, our literature survey revealed 

dearth of reports on ADR profiles in cancer chemotherapy. Although individual case reports are there, few 

focused studies were encountered [Shepherd GM, 2003]. The situation is even more serious in the Indian 

context [Kshirsagar NA, 1993]. A medline search with a last 10 years limit revealed no published Indian 

study of ADR profiling of anticancer drugs. 

The ADR prevalence encountered suggest that practically all patients receiving cytotoxic drugs suffer one 

or more ADRs. The spectrum of drugs encountered is typical of a medical oncology unit subjecting patients 

to various combination chemotherapy regimens. However, the percentage figures indicating involvement of 

individual drugs in adverse events has to be interpreted with caution since it may simply be dependent on 

the frequency of usage of the drug. Thus, cisplatin being the most frequently incriminated drug does not 

necessarily mean that it is the one most prone to cause ADRs; it may reflect the fact that cisplatin is one of 

the most widely used anticancer drugs in that unit. It may be noted that none of the patients surveyed were 

on interferons or other types of biological response modifier drugs. 

The overall profile of ADRs encountered is also typical of the acute treatment-emergent adverse events 

likely to be encountered in a medical oncology unit. Expectedly, nausea with or without vomiting, was the 

most common event. However, it has already been mentioned that one of the limitations of this study was 

the inability to monitor patients serially, since patients were admitted, received their chemotherapy and 

were discharged in 1 or 2 days. Thus no attempt was made to detect events like peripheral neuropathy or 

neutropenia which requires serial monitoring of the patient, either clinically or through laboratory tests. 

Even in instances like gum bleeding, which suggests underlying laboratory abnormalities like reduced 

platelet count, there was no scope of recalling the patients for review of their test records. Only a few 

patients admitted for repeat cycle therapy could be linked to previous cycles. The spectrum of ADRs 

encountered for individual drugs also matched their known ADR profiles and there were no surprising 

events. In the 3-month span of the study it was not reasonable to expect detection of chronic or delayed 

ADRs like doxorubicin-induced cardiomyopathy. 

The other limitation of the study was the inability to obtain full-time support of the oncologists in the 

monitoring activity, despite their best intentions. This is needed to understand the ADR in the context of the 

patient’s history and clinical examination and distinguish it from the symptomatology produced by disease 

or other drugs. In fact the team approach works best in focused or intensive monitoring[WHO, 2004] and 

the physicians’ enormous routine workload meant that the team in our case was less than optimum. 

Pharmacovigilance is an arm of patient care. It aims at making the best use of medicines for the treatment 

or prevention of disease. No one wants to harm patients, but unfortunately any medicine will sometimes do 



just this. Good pharmacovigilance will identify the risks and the risk factors in the shortest possible time so 

that harm can be avoided or minimized. When communicated effectively, this information allows for the 

intelligent, evidence-based use of medicines and has the potential for preventing many adverse reactions. 

This will ultimately help each patient to receive optimum therapy, and on a population basis, will help to 

ensure the acceptance and effectiveness of treatment regimens and health programs. Our study has 

therefore fulfilled, however modestly it might be, an important medical need, the full extent of which can 

only be addressed through a concerted multifaceted and ongoing approach. 

CONCLUSIONS 

Despite the short-comings, cross-sectional observational monitoring in an oncology unit can offer a 

wealth of pharmacovigilance data. Treatment emergent acute adverse events can be readily picked in 

general. The yield could be better if monitoring is focused on individual drugs or formulations and the 

monitoring team includes a committed oncologist. If combined with serial clinical and laboratory 

monitoring of the same patients, a fairly comprehensive ADR profile can be built up for individual drugs. 

ACKNOWLEDGEMENTS 

Authors are very much thankful to the IPGME & R, Kolkata Department of Pharmacology and Calcutta 

Medical College and Hospital, Kolkata for providing facilities for completion this short term research 

work. 

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