CANCER
Basically cancer is a disease of cells characterized by:
- Uncontrolled growth of abnormal cells, not regulated by external signals, usually resulting in the formation of a tumor.
- Ability of the growing cells to invade surrounding tissue, spread to new sites and establish new growths – metastasize at distant sites.
- – A neoplasm is benign, if only the first feature is present and
- – It is malignant if the second feature is also present.
- – Cancers of epithelial tissues are called carcinomas and
- – Cancers of non- epithelial tissues (mesenchymal) are called sarcomas.
- Cancer is one of the major causes of death in world.
- The treatment of cancer is still unsatisfactory due to certain characteristics of the cancer cells—like capacity for uncontrolled proliferation, invasiveness and metastasis.
- The cancer cells are our own cells, not like microbes which means that, drugs which, destroy these cells can also affect normal cells.
- The host defense mechanisms which help us in infections is not doing so in cancers as these cancer cells are also host cells.
- Moreover, the cancer cells can be in a resting phase during which they are not sensitive to anticancer drugs but can start multiplying later—resulting in recurrence. These features have made cancer chemotherapy more difficult.
The abnormal behavior of the cancer cells leads to illness in the host as a result of:
- Pressure effects of the local tumor growth.
- Destruction of the organ involved by the primary growth or its metastases.
- Systemic effects as a result of new growth.
Six different modes, either used alone, sequentially or concurrently are employed in the therapy of cancer:
- Chemotherapy (Cytotoxic drug therapy or chemotherapy)
- Surgery
- Radiotherapy
- Endocrine therapy
- Immunotherapy and biological therapy
- Gene therapy.
Cytotoxic drug therapy (chemotherapy) is employed in cancer to:
- Eradicate the disease.
- Control symptoms of the disease. In this context cytotoxic drugs may be used
- After surgery or radiotherapy as adjuvant chemotherapy.
- Together with surgery or radiotherapy as palliative therapy.
- Alone, as symptomatic therapy for controlling local physical effects of a tumor mass.
The main problem with chemotherapy of cancer is that:
- In chemotherapy of infections, the invading microbes are biologically foreign to the host and the metabolic reactions of its cells are so different from those of the host tissues that a chemotherapeutic agent can attack them selectively without affecting the host tissue cells. No such clear cut difference can be demonstrated between cancer and normal cells, as a result the anticancer drugs lack the specificity of antimicrobial drugs and have a much lower margin of safety. These 444drugs, therefore, not only act on the cancer cells but also attack dividing normal cells of the bone marrow, gastrointestinal tract, lymphoid tissue, hair follicles and spermatogenic cells, resulting in a large number of side effects.
- In infections, the body helps the antimicrobial drug with its own defense mechanism in the form of antibody production, phagocytosis, etc. in the eradication of the causative organism. Such defense mechanism is usually lacking or ineffective in cancer. It is, therefore, necessary to give anticancer drugs in such doses, so as to destroy all the cancer cells. Due to lack of selectivity of anticancer drugs, it is often impracticable to use such large doses. Hence, even after satisfactory initial treatment, the possibility of recurrence remain always there.
- Neoplastic tissue can develop resistance to drugs.
CLASSIFICATION OF DRUGS USED IN MALIGNANCY
Cell cycle nonspecific drugs
- Alkylating agents
- Mechlorethamine-cyclophosphamide (causes alopecia), melphalan, chlorambucil.
- Nitrosoureas-highly lipid soluble can cross blood-brain barrier, useful in brain tumors-carmustine, lomustine, semustine.
- Miscellaneous: Thiotepa-(ovarian cancer), busulfan-(chronic myeloid leukemia) cisplatin-(oral and genitourinary cancer), procarbazine.
- Antibiotics: Anthracyclines-doxorubicin, daunorubicinbroad spectrum, useful in many cancers, cardiotoxic, causes total alopecia. Plicamycin-used to reverse hypercalcema associated with malignant disease. Mitomycin-used for topical and intravesical treatment of small, bladder papillomas.
Cell-cycle specific drugs
- Antimetabolites-all used in combination with allopurinol to avoid occurrence of Hyperurecimia.
- [Dihydrofolate reductase (DHF Rase) inhibitor]-methotrexate-also used in psoriasis, Rheumatoid arthritis.
- Pyrimidine antagonists-cytarabine, fluorouracil.
- Purine antagonists-mercaptopurine, thioguanine, gemcitabine-pancreatic cancer, capacitabine.
- Bleomycin-causes pulmonary fibrosis, does not have significant myelosuppressive effect.
- Plant alkaloids: prodophytotoxins, vincristine, vinblastine, paclitaxel; all these bind to microtubular proteins and cause depolymerization of microtubules, resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle and interference with chromosome segregation.
Hormonal agents
- Glucocorticoids-prednisolone-used mainly in hematological cancers-acute leukemia, lymphoma.
- Estrogen and androgen inhibitors-tamoxifen-post menopausal breast cancer. Flutamide-prostatic cancer.
- Gonadotrophins-releasing hormone agonist-antagonists-leuprolide, goserelin-initial stimulation followed by prolonged inhibition of FSH and LH-metastatic prostate carcinoma.
- Aromatase inhibitors-aminoglutethimide, anastrozoleboth prevent conversion of adrenal androgen to estrone. Aminoglutethimide prevents synthesis of steroids-conversion of cholesterol to pregnenolone. Given with hydrocortisone. Used as second line drugs for metastatic breast cancer.
Immunotherapy
- Active non-specific immune stimulation-BCG vaccine.
- Active specific immune stimulation-C-Vax melanoma cell vaccine.
- Immunomodulators-Levamisole.
- Cytotoxic Cytokines-Interferon-alpha (α).
- Immunostimulatory cytokines-IL-2.
- Adaptive cellular immunotherapy-LAK cells, TIL, antigen-pulsed dendritic cells.
- Monoclonal antibodies-anti-CEA, CD20,HER-2,ECF, Mabs. (Monoclonal antibodies)
Cell cycle and anticancer drugs: Cellular multiplication involves the passage of the cells through a cycle called cell cycle. The various phases of cell cycle are:
- After mitosis, some of the daughter cells pass into resting phase or non proliferative phase G0 phase and do not enter the cell-cycle phase G1, immediately.
- The interval following cell division to the point where DNA syhthesis starts again, is known as presynthetic phase or G1 phase.
- This is followed by a phase during which synthesis of DNA occurs called the S phase.
- This is then followed by premitotic or post DNA synthetic phase called G1 phase.
- This is followed by mitotic or M phase, during which the chromosomes separate into two daughter cells.445These daughter cells have the option of either entering the G1 phase or remain in the G0 phase. See Fig. 13.1.1.
Most of the anticancer drugs act specifically on the processes like DNA synthesis, transcription or the mitotic phase and are called – cell cycle phase specific drugs. These drugs do not act on the cells in G0 phase. Some drugs kill the cells during all or most of the phases of cell cycle including G0 phase and are therefore, called cell cycle phase non- specific drugs.
Phase specific drugs or schedule dependent drugs
- Antimetabolites – methotrexate, 6- mercaptopurine (6-MP) 5- fluorouracil (5-FU), cytarabine – act on the S phase.
- Hormones – prednisolone – act on the G1 phase.
- Natural products – vincristine, vinblastin, vindesine, asparaginase – act on M phase. Paclitaxel, docetaxel.
- Miscellaneous – procarbazine, hydroxyurea.
Phase nonspecific drugs or dose dependent drugs
- Alkylating agents: Nitrogen mustard, carmustine, busulphan, chlorambucil, cyclophosphamide, cisplatin.
- Antibiotics: Bleomycin, dactinomycin, doxarubicin, daunorubicin, mitomycin C.
Mode of action of drugs (Fig. 13.1.2)
- Alkylating agents: They act by transferring alkyl groups to DNA during cell division, resulting in DNA strand breakage or cross linking of the two strands, so that normal synthesis of DNA is prevented.
- Antimetabolites: These are synthetic analogues of normal metabolites and act as competitive antagonists of folic acid – methotrexate, purines.
Principles of drug therapy: The common anti-cancer practice is to use a combination of two to six drugs, which are given simultaneously or closely related in time. Combination of drugs is more effective than single agents and is achieved by:
- Combining drugs, which are active alone and have different mechanisms of action.
- Combining drugs with different toxicities.
Cytotoxic drugs are given in intermittent regimens. Pulses of drug or drug combination are given at 3–4 weeks intervals, in maximum tolerated doses, thus increasing the effectiveness and reducing the toxicity of the combination and providing adequate time for recovery of the normal cellular elements depressed by the drugs. Usually, phase non-specific drugs are employed first, followed by phase specific agents. The former reduces the non- proliferative cell pool (G0) which stimulates the survivors to enter multiplication phase, where they are killed, by using phase specific drugs.
In addition to oral and IV routes cytotoxic drugs can also be given intrathecally to achieve greater concentrations in the CSF, intra-arterially into a limb, head and neck or the liver to achieve localized effects at these sites and intraperitoneally or intrapleurally to increase the local concentration of the drug (s).
Drug therapy of oral cancers: Carcinomas of the oral cavity present as non-healing ulcers, changes in the fitting of dentures, or as other painful lesions.
- For small localized lesions in the oral cavity, surgery is preferred to avoid long term complications of radiations, such as xerostomia and dental decay.
- For locally advanced disease, with metastasis in the lymph nodes – extensive surgery or radiotherapy, if surgery is not possible, is employed.Most cancers reoccur, usually within two years and cause death. To improve the survival period, cytotoxic drug therapy with cisplatin and 5-fluorouracil, with or without bleomycin or mitomycin, is given before surgery or radiotherapy.
Treatment of xerostomia- (dryness of mouth) following radiotherapy can be relieved by:
- Frequent sips of cold drinks, sucking pieces of ice or sugar free fruit drops.
- Use of artificial saliva of neutral pH and having electrolyte composition corresponding approximately to the normal saliva.
- Pilocarpine nitrate tables, 5 mg, orally, three times a day with or after meals.
ALKYLATING AGENTS
Actions: Alkylating agents exert cytotoxic, immunosuppressant and radiomimetic effects (similar to radiotherapy).
Mechanism of action: These drugs form highly reactive derivatives which transfer alkyl groups to various cellular constituents and bind them with covalent bonds. Alkylation's of DNA results in breakage of DNA strand.
Mechlorethamine: (Mustine HCL) is given IV as it is a highly irritant compound. It is used in Hodgkin's (MOPP regime) and other lymphomas.
Cyclophosphamide is converted to its active metabolite aldo-phosphamide in the body. It can be given orally. It causes cystitis due to a metabolite acrolein. This can be prevented by giving IV Mesna, irrigating the bladder with acetylcysteine, and by taking in large amounts of fluids. Mesna and acetylcystine contain – SH groups which bind the toxic metabolites and inactivate them.
Cyclophosphamide is used in Hodgkin's lymphoma, leukemias in children and as an immunosuppressive agent.
Ifosfamide has actions and toxicities similar to cyclophosphamide.
Chlorambucil is very effective against lymphoid series. It is the drug of choice in chronic lymphocytic leukemia.
Melphalan is given orally in multiple myeloma.
Busulfan (MYLERAN) has selective activity against cells of the myeloid series and is the drug of chioce in chronic myeloid leukemia.
Nitrosoureas are effective in meningeal leukemias and brain tumors because they cross the blood-brain barrier.
Dacarbazine is useful in malignant melanoma.
ANTIMETABOLITES
Methotrexate: It is dihydrofolate reductase inhibitor: It binds to dihydrofolate reductase and prevents the formation of tetrahydrofolate (THF). This THF is a coenzyme essential in several reactions in protein synthesis. The deficiency results in inhibition of protein synthesis. Thus rapidly multiplying cells are most affected.
Actions
- Cytotoxic actions – methotrexate mainly affects bone marrow, skin and gastrointestinal mucosa.
- It also has immunosuppressant and anti-inflammatory properties.
- Methotrexate toxicity can be largely prevented by administering folinic acid. This folinic acid gets converted to a form of THF that can be utilised by the cells.
Uses of Methotrexate: It is curative in choriocarcinoma and is useful in acute leukemias, breast cancer and soft tissue sarcomas. It is also used in rheumatoid arthritis and psoriasis.
6-Mercaptopurine (6-MP): It is converted to a metabolite which inhibits purine synthesis. 6-MP is metabolised by xanthine oxidase. Allopurinol inhibits xanthine oxidase and thus prolongs the action of 6-MP.
Uses: 6-MP is used in acute leukemias in children, choriocarcinoma and some solid tumors.
5-Fluorouracil: (5 FU) inhibits the synthesis of thymidylate and thereby inhibits DNA synthesis. It is used in carcinoma of the stomach, colon, rectum, breast, and ovaries.
Cytarabin arabinoside: It is the drug of choice in acute myeloid leukaemia in adults. Also used in the treatment of Hodgkin's & Non-Hodgkin's Lymphomas.
ANTIBIOTICS
Actinomycin D (Dactinomycin) acts by inhibiting DNA–dependent RNA synthesis. It is one of the most potent anticancer drug and is used in Wilms tumor, rhabdomyosarcoma, choriocarcinoma and some soft tissue sarcomas.
Daunorubicin and doxorubicin
- They act by inhibiting DNA synthesis. Cardiotoxicity with hypotension, arrhythmias and CCF, is unique to both these drugs. They also cause vomiting, stomatitis, alopecia and bone marrow depression.
- Daunorubicin is used in acute leukemias while doxorubicin is useful in solid tumors and in acute leukemias.
Epirubicin and mitoxantrone are analogs of doxorubicin which are less cardiotoxic.
Mitomycin C is converted to an alkylating agent in the body. It is used in cancers of the stomach, lungs and cervix.
Bleomycin
- It forms free radicals and causes breakage in DNA strand. It has the advantage of the unique mechanism of action and is less toxic to the bone marrow—this is advantagenous in combination regimens.
- It is used in solid tumors—testicular tumors, squamous cell carcinoma of the head, neck and esophagus.
- It's most serious toxicity is pulmonary fibrosis and cutaneous toxicity but does not cause significant bone marrow depression.
Mithramycin (Plicamycin) is highly toxic, used in disseminated testicular tumors and in severe hypercalcaemia due to bone cancers. It reduces plasma calcium levels by its action on osteoclasts.
VINCA ALKALOIDS
Vincristine and vinblastine are obtained from vinca rosea, the periwinkle plant. They bind to microtubules in the mitotic apparatus and arrest cell division in metaphase. They are spindle poisone. The alkaloids differ in toxicity.
Vincristin (ONCOVIN). Vincristine is neurotoxic while bone marrow depression is less. It is used in leukemias, Hodgkin's lymphoma, Wilms’ tumor and brain tumor.
Vinblastine causes bone marrow depression, alopecia and vomiting. It is used with bleomycin and cisplatin (VBC) in testicular tumors; it is also useful in Hodgkin's lymphoma.
HORMONES IN CANCER CHEMOTHERAPY
Glucocorticoids: Due to their lympholytic action, glucocorticoids are used in acute leukemias and lymphomas. Rapid clinical improvement is seen but duration can vary from 2 weeks to 9 months. They are used for initiation of therapy due to their rapid action.
Glucocorticoids are also of value in the following:
- With radiation therapy to reduce radiation edema
- In intracranial tumors to reduce cerebral edema and
- For symptomatic relief in critically ill patients.
Prednisolone or dexamethasone are commonly used.
Estrogens are useful in (i) prostatic carcinoma as it is an androgen dependent tumor, (ii) breast cancer in males and in postmenopausal women—estrogens are used in advanced cases where surgery or radiotherapy cannot be employed.
Anti-estrogens: Tamoxifen is an estrogen receptor antagonist used in estrogen receptor containing breast cancer.
Progestins are useful in the palliative management of endometrial carcinoma.
Androgens are used in the palliative treatment of breast cancer in postmenopausal women along with oophorectomy.
Antiandrogen: Flutamide is used in prostatic cancer.
Fostestrol also used in carcinoma prostate.
MISCELLANEOUS
Procarbazine is effective orally in Hodgkin's lymphoma (MOPP reimen component). It damages DNA. This may make it carcinogenic.
Cisplatin gets converted to its active form in the cell, inhibits DNA synthesis and causes cytotoxicity. It causes ototoxicity, nephrotoxicity, peripheral neuropathy, nausea, vomiting and anemia. Anaphylactoid reactions can follow its use. It is relatively less toxic to bone marrow. Cisplatin is used in ovarian and testicular tumors and cancers of the head and neck.
L-asparaginase: The amino acid asparagine is synthesized by normal cells but malignant cells are unable to synthesize asparaginase and depend on the supply from the host. Asparaginase is an enzyme that converts asparagine to aspartic acid and deprives the malignant cells of asparagine supplies resulting in inhibition of protein synthesis. It is used in acute leukemias.
GENERAL ADVERSE EFFECTS TO ANTICANCER DRUGS (Table 13.1.1)
Since most anticancer drugs act on the rapidly multiplying cells, they are also toxic to the normal rapidly multiplying cells in the bone marrow, epithelial cells, lymphoid organs and gonads. Thus the common adverse effects are:
- Bone marrow depression: resulting in leukopenia, anemia, thrombocytopenia and in higher doses—aplastic anemia. In such patients, infections and bleeding are common.
- Other proliferating cells: GIT – stomatitis and ulcers; alopecia (loss of hair), reduced spermatogenesis in men and amenorrhea in women (due to damage to the germinal epihtelium).448
- Immediate adverse effects: Nausea and vomiting are very common with most cytotoxic drugs. Prior treatment with powerful antiemetics is required.
- Teratogenicity: All cytotoxic drugs are teratogenic and are therefore contraindicated in pregnancy.
- Carcinogenicity: Cytotoxic drugs themselves may cause secondary cancers, e.g. leukemias are common after treatment of Hodgkin's lymphoma.
- Apart from the above, the adverse effects unique to some drugs are discussed under individual drugs.
Responses of tumors to cytotoxic drugs
- Cancers for which chemotherapy can be curative:
- Acute lymphoblastic leukemia ALL in children
- Acute myeloid leukemia. (AML)
- Choriocarcinoma
- Non-Hodgkin lymphomas
- Wilm's tumor.
- Tumors that are sensitive to chemotherapy, resulting in remission that generally prolong life:
- Breast carcinoma.
- Chronic lymphocytic leukemia.
- Ovarian carcinoma.
- Osteogenic sarcoma.
- Tumors that are sensitive to chemotherapy where life is sometimes prolonged:
- Cervical carcinoma.
- Gastric carcinoma.
- Head and neck tumors.
- Tumors that are refractory to currently available chemotherapy:
- Colorectal carcinoma.
- Non-small cell bronchogenic carcinoma.
- Carcinoma of the pancreas.
- Melanoma.
Drug Interaction
- With alcohol procarbazine produces disulfiram like reaction.
- Salicylates, phenothiazines and sulfonamide displaces methotrexate from plasma protein binding site and produces toxicity.
- Xanthine oxidase metabolizes 6 MP, therefore if xanthine oxidase inhibitor (Allopurinol) is used with 6 MP, its concentration rises to toxic level and reduction of dose is required (approximately 1/3 to 1/4 th level).
Other Uses of Anticancerous drugs
- As immunosuppresant: Cyclophosphamide, azathioprine, etc.
- To treat psoriasis: Methotrexate
- To treat viral infections: Cytarabine
- As an adjuvant in AIDS: Hydroxyurea
- As an abortifacient: Methotrexate
- In management of sickle cell anemia: Hydroxyureas
Important terminologies related with chemotherapy
- Induction of chemotherapy: Also called primary chemotherapy.
- Secondary chemotherapy: Second Line or additional therapy.
- Adjuvant chemotherapy: Chemotherapy of the induction with therapy by surgery raditation.
- Neo-adjuvant chemotherapy: Initial chemotherapy prior to surgery/radiation to reduce tumor mass.