General Principles in Chemotherapy of Cancer

GENERAL PRINCIPLES IN CHEMOTHERAPY OF CANCER

1. In cancer chemotherapy, analogy is drawn with bacterial chemotherapy; the malignant cell being viewed as an invader. However, there are two main differences—

a) Bacterial metabolism differs markedly from that of the host, while malignant cells are in fact host cells with deranged regulation of growth and differentiation and only minor other differences. Therefore, selectivity of drugs is limited. A number of measures which enhance selectivity of drugs for the tumour need to be exploited. However, lately some unique tumour antigens and oncogenes (like the CML-tyrosine protein kinase gene) have been identified, which provide specific targets for drug therapy.

b) Infecting microorganisms are amenable to immunological and other host defence mechanisms. This is absent or minimal against cancer cells.

Human interferon α-2 and other cytokines (interleukin2, tumour necrosis factor, etc.) that can modify the biological responses to tumour cells are being used as adjuvants in treating neoplasms. They appear to have some direct inhibitory effect on malignant cells, in addition to reinforcing immunological defence against these.

2. A single clonogenic malignant cell is capable of producing progeny that can kill the host. To effect cure, all malignant cells must be killed or removed. Survival time is related to the number of cells that escape chemotherapeutic attack.

3. In any cancer, sub-populations of cells differ in their rate of proliferation and susceptibility to cytotoxic drugs. These drugs kill cancer cells by first order kinetics, i.e. a certain fraction of cells present are killed by one treatment.

4. Drug regimens or number of cycles of combined chemotherapy which can effectively palliate large tumour burdens may be curative when applied to minute residual tumour cell population after surgery and/or irradiation. This is the basis of the combined modality approach (see Fig. 62.1).

5. Whenever possible, complete remission should be the goal of cancer chemotherapy: drugs are often used in maximum tolerated doses. Intensive regimens used earlier yield better results.

6. Formerly cancers were treated with one drug at a time. Now a combination of 2–5 drugs is given in intermittent pulses to achieve total tumour cell kill, giving time in between for normal cells to recover (Fig. 62.1).

Synergistic combinations and rational sequences are devised by utilizing:

·            Drugs which are effective when used alone.

·            Drugs with different mechanisms of action.

·            Drugs with differing toxicities.

·      Empirically by trial and error; optimal schedules are mostly developed by this procedure.

·            Drugs with different mechanisms of resistance.

·            Drugs with known synergistic biochemical interactions.

· Kinetic scheduling: On the basis of cell cycle specificity/nonspecificity of the drugs and the phase of cell cycle (see box) at which the drug exerts its toxicity.

Cytotoxic drugs are either cell cycle specific (CCS) or cell cycle nonspecific (CCNS).

Cell Cycle Nonspecific:  Kill resting as well as dividing cells, e.g. nitrogen mustard, cyclophosphamide, chlorambucil, carmustine, dacarbazine, busulfan, L-asparaginase, cisplatin, procarbazine, actinomycin D.

Cell Cycle Specific: Kill only actively dividing cells. Their toxicity is generally expressed in S phase. However, these drugs may show considerable phase selectivity, e.g.—

G₁:  Vinblastine.

S : Mtx, cytarabine, 6TG, 6MP, 5FU, hydroxyurea, mitomycin C, doxorubicin, daunorubicin.

G₂: Daunorubicin, bleomycin, etoposide, topotecan.

     M: Vincristine, vinblastine, paclitaxel, docetaxel.

Phases of cell cycle

It is logical to use cell cycle specific drugs in short courses (pulses) of treatment. This allows noncycling cells (which are generally less susceptible to drugs) to reenter the cycle between drug courses. The CCS drugs are generally scheduled after a course of CCNS drug(s) to improve the cell kill. The CCS drugs are more effective in haematological malignancies and in solid tumours with a large growth fraction, while the CCNS drugs are effective in these as well as in solid cancers with a small growth fraction.

Many regimens have been devised by taking into consideration the above factors and by observing patient response.

One popular combination has been the MOPP regimen, which has yielded over 80% response rate in Hodgkin’s disease. It is illustrated in Fig. 62.2. For optimum remission 6–11 cycles may be needed. Maintenance therapy thereafter does not produce additional benefit.

Another combination that has produced almost 100% response in Ewing’s sarcoma is illustrated in Fig. 62.3.

Similarly many other regimens have been devised for different tumours.

VAMP: Vincristine + Amethopterine (Mtx) + 6MP + Prednisolone: used in acute leukaemia.

COAP: Cyclophosphamide + Oncovin (Vincristine) + AraC (Cytarabine) + Prednisolone.

POMP: Prednisolone + Oncovin + Mtx + Purinethol (6MP).

CART: Cytarabine + Asparaginase + Rubidomycin (Daunorubicin) + 6TG.

BACOP: Bleomycin + Adriamycin (Doxorubicin) + Cyclophosphamide + Vincristine + Prednisolone.

7. Tumours often become resistant to any drug that is used repeatedly due to selection of less responsive cells. Such selection is favoured if low dose of a single drug is used.

Several mechanisms of tumour resistance have been recognized. Mutations altering the target biomolecule confer specific (to single drug) resistance. An important mechanism of multidrug resistance is overexpression of MDR 1 gene which increases the concentration of Pglycoprotein (an efflux transporter) on the surface of cancer cells, resulting in pumping out of the chemotherapeutic agents, especially natural products like vinca alkaloids, anthracycline antibiotics, taxanes, etc.

The currently preferred drugs in chemotherapy-responsive malignancies are listed in Table 62.1.

Toxicity Amelioration

High doses and intensive regimens are being employed aiming at cure of the malignancy. The associated toxicity may be ameliorated to some extent by—

1. Toxicity Blocking Drugs: Folinic acid rescue has permitted administration of > 100 fold dose of Mtx. It is professed that normal cells are rescued more than the cancer cells— therapeutic index is increased.

·     Cystitis caused by cyclophosphamide and ifosphamide can be blocked by systemically administered mesna and by irrigating the bladder with acetylcysteine. Both these are –SH containing compounds that combine with and detoxify the toxic metabolites in the bladder. Generous fluid intake and frequent bladder voiding also helps.

·     For controlling cytotoxic drug induced vomiting, ondansetron, a 5HT₃ antagonist, has surpassed the efficacy of metoclopramide, which nevertheless is still used (see Ch. No. 47). Addition of dexamethasone and/or lorazepam further enhances the protection against vomiting.

Hyperuricaemia occurring as a consequence of rapid destruction of bulky tumour masses and degradation of large amount of purines can be reduced by allopurinol, alkalinization of urine and plenty of fluids. Corticosteroids also reduce hyperuricemia.

Hypercalcaemia occurring as a complication of certain malignancies like myeloma, cancer breast/prostate, etc. may be aggravated by chemotherapy. It is treated by vigorous hydration and i.v. bisphosphonates (see Ch. No. 24).

Drugs given in pulses with 2–3 week intervals for normal cells to recover improve the efficacy of therapy: malignant cells recovering more slowly.

Selective exposure of tumour to the drug by intraarterial infusion into a limb or head and neck; intrapleural/intraperitoneal injection— especially for rapidly accumulating pleural effusion or ascitis; topical application on the lesion—on skin, buccal mucosa, vagina, etc. may reduce systemic toxicity.

Platelet and/or granulocyte transfusion after treatment—to prevent bleeding or infection.

Use of biological response modifiers like recombinant GMCSF/GCSF hastens recovery from cytotoxic drug induced myelosuppression.

Molgramostim (LEUCOMAX 150, 300, 400 μg/vial for s.c./i.v. inj) is a colony stimulating factor. Injected daily beginning one day after last dose of myelosuppressant chemotherapy, it hastens recovery of neutrophil count.

Interleukin2 (Il2) is a cytokine biological response modifier that itself has antitumour property by amplifying killer Tcell response.

Bone marrow transplantation after treatment with high doses of myelosuppressant drugs.

Thalidomide (banned in 1960 for its teratogenic effect) has anxiolytic, antiemetic, adjuvant analgesic/antipyretic properties and has been found to counteract cancer associated cachexia. It probably acts by suppressing TNFα and by modulating IL-2