Chemotherapy drugs have an anti-mitotic action which is more pronounced in cells that have a high rate of cell division. The rate of tumor growth varies from one tumor to another, but also in different parts of the same tumor. This is mainly due to genetic, but also external and internal variables in the particular microenvironment.

Various models explaining tumor growth have been proposed. According to the Gompertzien model, growth takes place through an initial slow phase, followed by exponential proliferation and then a significant decrease in proliferation once the tumor mass reaches a critical volume. Growth is thus based on a sigmoid curve. The slowdown is explained by the mismatch between availability of metabolic building blocks and the metabolic needs of tumor cells, leading to anoxia and tumor necrosis. A significant fraction of tumor cells will then enter the quiescent cell phase (G0) and become insensitive to chemotherapy. This type of resistance is termed the kinetic type.

The proliferation of tumor cells may also be affected by genetic mutations, which lead to cellular resistance (the genetic type of resistance) with selection of a cell clone with a proliferative advantage. Metastatic lesions, which occur after multiple cell divisions, as well as large tumors are also more likely to be more resistant to chemotherapy. According to the mathematical model of Goldie and Coldman, when a tumor is detected, it already contains resistant clones, of which the magnitude depends on the frequency of genetic mutations and of the tumor mass.

Other mechanisms of tumor resistance to chemotherapy include modification of the chemotherapy receptor and metabolic inactivation or excretion of the active molecule of the drug. The tumor cell may also be able to repair chemotherapy-induced damage.

Chemotherapy resistance may occur to several different agents simultaneously. The acquisition of this multi-drug resistance (MDR) is due to the expression of p-glycoprotein and/or multi-drug resistance-associated protein on the tumor cell membrane. The presence of these two proteins is associated with a poor treatment response and prognosis.

The induction of apoptosis is one of the predominant mechanisms of action. Apoptosis is a physiological cell death in which the cell condenses and fragments without altering surrounding tissues and without causing an inflammatory reaction. The cell cycle is divided into four phases (Fig. 23.1). The critical check points at which the cell has to either undergo DNA repair and continue the process of division or activate apoptosis, lie between phases G1 and S and phases G2 and M. At these critical points, the cell requires the interaction of cyclins and enzymes called cyclin-dependent kinases to regulate these processes.

Anti-mitotic drugs may be phase independent or have an effect only in certain phases of the cell cycle. For example, cytarabine is phase S-dependent, while vincristine only affects cells in phase M. Depending on their mechanism of action, the chemotherapy drugs are classified into four major groups : the alkylating agents, topoisomerase inhibitors, the antimetabolites, and the plant alkaloids (Table 23.1).

Alkylating agents are drugs that have the property to transfer an alkyl group to proteins that bind together to form the double helix DNA structure. DNA synthesis is impaired due to this alkylation process, but the alkylating agents are active in all phases of the cell cycle. They are important in the treatment of slow-growing cancers , but are also used widely in the treatment of leukemia, lymphoma, sarcoma, neuroblastoma, nephroblastoma, retinoblastoma, osteosarcoma, Ewing sarcoma, germ cell tumors, and brain tumors.

Antimetabolites also interfere with DNA synthesis and are S phase-dependent. Their activity is dependent on rapid cell proliferation. Some have a structural analogy with physiological molecules (folic acid, purine or pyrimidine antagonists), while others have an inhibitory effect on enzymes necessary for DNA synthesis.

Inhibitors of topoisomerases play a major role in the restructuring (coiling and uncoiling) of DNA for transcription, replication, and mitosis. Depending on their mechanism of action, these drugs are grouped into camptothecin derivatives inhibiting topoisomerase I (topotecan and irinotecan) and the epipodophyllotoxins (etoposide and teniposide) inhibiting topoisomerase II.

Anthracyclines are also known as antitumor antibiotics and were derived from the Streptomyces species. The mechanism of action occurs via multiple pathways, such as impaired DNA synthesis, DNA intercalation, inhibition of topoisomerase I, induction of apoptosis, the generation of free radicals and an anti-angionetic action. These drugs are usually red or orange in color (Fig. 23.2). It is important to limit the cumulative dose of anthracyclines in order to reduce the risk of cardiotoxicity.

Spindle poisons bind to microtubules, which interfere with the formation of the tubules. They are phase M-dependent.

Recent developments: Research in the field of cancer drugs have different focus areas, e.g. reduction in toxicity, improving efficacy, and the development of novel agents. Liposomal anthracyclines have been developed in order to reduce the cardiotoxicity of this class of drugs. Asparaginase conjugated to polyethylene glycol (PEG-asparaginase) reduces immunogenicity and has a longer half-life. New classes of drugs specifically targeting tumor cells have emerged, e.g. rituximab, targeting tumor cells expressing CD20 on their surface, and many other monoclonal antibodies.

Most cancer drugs are metabolized by the liver and eliminated via urinary excretion. For this reason, it is essential to determine renal and hepatic function prior to starting treatment, as well as intermittently during treatment. In the case of renal or hepatic insufficiency, dosages should be adjusted. Drug interactions must also be taken into account. For example, the use of anti-convulsants increases the catabolism of some chemotherapeutic agents.

First-line treatment protocols typically involve combination therapy, while monotherapy is sometimes used in metronomic or palliative therapy . The goal of combination therapy is to overcome drug resistance by targeting tumor cells in various ways.

To understand and adapt chemotherapy treatment, it is important to know the behavior of each drug once it has been administered, e.g. bioavailability, distribution, biotransformation, and excretion. The bioavailability of drugs given by mouth may vary from one individual to another, as well as in the same individual at different points in time. Hepatic metabolism can significantly reduce the bioavailability of some drugs (e.g. 6-mercaptopurine). Several drugs are transported bound by albumin. A decrease in albumin will thus result in a high concentration of free drug and consequently more toxicity. Furthermore, third space dissemination (ascites, pleural effusion) is responsible for a decrease in drug clearance and greater toxicity. This is noted in particular when high-dose methotrexate is administered to patients with non-Hodgkin lymphoma. Drug clearance may also be reduced in the case of renal or hepatic failure (Table 23.2) and doses of certain drugs should be adjusted as indicated in Table 23.2.

Inherited or acquired impaired hepatic metabolism may cause major toxicity. In patients with a deficiency of thiopurine methyl transferase, an enzyme that degrades azathioprine and 6-mercaptopurine, these drugs are the cause of excessive toxicity at normal doses. Drugs metabolized by microsomal P450 in the liver have a reduced clearance when ketoconazole or anti-retroviral drugs are administered concomitantly and increased clearance in case of simultaneous treatment with anti-convulsants. Examples of such drugs include cyclophosphamide, the vinca-alkaloids, and the epipodophyllotoxins.

Chemotherapy is usually administered in timed cycles in order to allow normal tissues to regenerate in between cycles. Usually the more intensive the chemotherapy, the longer the time interval between treatment cycles. In more recent years, dose-dense chemotherapy protocols have been studied to determine whether outcome would be improved, for example giving chemotherapy cycles 2 weekly instead of every 3 weeks with supportive granulocyte colony stimulating factor. Several cycles are needed to eliminate the disease. The disappearance of clinical and radiological signs that signifies remission, does not equate to cure since continued chemotherapy is required in order to eradicate all undetectable tumor cells.

When protocols are designed, the method of administration and dose of a drug are also important factors to take into account. For example, methotrexate is given intravenously at high doses in order to achieve better central nervous system (CNS) penetration in the treatment of acute leukemia and is also given intrathecally to eradicate leukemic blasts in the cerebrospinal fluid and prevent CNS relapse.

The method of administration of chemotherapy drugs is varied according to what preparation of the drug is available. Chemotherapy regimens for leukemias and non-Hodgkin lymphomas include oral, intravenous, intramuscular, and intrathecal drugs. Hodgkin lymphoma and solid tumors are usually treated only with intravenous chemotherapy. Asparaginase may be given intravenously or intramuscularly, but the incidence of anaphylaxis is significantly reduced when given intramuscularly, thus most pediatric oncology units use the intramuscular route. Whenever asparaginase is being administered, a trolley should be prepared with the necessary drugs and equipment to treat anaphylaxis, if it should occur. The patient should also be observed for at least 1 hour. Glucocorticosteroids are equally effective whether it is given orally or intravenously. In some countries it may be difficult to obtain oral dexamethasone, thus the intravenous form may be used.