Principles of Chemotherapy

transcript

Principles of chemotherapy SARAH ROBINSON Senior Research Physiotherapist, 7'he Royal Marsden Hospital, Fulham Rd, London SW3 61, UK

ROBINSON S. (1993) European Journal of Cancer Care 2, 55-65 Principles of Chemotherapy

In the last 40 years, 30 or more chemotherapy agents have been developed that have efficacy against a variety of malignant diseases. Over the years changes have occurred in treatment regimens that have brought dramatic results against certain cancers.

This paper outlines the historical background on which the discovery and development of anti-cancer drugs is based, the importance of the cell cycle in the action of chemotherapy agents against tumour cells, tumour growth and ceil kill hypothesis. The mode of action of classes of anti-cancer drugs is summarized, including the alkylating agents, antimetabolites, antibiotics, intercalating agents and the vinca alkaloids. The toxicity of chemotherapy on the normal proliferating cells of the body, the side-effects this produces and their frequency are discussed. The theory behind the development of combination chemotherapy and high-dose chemotherapy is examined.

Also remarked upon in this paper are topics such as the tumour-specific spectrum of anti-cancer drugs, response, resistance and selectivity.

The paper finishes by discussing the role of chemotherapy in the treatment of mahgnant disease and concludes that chemotherapy may be used to cure some patients, although the total number is a small proportion of the total number of patients who contract cancer. A larger proportion of the total will benefit sigmhcantly from chemotherapy when it is used as part of an overall treatment plan in conjunction with other forms of treatment. Chemotherapy remains, for the large part, a treatment modality which continues to undergo investigation. Critical appraisal of the results is needed to improve future therapy.

Keywords: cell cycle, chemotherapeutic agents, cancer treatment

HISTORICAL BACKGROUND

Sulphur mustard was originally synthesized in 1854 and was used in World War One as an offensive weapon when it was found that very low concentrations could effectively incapacitate unprotected combat troops by causing severe irritation of the respiratory tract and eyes. It was soon recognized that sulphur mustard also had effects on the rapidly dividmg cells of the gastro-intestinal tract and blood-forming organs. Soldiers who died as a result of exposure to mustard gas had virtually no bone marrow left. It was also found that those who survived suffered a fall in their whte blood cell count (Krumbhaar &

European I o m d of Cancer Care, 1993,2,55-65

Rrumbhaar, 1919). These observations led to research into chemicals related to mustard gas as treatment for leukaemia and in 1941 the first patient was treated with nitrogen mustard, a chemical with a structure similar to that of mustard gas. Therefore, it was through toxic effects that the early anti-cancer drugs were discovered and the modem era of chemotherapy started.

During the 1940s the structure of the B vitamin, folic acid, was elucidated and it became possible to measure the level of folic acid in the blood of patients. It was noticed that folic acid levels were low in children with leukaemia, but it was discovered that supplementing the diet with folic acid tended to accelerate rather than halt the disease. Subsequently, chemists were able to make methotrexate,

ROBINSON Principles of chemotherapy

a potent antagonist of folic acid and, therefore, an effective anti-tumour agent (Farber et d., 1948). In 1958, researchers investigating the periwinkle plant

because of its reputed activity in the treatment of diabetes, found that some of their extracts caused bone marrow suppression in animals (Noble et d., 1958). They investigated the products as anti-cancer agents and were able to isolate two drugs, vincristine and vinblastine.

The continuing search for effective drugs in the treatment of human cancer has resulted in the investigation of metal-based compounds includq arsenic, mer- cury, gold and platinum. Although several metal-based complexes have demonstrated cell-lulhng activity, only the platinum-containing complexes have exhibited a hgh degree of success. The actual development of the ongmal drug, cis-diamminedichloroplatinum (II) (DDP), is an example of an accidental discovery. While investigating the effect of an electric current on the mobility of bacteria it was noted that motility not only ceased, but the bacteria formed filamentous chains (Rosenberg et al., 1965). Because this type of bacterial structure is observed in non-dividmg cells an investigation was undertaken to

, 1940. 1950 I!

identlfy the cause of the growth inhibition. After a series of studies the agent responsible was identified as DDP. It was recognized that any complex so effective in altering bacterial growth may also have important anti-tumour activity. Studies were therefore initiated to assess this property of DDP (Rosenberg et d., 1969). By 1969, the activity of DDP in experimental tumour systems provided the impetus for limited human studies. Subsequently, DDP was shown to be curative against metastatic testicular carcinoma when combined with other established oncolytics (Einhom & Fumas, 1976; Rozencweig et d., 1977). By 1983, DDP had become one of the most widely used anti-cancer drugs having proven efficacy against testicular, ovarian, and head and neck cancers.

There has been a steady growth in the number of anti- cancer drugs available since they were first introduced into clinical use over 40 years ago. In the last 40 years, 30 or more agents have been developed that are effective against a variety of ma4gnant diseases (Fig. 1). Over the years, changes have occurred in treatment regimens that have brought dramatic results against certain cancers.

Smgle-agent drug therapy was the accepted treatment

Anti-cancer Drugs

I (IFN) Interferon I (VP16) Etopwide

I I TMX Tarnoaifen

, . . (PDN Prednisone (AMPT) Aminopterin (HNe) Nitrogen mustard (And) Androgens (Est ) Estrogens

0 1970 1980 1985

Year of ocquisition Figure 1 Time sequence of anti-cancer drug discovery.

European 10urna.l of Cmcer Care

Table 1 Tumours curable with chemotherapy

Cure is possible in patients with:

0 gestational choriocarcinoma 0 advanced Hodgkin's disease 0 non-Hodgkin's lymphoma 0 Burkitt's lymphoma 0 childhood leukaemias 0 testicular tumours

stonehill (1978).

regimen in the earlier days of chemotherapy development. Today, combination chemotherapy has resulted in long- term remissions (Krakoff, 1977), more effective prevention of resistance to drugs and tolerable side-effects with maximum doses (MurinSon, 1981). Forty years ago it was believed that chemotherapy was

ineffective against cancer. Fifteen years ago, only haema- tological and embryonic tumours were thought to be treatable by cancer chemotherapy. Today, combination chemotherapy and adjuvant chemotherapy have achieved great success in the treatment of many malignant diseases. Table 1 shows the tumours which are curable with chemotherapy.

The majority of successful anti-cancer drugs (with the exception of hormonal agents) are antiproliferative drugs. This means they are toxic to dividmg cells or that they

Figure2 Stages in the cell replication cycle.

prevent cells from dividmg. Since cancer cells exhibit uncontrolled cell division it is not surprising that antiproliferative agents work against them.

THE CELL CYCLE

The cell cycle describes a sequence of steps through which both normal and neoplastic cells grow and replicate. This process of cell growth and replication involves five steps or phases, Go, G1, S, G2 and M (Fig. 2).

The letter G denotes gap phases: time periods in which cells are either preparing for the more active phases of DNA synthesis and mitosis, or resting. G1 is referred to as the first gap or first growth phase. Dunng t h i s phase, the cell prepares for DNA synthesis by producing RNA and protein. G1 includes a resting phase, &. The GI phase is hrghly variable in length as a result of accommodating &, in which the cell is not actively committed to division. G1 may last as long as 30 hours, although most values lie

G,= Resting stage I I

- - GI = RNA and protein

synthesis S= DNA synthesis G,= Construction of

mitotic oppomtus M = Mitosis

ROBINSON Principles of chemotherapy

between 5 and 10 hours. Cells in are considered to be out of the cell cycle; that is, cellular activity does not include replication when the cell is in Go. Cells can remain in GO for varying lengths of time and can be recruited back into GI dependmg on the needs of the organism. In this way, cells in GO are in a ‘cellular reservoir’. Resting cells can be drawn from G,-, to add to the supply of dividing cells in the cell cycle.

The synthesis of DNA is the major event occurring during the S phase. DNA is the genetic code of infor- mation necessary for the growth, repair and reproduction of the cell. Many anti-neoplastic drugs work by causing ’irreparable disruption in the organization of the DNA code during DNA synthesis. The disruption ultimately results in cell death. The S phase lasts between 10 and .30 hours.

G2 is the second growth period or second gap. The synthesis of RNA and proteins continues as the cell prepares itself for mitosis. Production of the mitotic spindle apparatus also occurs during this phase. Gz lasts between 1 and 12 hours.

Actual mitosis or cell division occurs during the M phase (Fig. 3). The mitotic process consists of four phases: prophase, metaphase, anaphase and telophase. Durmg the M phase, the cell divides into two daughter cells, each one containing the same number and kind of chromosomes as the parent cell. At the completion of the M phase, the cells will either re-enter the cell cycle at G1 to undergo further maturation and replication, or await activation by resting in Go. Normally, cells spend about 1 hour in M phase.

It has been suggested that 90% of human tumour cells have cell cycle times within the range IS120 hours, with an average of 48 hours.

Anti-neoplastic drugs affect both normal and malignant cells by altering cellular activity during one or more phases of the cell cycle. Although both types of cells &e as a result of irreparable damage caused by chemotherapy, normal cells have a greater ability to repair minor damage and to continue living than do cancer cells. The increased vulnerability of malignant cells is exploited to achieve the therapeutic effects seen with administration of anti- neoplastic drugs.

CELL CYCLE ACTIVITY OF CHEMOTHERAPEUTIC AGENTS

Anti-cancer drugs can be classified accordmg to their cell cycle activity.

Cell cycle phase-specific agents

These kill proliferating cells only in a specific phase of the cell cycle, GI, S, Gz and M. For example, vinca alkaloids,

vincristine and vinblastine are lethal only to cells in the M phase, while 5-fluorouracil(5FU) and methotrexate inhibit DNA synthesis and are, therefore, specific to the S phase. Because phase-specific agents depend on cells being in a specific phase to work, they are most effective against cells that are rapidly dividing. Rapid division assures that the cell will pass through the phase in which it will be vulnerable to the effects of the drug. The anti-metabolites and bleomycin are examples of phase-specific agents. Cells that spend most of theix time in GO will not be affected sigdicantly by cycle-specific agents. However, there is a proportion of cells (both normal and malignant) which are not killed, even with massive increases in dose. These resistant cells reflect the fact that cell cycle phase-specific drugs are toxic only to cells in particular phases of the cell cycle. Bone marrow and tumour cells not in this phase of the cell cycle at the time of drug treatment escape toxicity. These particular agents produce a greater cell kill if an amount of drug is divided and given in multiple repeated fraction, rather than as a large single dose. Table 2 shows the drugs considered to be phase-specific and the phase in which they are active.

Table 2 Cell cycle phase-specifk agents

Phase of the cell cycle Agents

G1 phase

& phase

S phase

M phase

L-asparaginase Prednisone Bleomycin Etoposide Cytarabine 5-fluorouracil Hydroxyurea Methotrexate 6-thiogUanine Vinblastine Vincristine Vindesine

Cell cycle phase non-specific agents

These do not depend on the phase of the cell to be active. Rather these agents affect cells in all phases of the cell cycle. Resting cells are as vulnerable as dividmg cells to the cytotoxic effects of these agents. Consequently, phase non-specific agents have been found to be some of the most effective drugs against slow-growing tumours. The cytotoxic effects of cell cycle phase non-specific agents do, however, depend upon a cell that at some time either attempts division or attempts to repair drug-induced damage. The lethal effect that has already occurred intracellularly, is then expressed. These drugs kill increasing numbers of cells with increasing dose. A slngle bolus injection generally kills the same number of cells as

European Iournal of Cancer Care

Table 3 Cell cycle phase non-specific agents

DNp group Agents Alkylating agents Busulphan

Chlorambucil Cisplatin Cyclophosphamide Mechlorethamine Melphalan

Nitrosoureas Camustine (BCNU) Lomustine (CCNU] Semustine (MeCCNU) Streptozocin

Antibiotics Dactinomycin Daunorubicin Doxorubicin Mitomycin

Miscellaneous Dacarbazine Procarbazine

repeated fractions t0talh.q the same amount. The effects of toxicity will determine the dose limit. Table 3 indicates the drugs which are considered to be phase non-specific agents.

TUMOUR GROWTH

Tumours grow by a progressive, steady expansion (Fig. 4). Three characteristics of cells should be considered when

assessing tumour growth.

Concer: rapid proliferation followed by continuous but slowed proliferation

cell birth =cell death

Time -----) Figure 4 Diagram to show normal cell growth compared with tumour growth.

Cell cycle time

This is defined as the amount of time needed for the cell to complete an entire cycle from mitosis to mitosis. Cycle times for cancer cells vary from 24 to 120 hours, with most ranging from 48 to 72 hours. They vary widely accordmg to histological type. However, within a particdar tumour

type, they are relatively constant. Normal cells, e.g., bone marrow precursor cells, have similar if not faster cycle times than cancer cells. It is easy to understand, therefore, how toxicities to normal cells occur as chemotherapy acts on all rapidly dividmg cells, not just those that are m-t.

Growth fraction

This is the fraction of cells in the tumour that is dividug at any given time. In the early stages of tumour development (when the tumour volume is low), the growth fraction is lugh and the tumour doubles its volume (tumour doublmg time) relatively rapidly. As the tumou~ grows, however, space becomes restricted, and it out-grows its blood and nutrient supply so that the tumour doubhg time decreases.

Rate of cell loss

This is the fraction of the total number of cels that die or leave the tumour mass. Cell loss can be a major determinant of tumour growth rate. Cells are lost fxom a tumour mass by a variety of mechanisms, includmg death and migration (metastases).

Tumour growth will be the net effect of these three factors.

The earliest point at which a solid tumour can be detected clinically is when it contains 5 x lo8 cells and measures 1 cm in diameter. Tumour growth characteristics partially determine the choice of chemotherapeutic agents used against a tumour. For example, when the tumour volume is low, a large percentage of cells are d i v i d q and are thus vulnerable to cell cycle phase- specific agents. Likewise, when the tumour volume is hgh, fewer cells will be dividing and agents effective regardless of cell division characteristics (phase non- specific agents) would be used.

CELL KILL HYPOTHESIS

The cell kill hypothesis is the theoretical ability of chemotherapeutic agents to kill cancer cells. A certain drug dosage will kill a constant percentage of cells rather than a constant number of cells. Repeated doses of chemotherapy are thus needed to reduce the total number of cells. The number of cells left after chemotherapy depends on the results of the previous dose, the time between doses and the doublmg time of the tumour.

Example

A small tumour of less than 3 cm in diameter probably contains 10 000 billion cells and has a mass of about 10 g.

R 0 B I N S 0 N Principles of chemotherapy

If successful chemotherapy is given, it has been shown that the same proportion of cells is killed with each dose (Skipper et al., 1970). If the chemotherapy is active enough to kill 90% of the tumour cell with each dose, after two courses the tumour has a mass of only 0.1 g and would be too small to detect clinically. However, the patient is not cured. Up to a further eight courses may be necessary to do this even if resistance of the tumour does not develop. For .this reason, it is common to administer repeated courses of chemotherapy to patients even when their tumours are apparently in remission (Fig. 5).

Tumour diameter

-5.8 cm - 2.6 cm

In -1.2cm - 6.0 mm - 2.6 mm

e - 1.0 mm c 0

Courses of chemotherapy

Figwe 5 Effect of chemothaapy on tumour cells. A sensitive tumour cured by chemotheqy. B: resistant tumour not affectd by chemotherapy.

CHEMOTHERAPEUTIC AGENTS

Alkyhting agents

Nitrogen mustard (mustine) is a reactive chemical which is capable of combining with large molecules such as DNA. Nitrogen mustard and other similar drugs are bifunctional, which means that they can react with DNA at more than one site. In this way they are capable of joining the two strands of DNA together and cross- lrnkrng it. DNA which is cross-linked is prevented from replicating because the two strains cannot be separated. Aurylating agents also prevent replication by inhibiting WA, DNA and proteh synthesis in rapidly dividmg tissues.

Nitrogen mustard is one of a family of drugs known as alkylating agents, all of which act by this means. Other drugs in the family are melphalan, chlorambucil, cyclo- p hosphamide, ifosfamde, treosulphan and busulphan. Nitro- soureas such as carmustine (BCNU) and lomustine (CCNU) probably act by a similar mechanism. The heavy metal compounds cisplatin and carboplatin are also thought to have PIOperties that cause iuter- and intra-strand alkylation.

As a class, alkylating agents are considered cycle non- specific. They exert their lethal effects throughout the cell cycle, but tend to be more effective against rapidly dividing cells. The alkylating agents have been proven to be cytotoxically active against lymphomas, Hodgkin's disease, breast cancer and multiple myeloma.

Antimetabolites

Methotrexate interferes with cell division in a different way-stopping the cell from making the extra DNA necessary for replication. DNA is formed from four bases, thymine, cytosine, adenine and guanine. Folic acid is needed by the cell to make adenine, guanine and thymine. Methotrexate acts by preventing the cell from converting folic acid from an inactive form to its active form. All drugs which interfere with the manufacture of DNA

are called antimetabolites. Apart from methotrexate, most of them are molecules which mimic the natural bases and in that way interfere with their function. Examples of other antimetabolites are 5-fluorouracil [ SFU), 6-mercap- topurine (6MP), hydroxyurea, 6-thioguanine (6TG) and cytosine arabinoside (ara-C). Most antimetabolic cytotoxic activity occurs during the S phase of the cell cycle and these drugs are, therefore, most effective when used against rapidly dividmg cell populations.

AntibiOtiC.9

The anti-tumour antibiotics are agents that are isolated from micro-organisms. As a class they are cell cycle non- specific and appear to have several different mechanisms by which they produce their cytotoxic effects. Bleomycin, mithramycin and mitomycin C are examples of antibiotic anti-cancer agents.

Intercalating agents

Examples of intercalating agents (of which the anti- tumour antibiotics are a subgroup) are doxorubicin (adriamycin), epirubicin, daunorubicin, actinomycin D and mitozantrone. The two strands of DNA form a double helix. The strands are held together because the bases on opposite sides join to each other in pairs. Adenine pairs with thymine and guanine with cytosine. Intercalat- ing agents are drugs which can bind in between the base pairs and thus interfere with the function of DNA.

Vinca alkaloids (spindle poisons)

After the DNA has replicated, but before the cells can divide the two identical copies of the DNA must be removed physically to the opposite ends of the cell. This is accomplished by spindles-minute protein fibres

European Journal of Cancer Care

(microtubules] which are formed in the cell and subsequently pull the chromosomes apart. Vincristine, vinblastine and vindesine prevent cellular proliferation by interfering with the function of the microtubules.

Plant alkaloids work by crystalluing the microtubular mitotic spindle proteins during metaphase, which arrests mitosis causing cell death. The action of plant alkaloids is considered cell cycle phase-specific, occurring during the M phase.

Some toxicities, although not life-threatening, can seriously affect the quality of life of the patient. The most common of these are na~sea and vomiting (which to some degree affect nearly all patients receiving chemotherapy] and alopecia.

Unlike toxicity to rapidly dividmg cells where there is a capacity for stem cell renewal, the toxicity to other organs

Table 4 The major potentidy life-threatening organ toxicities of anticancer drugs and their frequencies

THE SIDE-EFFECTS OF ANTI-CANCER DRUGS Orcan svstem Frequency of toxicity (%)

The positive impact of chemotherapy on survival of cancer patients can be seen from the survival rates for cancer patients; in the United States this is a p p r o a c h 50%, compared to 40% in the early 1960s before the widespread use of chemotherapy (DeVita, 1989). Chemotherapy can be curative in about 12% of human cancers including choriocarcinoma, Acute Lymphoblastic Leukaemia (ALL], Wilm’s tumour, Hodgkin‘s disease and testicular cancer. However, most human cancers remain resistant to chemotherapy.

Since the most prominent feature of cancer tissues is their capability for uncontrolled cell division (with the subsequent capability for metastasis and invasion of other adjacent organs), it is not surprising that the drugs whch have been found to be most effective against them are mostly antiproliferative agents, nor is it surprising that these drugs are also toxic to the normal proliferating tissues of the body. Sgnhcant patient toxicity continues to be closely associated with the use of all effective anti- cancer drugs.

The toxicities found to occur with anti-cancer drugs have been reported to affect almost every organ system and tissue. The most commonly affected organs and tissues are those with rapidly dividmg cells, particularly the bone marrow, gastrointestmal tract, germinal epithelium lymphoid tissues and hair follicles. This occurs because most currently used anti-cancer drugs were initially selected for their ability to kill rapidly dividmg cells.

Almost without exception these drugs are toxic to the bone marrow. When bone marrow toxicity occurs it results in a fall of the white cell count (leucopenia) and platelet counts (thrombocytopenia) 7-28 days after treatment. Anaemia may also occur. The patient may then be at risk of infection or haemorrhage and may need supportive therapy, such as antibiotics or platelet transfu- sions, for a short period until recovery occurs. The most troublesome side-effects of anti-cancer drugs are frequently quite unrelated to their antiproliferative activity. Many cause nausea and vomiting while some individual drugs are toxic to organs such as the heart, kidneys, bladder, lungs or brain.

Gastrointestinal Bone marrow Hepatic Renal Cardiovascular Neuromuscular Respiratory

92 88 52 40 40 28 20

tends to be irreversible or only partially reversible after drug treatment is stopped. It then becomes a matter of clinical judgement as to how much drug toxicity a patient can tolerate before their well-being and life-quality are irreparably degraded, welghed against the possibility of therapeutic benefit to their disease. Table 4 shows the major potentially life-threatening organ toxicities and their frequencies. In addition to these acute side-effects, some anti-cancer

drugs also have long-term side-effects. It has been shown that patients successfully treated (particularly with alkylating agents] may develop other tumours, such as myeloid leukaemia, many years later (Calvert, 1983).

A frequent h d m g is one of great variability in the toxic response to anti-cancer drugs between patients. Factors which might cause a difference in toxic responses are the age and sex of the patient, the severity of the disease, concomitant renal or hepatic dysfunction and prior chemotherapy. The dose of anti-cancer drug is titrated to suit the individual, thereby accommodating each patient’s unique variation in toxicity. Unfortunately, deaths still occur, but this hazard of anti-cancer drug therapy is tolerated because of the belief that the higher the dose of anti-cancer drugs given, the more likelihood there is of a favourable therapeutic response.

The therapeutic effect of anti-cancer drugs against sensitive tumours such as the leukaemias, the lymphomas, testicular cancer and small cell lung cancer, shows a clear dose dependency. The clinical evidence indicates that the dose-response relationship for anti-tumour activity is steep. Unfortunately, so is the dose-response relationship for toxicity and s@icant morbidity is almost invariably associated with attempts at curative therapy.

ROBINSON hinciples of chemotherapy

EXTRAVASATION

Severe toxicity can occur when chemotherapeutic agents accidentally leak into the area around an intravenous (IV) infusion site. Tissue necrosis increases in severity over several weeks and results in slowly healing ulcers. These ulcers are a source of severe pain and even functional impairment for many months. In severe cases the lesion may extend to deep structures such as underlying tendon or bone, resulting in the loss of joint mobility. Estimates of the frequency of extravasation range from 0.5 to over 6%.

COMBINATION CHEMOTHERAPY

It is common clinical practice to limit any possible lethal toxicity of anti-cancer drugs while maintaining the west therapeutic effect, by giving drugs in combination so that toxic effects are spread among different organs. This approach, known as sub-additive host toxicity, leads to a wider range of side-effects and greater discomfort to a patient, but minimizes the risk of the lethal effect of the drugs.

Single-agent chemotherapy was used in the early development of cancer chemotherapy and very few tumours were cured by its use. However, combinations of chemotherapeutic agents have been found to produce superior clinical responses, as indicated by the good results obtained in the treatment of leukaemia, lymphomas and testicular teratomas.

Factors considered desirable in drug combinations are:

each drug should be active when used alone against the tumou~ in question; the drugs should have different mechanisms of anti- tumour action, complementing each other to produce maximal cell kill; the toxic effects of the drugs should not overlap; that is, they should occur in different organ systems, so that each drug can be given at or near its maximum tolerated dose, without excessive morbidity.

An example of this approach is the MOPP regimen, (mechloroethamine, oncovin, procarbazine, prednisone) used to treat Hodgkin’s disease. In the era of single-agent chemotherapy, responses to Hodgkin’s disease were usually of short duration (2-6 months) and the disease was incurable. Today, the MOPP regime produces complete remission in 81% of patients and, in approxi- mately half of all cases, remissions persist for 10 years or more and these patients can be considered cured.

There are other rationales that are sometimes used for combining anti-cancer drugs. The cytokinetic rationale relies on the fact that some anti-cancer drugs are more

active against cells in one phase of the cell cycle than another. Most combinations of chemotherapeutic agents used clinically involve cell cycle phase-specific drugs, for example, vincristine, methotrexate or cytosine arabinoside, combined with drugs that are cell cycle phase non- specific, for example, 5-fluorouracil (5FU), alkylating agents and anti-cancer antibiotics. The MOPP regime contains both cell cycle phase-specific and non-specific

There are a number of reasons why combination therapy drugs.

may work better than the use of a smgle agent.

The use of several drugs in combination may reduce the likelihood of resistance emerging. The use of combinations of drugs with different toxicities may allow more treatment to be given than could be achieved by increasing one drug to a fnaximum dose. It is possible that the drugs may interact with each other so that the effect of two drugs can be greater than the s u m of their individual effects.

THE TUMOUR-SPECIFIC SPECTRUM OF ANTI-CANCER DRUGS

The different types of malignant disease have been found by experience to tend to respond to different classes of anti-cancer drugs. For example, leukaemias tend to be responsive to antimetabolites and intercalators, breast cancer to intercalators and alkylating agents, and ovarian cancer to alkylating agents and platinum drugs.

RESPONSE

When a patient with cancer is treated with an anti-cancer drug it is hoped that the size of the tumour will decrease. If this occurs it is called a response.

0 A complete response is defined as the complete disappearance of all detectable signs of the disease.

0 A partial response is defined as the reduction by 50% of two measurable diameters of the tumour.

0 A minor response means that there is reduction in the rumour, but that it is not sufficiently large to be a partial or complete response.

Cures are only achieved when the chemotherapy is sufficiently good to induce complete responses for a prolonged period of time, e.g. 10 years, without relapse. Partial responses may or may not improve survival, but usually relieve symptoms. Partial responses may also be of value when the chemotherapy is being administered as

European Journal of Cancer Care

part of a combined modality treatment protocol. Minor responses are not usually of signrficant benefit unless they are very long-lasting.

RESISTANCE

Since anti-cancer drugs damage normal proliferating tissues as well as tumour tissues, courses must be given at sufficient intervals for the normal tissues to recover. If the normal tissues recover faster than the tumour, the chemotherapy is successful, but if the tumour recovers faster than the normal tissues, the chemotherapy cannot be successful and the tumour is said to be resistant. Many tumours are intrinsically resistant to chemotherapy. Other turnours respond initially, but then cease to do so. This is because of the emergence of cells within the tumour which are no longer susceptible to the drug.

SELECTIVITY

The fact that good results may be achieved by the use of anti-cancer drugs in the treatment of some mahgnant tumours show that, in these cases at least, the drugs show some selective toxicity to the tumour as opposed to the normal prohferatmg tissues. A range of factors governs the sensitivity of a tumour to a drug.

Pharmacology of the drug-its distribution around the body and into the tumour. Transport of the drug across the cell membrane into the tumour. Retention of the drug within the tuxnour. Specific features of the tumour cell metabolism which may lead to the drug being more toxic to it than to the normal tissues.

It is probable that tumours which respond to chemotherapy do so because a number of factors of this type are operative.

HIGH-DOSE CHEMOTHERAPY

A few drugs (those for which the major toxicity is to the bone marrow) may be used in very h& doses if the bone marrow is taken from the patient before treatment and returned later. In this way doses of the drug which are severely toxic to the bone marrow may be given safely because the bone marrow autograft is not exposed to the drug and when returned to the patient will retum the blood count to normal within a few weeks. However, bone marrow autografting will not reduce other toxicities resulting from high-dose chemotherapy. In practise, only

a few drugs can be given in this way: melphalan, BCNU, carboplatin and busulphan.

THE ROLE OF CHEMOTHERAPY

Chemotherapy is just one of several modalities available to treat cancer patients, and may be used in the following ways.

1. As the sole treatment for the disease: defmtive chemotherapy. The earliest disease found to be curable by chemotherapy was choriocarcinoma (Bagshawe, 1977), a rare tumour arising from the foetal tissues during pregnancy. Untreated, it metastasises rapidly and fatally, but the majority of patients are now cured by the use of smgle-agent or combination chemotherapy. The treatment of childhood leukaemia has also been revolutionized by the use of chemotherapy. The advent of methotrexate, the vinca alkaloids, prednisone and other antimetabolites, coupled with the introduction of cranial irramation and the development of suitable combination protocols, has resulted in as many as 70% of patients being cured (Mott, 1984). Many other childhood tumours have also proved to be relatively chemosensitive, so that overall over 50% of children with cancer are now cured. Chemotherapy also has a major role in the curative treatment of leukaemia and lymphomas (Hodgkin’s and non-Hodglun’s) in adults. Another disease where the prognosis has been slgnifi- cantly improved by the use of combination chemotherapy is testicular teratoma. The use of an intensive combination of cisplatin, bleomycin and vinblasthe produces an extremely lllgh complete response rate and a cure rate of 80-90% (Newlands et al. 1983). 7‘he.types of malignant disease which may be treated definitively by chemotherapy are listed in Table 1. These diseases constitute only a small proportion of the total number of cancer cases which are seen. However, the importance of chemotherapy is greater than this fact, taken at face value, would imply. Nearly all the types of cancer which are cured by chemotherapy occur predominantly in children and young adults, while those in which chemotherapy is of less use occur more frequently with advancing age. If the role of chemotherapy is calculated in terms of the number of ‘person-years’ saved, its contribution is considerably more. 2. As a means of reducing the size of a tumour to

expediate the subsequent use of surgery or radiotherapy: neo-adjuvant chemotherapy. An advanced squamous carcinoma of the nasopharynx may invade many vital structures around the facial area to such a degree that surgery would be impossible, or at least very mutilating. In these circumstances it may be possible to reduce the size of the tumour to more manageable proportions using chemotherapy and subsequently to remove or irradiate it.

ROBINSON PrincipIes of chemotherapy

Chemotherapy can, therefore, be used to debulk a tumour before it is irradiated and thereby improve, in theory at least, its chances of respondmg favourably to the subsequent radiotherapy. Neo-adjuvant therapy is of most interest in head, neck and bladder tumours since local complications are important in these areas; and both radiotherapy and surgery are used, but the results of treatment need to be improved. Whether there is any signhcant gain to be made in the cure rate or survival time from the use of chemotherapy in these diseases remains to be established (Calvert, 1985).

3. Following treatment with radiotherapy or surgery, with the objective of eliminating any remaining tumour cells and thus reducing the chance of a subsequent relapse: adjuvant chemotherapy. The first diseases in which adjuvant chemotherapy was found to be useful were children’s tumours such as rhabdomyosarcoma and Ewing‘s tumour. However, the first common cancer in which the use of adjuvant chemotherapy was investigated was breast cancer. Breast cancer is a moderately chemosensitive disease, response rates of about 70% being achieved by the use of combination chemotherapy (Craig-Henderson, 199 1). However, resistance occurs readily, so that the median duration of response is only about 9 months. The probabihty of achieving a cure in patients who have a tumour which is likely to become resistant is increased if the tumour burden is as low as possible at the time of treatment. Adjuvant chemotherapy is, therefore, given to patients with breast cancer who are known to be at h& risk of relapse. It is given immediately after surgery when the tumour burden is lowest, in the hope that it may cure the patient at this stage, although the same chemotherapy would only have been capable of causing a temporary remission if given after the patient had obviously relapsed. The use of chemotherapy in combination with other modalities of treatment may often serve a debulking role and assist in the control of distant metastases at the same time.

4. To treat a patient who has relapsed following initially successful treatment with another modality: salvage chemotherapy. Some diseases are not usually treated by chemotherapy in the first instance, for example, stage I or II Hodgkm’s disease and early stage testicular seminoma. In these cases the disease is normally confined to areas which can be effectively irradiated and cure rates using radiotherapy alone are quite high. However, these patients do sometimes relapse and since their disease is usually sensitive to chemotherapy they may be ‘salvaged’ at th is later stage by its use.

5. To relieve symptoms and, possibly, to prolong life in patients for whom other modalities have failed (including previous chemotherapy) or are known to be of no use:

palliative chemotherapy. For this reason palliative chemotherapy is frequently given to patients for whom there is little chance of response or cure. When giving such treatment it is clearly important that the costbenefit ratio to the patient is carefully considered. Ovarian cancer is an example. Using platinum-containing therapy well over 50% of patients respond to chemotherapy, and overall, 30% of patients will be alive 4 years later (Wiltshaw et al., 1986), although strictly spealung the chemotherapy is palliative because it is unlikely that any of these patients is actually cured.

6. To investigate the usefulness of a new drug whose role is not proven at the time of treatment: experimental chemotherapy. Since there are a large number of cancer patients for whom the anti-cancer drugs which are currently available have little or nodung to offer, it is clearly necessary to devise better methods of systemic treatment. Whether the products of t h i s research are new cytotoxic drugs, biological products, antibody-targeted drugs or non-cytotoxic anti-cancer agents they st i l l have to be tested to establish their role.

CONCLUSION

A number of broad working principles for the use of cancer chemotherapy and for the design of treatment protocols have been generated alongside the development of anti- cancer drugs. Drugs may be divided into various classes accordmg to their biochemical mechanism of action. The biochemical features which place a particular drug in a particular class are, on the whole, reflected in the drug‘s properties when assessed at the level of cell kinetics.

At a more basic level, there are many aspects of cancer chemotherapy which are poorly understood. Although it is quite clear that patients with some diseases, such as testicular teratoma, are readily cured by chemotherapy while those with other diseases, such as carcinoma of the colon, are not, there is no really satisfactory explanation as to why this should be the case. Chemotherapy may be used to cure some patients, although the total number is a small proportion of the total number of,patients who contract cancer. A larger proportion of the total (about 35%) will benefit sqmticantly from chemotherapy when it is used as part of an overall treatment plan in conjunction with other forms of treatment. Chemother- apy remains for the large part, a treatment modality which continues to undergo investigation. Critical appraisal of the results is needed to improve future therapy.

References

Bagshawe K.D. (1987) Lessons from choriocarcinoma. Proceedmgs from the Royal Society of Medicine, 70,303306.

Europeun Journal of Cancer Cure

Calvert A.H. (1983) Carcinogenic effects of anti-cancer drugs. Cancer Topics 4, 98-99.

Calvert A.H. (1985) Chemotherapy. In: J. M. Henk and J.D. Langdon (eds) Malignant Tumours of the Oral Cavity. Edward h o l d , London, pp. 127-152.

Craig-Henderson, I. (1987) Chemotherapy for Metastatic Disease. In: J. R. Harris, S. Hellman, I. Craig-Henderson and D. W. Kime (eds) Breast Disease. J.B. Lippincott, Philapdelphia, pp. 428-479.

DeVita V.T. (1989) Principles of Chemotherapy. In: V.T. DeVita, S. Hellman and S. A. Rosenberg (eds) Cancer: Principles and Practise of Oncology, 3rd edn. Lippincott, Philadelphia, pp. 276-300.

Einhom L. W Fumas B. (1976) Improved chemotherapy in disseminated testicular cancer. Journal of Clinical Haematol- ogy and Oncology 7,662-671.

Farber S., Drumond L.K., Mercer R.D., Sylvester R.F. h Wolf J.A. (1948) Temporary remission in acute leukaemia in children produced by the folic acid antagonist 4-amino-pteroylglutamic acid. New England Journal of Medicine 238, 787-793.

Krakoff I.H. (1977) Systemic Cancer Treatment: Cancer Che- motherapy. In: J. Horton and G. T. Hill (eds) Clinical Oncology. Saunders, Philadelphia.

Krumbhaar E.B. h Krumbhaar H.D. (1919) The blood and bone marrow in yellow cross gas (mustard gas) poisoning. Changes produced in the bone marrow of fatal cases. Journal of Medical Research 90,497-507.

Mott M.G. (1984) Mahgnant Disease in Chilcihood. In: K. R. Harrap, W. Davis and A. H. Calvert (eds) Cancer Chemother- apy and Selective Drug Development, Martinus Nijhoff, The Hague, pp. 123-133.

Murinson D.S. (1981) Clinical Pharmacology. In: S. N. Rosenthal and J. M. Bennett (eds) Practical Cancer Chemotherapy, New York Med id Examination, Garden City.

Newlands E.S., Rustin G. J.S., Begent R.H. J., Parker D. &a Bagshawe K.D. (1983) Further advances in the management of malignant teratomas of the testis and other sites. Lancet i, pp. 836-840.

Noble R.L., Beer C.T. h Cutts J.H. (1958) Further biological activities of vincaleukoblastine - an alkaloid isolated from Vinca rosea (L). Biochemical Pharmacology 1,347448.

Rosenberg B., Van Camp L. h Krigas T. (1965) Inhibition of cell division in Eschericia cofi by electrolysis products from a platinum electrode. Nature 205, 698-699.

Rosenberg B., Van Camp L., Trosko J.E. h Mansour V.H. (1969) Platinum compounds: A new class of potent anti-tumour agents. Nature 222,385486.

Rozencweig M., Von Hoff D.D., Slavik M. h Muggia F.M. (1977) Cis-diamminedichloroplatinum (II): A new anti-cancer drug. Annuls of Intemul Medicine 86,803-812.

Skipper H.E., Schabel F.M., Mellett L.B., Montgomery J.A., Wilkoff L.J., Lloyd H.H. h Brockman R.W. (1970) Implications of biochemical, cytokinetic, p h a c o l o g i c and toxicologic relationships in the design of optimal therapeutic schedules. Cancer Chemotherapy Reports 54,431-450.

Stonehill E.H. ( 1978) Impact of cancer chemotherapy on survival. Cancer 42, 1008-1014.

Wiltshaw E., Evans B., Rustin G., Gilbey E., Baker J. b Barker G. (1986) A prospective randomised trial comparing high-dose cisplatin with low-dose cispiatin and chlorambucil in advanced ovarian carcinoma. 1oumal of Clinical Oncology 4, 722-729.

Bibliography Burke M.B., Wilkes G.M., Berg D., Bean C.K. h Ingwerson K.

(1991) Cmcer chemotherapy: A Nurs% Approcch. Jones and Bartlett Publishers, Boston.

Calman K.C., Smyth J.F. h Tattersall M.H.N. (1980) Basic Principles of Cancer Chemotherapy. Mac& Press Ltd., London.

Dorr R.T. & Fritz W.L. (1980) Cancer Chemotherapy Handbook. Henry Kimpton Publiskers, London.

Powis G. h Hacker M.P. (eds) (1991) The Toxicity of Anti-Cancer Drugs. Pergamon Press, Oxford.

Principles of Chemotherapy

Documents