CHEMOTHERAPY

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INTRODUCTION
Chemotherapy (sometimes cancer chemotherapy) is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen. Most commonly, chemotherapy acts by killing cells that divide rapidly, one of the main properties of most cancer cells. This means that it also harms cells that divide rapidly under normal circumstances: cells in the bone marrow, digestive tract and hair follicles.

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 This results in the most common side effects of chemotherapy: myelosuppression (decreased production of blood cells, hence also immunosuppression), mucositis (inflammation of the lining of the digestive tract), and alopecia (hair loss).

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 Newer anticancer drugs act directly against abnormal proteins in cancer cells; this is termed targeted therapy and is technically not chemotherapy

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MILESTONES IN CHEMOTHERAPY

The first efforts were in the 1940s to 1950s,In a german air raid in Bari,Italy,one thousand people were exposed to certain mustard gas bombs, Autopsies of the victims suggested that profound lymphoid and myeloid suppression had occurred after exposure.
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Dr. Alexander theorized that since mustard gas all but ceased the division of certain types of Somatic cells whose nature it was to divide fast, it could also potentially be put to use in helping to suppress the division of certain types of cancerous cells

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-Faber in 1948 administered antifolates to children with ALL , these agents became the first drugs to be used in children with ALL.His reports were ridiculed during his time. -Remarkably, a decade later at the National Cancer Institute, Roy Hertz and Min Chiu Li discovered that the same methotrexate treatment alone could cure choriocarcinoma (1958), a germ-cell malignancy that originates in trophoblastic cells of the placenta. This was the first solid tumour to be cured by chemotherapy.
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-George Hitchings and Gertrude Elion, two pharmaceutical chemists who were working at the Burroughs Wellcome Co.in Tuckahoe, many purine analogues were tested, culminating in the discovery of 6mercaptopurine (6-MP), which was subsequently shown to be a highly active antileukemic drug. -The Eli Lilly natural products group found that alkaloids of the Madagascar periwinkle (Vinca rosea), originally discovered in a screen for anti-diabetic drugs, blocked proliferation of tumour cells
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-Combination Chemotherapy- In 1965, a major break-through in cancer therapy occurred. James Holland, Emil Freireich, and Emil Frei hypothesized that cancer chemotherapy should follow the strategy of antibiotic therapy for tuberculosis with combinations of drugs, each with a different mechanism of action

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This approach was extended to the lymphomas by Vincent T. DeVita and George Canellos at the NCI, who ultimately proved in the late 1960s that nitrogen mustard, vincristine, procarbazine and prednisone known as the MOPP regimen could cure patients with Hodgkin's and nonHodgkin's lymphoma

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-The landmark trials of Bernard Fisher, chair of the National Surgical Adjuvant Breast and Bowel Project, and of Gianni Bonadonna, working in the Istituto Nazionale Tumori di Milano, Italy, proved that adjuvant chemotherapy after complete surgical resection of breast tumours significantly extended survival particularly in more advanced cancer. -Gordon Zubrod had a particular interest in natural products, and established a broad programme for collecting and testing plant and marine sources, a controversial programme that led to the discovery of taxanes (in 1964) and camptothecins (in 1966).

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After 4 years of clinical testing in solid tumours, it was found in 1987 (Taxanes,23 years after its initial discovery) to be effective in ovarian cancer therapy. In 1996 a more stable analogue, irinotecan, won Food and Drug Administration (FDA) approval for the treatment of colon cancer
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Other effective molecules also came from industry during the period of 1970 to 1990, including anthracyclines and epipodophyllotoxins both of which inhibited the action of topoisomerase II, an enzyme crucial for DNA synthesis

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Principles of Chemotherapy
1.The Cells Kill Hypothesis of Skipper Skipper formulated some principles while studying tumor cells in mice suffering from leukemia which showed that: The survival of an animal was inversely related to the Tumor burden. Asingle leukemic cell is capable of multiplying and killing the host. For most drugs, there is a clear relationship between dose of the drugs and eradication of tumor cells.
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-A given dose of a drug kills a constant

fraction of cells and not a constant number. The same amount of drug is required to reduce the burden from one million cells to 10 cells as from 1 lacks to 1 cell. -Implication of this cell kill hypothesis is that tumors are best treated. when they are small in volume and the treatment must continue until the last cell is eradicated' -If the treatment is discontinued as soon as the tumor is no longer clinically detectable, at least 109 tumor cells will remain unkilled and relapse is inevitable
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2.The Norton Simon Hypothesis -In the tumor, which show Gompertizian type of growth Curves, the rate of regrowth increases as the tumor shrinks with the therapy. -Thus, the level of treatment adequate to initiate a regression maybe insufficientto maintain the regression and produce cure. -So to overcome this, Norton and Simon hypothesized that to counteract the slowing rate of regression in a tumor responding to therapy, it is necessary to increase the intensity of treatment as the tumor becomes smaller.
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-Some time radiotherapy and marrow transplantation can be used to intensify the treatment. -Multidrug regimens are used to attack residual population of cells, biochemically resistant to the initial combination of drugs

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3.The Goldie Goldman Model -In1979 Goldie and Goldman produced a model to explain the development of resistance to anticancer drug by the tumor cells and suggested that the populationof cells within the tumor were capable of randomly becoming resistant to the cytotoxic agents by means of spontaneous mutation.

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TYPES OF CHEMOTHERAPY

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Induction chemotherapy
-When the disease is locoregionally advanced or there is potential systemic spread, the chemotherapy initiated as a first line therapy prior to the main modality of treatment is known as induction, anterior or neoadjuvant chemotherapy. -Induction chemotherapy theoretically ensures better drug delivery and, aims at reduction of the tumor bulk

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-Higher doses of the chemotherapeutic regimens can be easily administered as the patient tolerance is better at the onset of treatment. -With the help of this type of treatment, tumors can be down staged and the organs can be preserved such as in oesophagus, bladder and breast cancers

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The neoadjuvant chemotherapy by producing tumor shrinkage could theoretically allow reoxygenation and reduction of the hypoxic component, and thereby renders the tumor more vulnerable to radiation cell kill. The possible disadvantage of induction chemotherapy is that, it delays the local treatment either by surgery or radiotherapy

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-Secondly, if there is intense chemotherapy related toxicity, it may become difficult to administer the primary mode of treatment. -Lastly, in a nonresponsive tumor or where an accelerated repopulation occurs, there may be progression of disease during this protracted course of chemotherapy.

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Adjuvant chemotherapy
-Adjuvant chemotherapy is administered when the disease is localized and has been controlled primarily by another therapeutic modality "(surgery "or radiation therapy). -For a vast majority of solid tumors where surgery and radiotherapy remain the local treatment modality, the patient may have the risk of local recurrence, lymph node or distant metastasis.
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-The loco-regional relapse rate can be reduced in these patients by the adjuvant chemotherapy.
-This form of therapy is given to reduce the incidence of systemic micro-metastasis thereby, increasing the possibility of disease-free and overall survival

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-There is a potential advantage in treating patients with adjuvant chemotherapy, after the local treatment. -Total tumor burden is reduced to a subclinical level and the chemotherapeutic agents are effective in eradicating the microscopic disease. -It is also realized that chemotherapy often fails to cure the disease, once the recurrence has occurred. -The benefits of adjuvant systemic treatment in a particular neoplasm is critically linked to the properly selected chemotherapy regimen

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-Suitable and specific, regimens have been evolved over the years in certain tumors e.g. osteogenic sarcoma, breast cancer and colorectal malignancies.
-On the other hand, the chemotherapy schedules are not yet fully standardized in cancers of ovary, lung and esophagus

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Primary chemotherapy
-In certain chemoresponsive ,tumors chemotherapy is administered as the treatment of choice such as in leukemias, lymphomas, choriocarcinoma and non-seminomatous germ cell tumors; -Currently, chemotherapy delivered as a curative approach is usually consisting of a combination of several drugs. This is commonly known as combination chemotherapy.

- Drugs that have shown antitumor activity against the disease are delivered in specific dose schedules.

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A number of principles have been recognized for the combination chemotherapy. 1.Only those agents of, proven effectiveness should be used. 2. Each agent used should have a different mechanism of action. 3. Each drug should have a different spectrum of toxicity. 4. Each drug should be used at maximum. 5. Drug combination should be administered in shortest interval between therapy cycles to allow for the recovery of normal tissues
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Typically,combination chemotherapy regimens are given as repetitive cycles for a defined period (number of chemotherapy courses or cycles is designed for a particular neoplasm). As far as possible the drug doses are given in a fixed schedule. The dose modification is needed when the patient has myelotoxicity (low blood counts), renal or hepatic dysfunction or poor tolerance to the given regimen.

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Certain guidelines are followed for the drug dose reduction. The response to the chemotherapy is periodically evaluated after every 2 3 cycles. The median duration of response is evaluated after the completion of chemotherapy schedules in terms of weeks or months and this is usually taken as the end point in evaluation

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Concomitant chemo-radiotherapy

-The main rationale for this strategy is utilization of direct interaction of radiotherapy and chemotherapy. -Generally, drug combinations believed to have radiation enhancing properties are utilized in this approach. -The drugs known to have this property are hydroxyurea, 5-FU and cisplastin. -However there are certain drugs which can cause dramatic increase in cutaneous and mucosal reactions and prove deleterious at times. These are adriamycin, mitomycinC and bleomycin.;

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 Simultaneous chemo-radiotherapy is given to improve the local control as well as to decrease the incidence of distant metastasis. Several studies have been carried out in the cancers of head and neck region, anal canal and esophagus with encouraging results. Radiation combined , with hydroxyurea proved more effective than radiation alone in a randomised trial in advanced cervical cancer. The chemoirradiation has also been tried as an alternative to the traditional surgery and radiotherapy combination in advanced laryngeal cancer.
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Salvage chemotherapy
Although objective is tumor regression, duration of survival and cure rates have also been the objectives of chemotherapy, there will be a group of patients who will need chemotherapy with an attempt to salvage the recurrent disease.
Whenever the first line of therapy, i.e. surgery, radiotherapy,chemotherapy or combinations fail, the patient is considered for salvage therapy. The salvage chemotherapy is generally attempted when the patient has a good performance status, there is reasonable expectancy of life, and the neoplasm is potentially chemosensitive. The common situations are germ cell tumors, lymphomas, leukemias and the less common malignancies are cancer of the breast, head and neck, colon,rectum and ovary Page 34

The role of chemotherapy as a palliative intent is not yet well defined and this is usually utilized in advanced or recurrent solid tumors to achieve tumor reduction and improve the quality of life. Radiotherapy and chemotherapy alone can control about 20-30 % of cancers. An interdigitation of these modalities in a logical sequence has led to excellent results in several tumors. The multimodal holistic approach in cancer has resulted in some completely curable cancers, namely, childhood ALL, Ewing's sarcoma, testicular tumor and medulloblastoma.
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The Classification of Anticancer Drugs

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According to chemical structure and resource of the drug; According to biochemistry mechanisms of anticancer action; According to the cycle or phase specificity of the drug

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According to chemical structure and resource of the drug:

Alkylating Agents, Antimetabolite, Antibiotics, Plant Extracts Hormones Others

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According to biochemistry mechanisms of anticancer action:

Drugs that Block nucleic acid biosynthesis Drugs that Directly influence the structure and function of DNA Drugs that Interfere the transcription and block RNA synthesis Drugs that Interfere with protein synthesis and function Drugs that Influence hormone homeostasis Others
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Drugs that Block Nucleic Acid (DNA, RNA) Biosynthesis

Antimetabolites: Folic Acid Antagonist: inhibit dihydrofolate reductase (methotrexate) Pyrimidine Antagonist: inhibit thymidylate synthetase (fluorouracil) ; inhibit DNA polymerase (cytarabine) Purine Antagonist: inhibit interconversion of purine nucleotide (mercaptopurine) Ribonucleoside Diphosphate Reductase Antagonist: (hydroxyurea)
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Drugs that Interfere with Protein Synthesis Antitubulin: vinca alkaloids and taxanes; Interfere the function of ribosome: harringtonines Influence amino acid supply: Lasparaginase Bind tubulin, destroy spindle to produce mitotic arrest
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Drugs that Interfere withTranscription and Block RNA Synthesis

They bind with DNA to

block RNA production. For eg: doxorubicin

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Drugs that Influence the Structure and Function of DNA

Alkylating Agent:
mechlorethamine, cyclophosphamide and thiotepa Platinum: cis-platinium

Antibiotic: bleomycin and

mitomycin C

Topoismerase inhibitor:
camptothecine and podophyllotoxin

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Drugs that Influence Hormone Homeostasis

These drugs bind to hormone receptors to block the actions of the sex hormones which results in inhibition of tumor growth. Estrogens and estrogen antagonistic drug Androgens and androgen antagonistic drug Progestogen drug Glucocorticoid drug gonadotropin-releasing hormone inhibitor: leuprolide, goserelin aromatase inhibitor: aminoglutethimide, anastrazole

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According to the cycle or phase specificity of the drug:

cell cycle nonspecific agents (CCNSA) cell cycle specific agents (CCSA)
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The Basic Concept of Cell Generation Cycle

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The cycle of cell replication includes: MMitosisphase G1Gap1, period before S phase SDNA synthesisphase o G2Gap2,period after S phase

Growth Fraction (GF

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According to chemical structure and resource of the drug Alkylating Agents

-Alkyl SulfonateBusulfan -Nitrogen MustardsMustine HCL, Cyclophosphamide, Melphalan and Chlorambucil -NitrorsoureasCarmustine (BCNU), Lomustine (CCNU),Semustine (Methyl-CCNU) -TriazineDacarbazine -EthylenimineThio- TEPA
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 They produce their effect by linking an alkyl group (R-CH2) covalently in protein and nucleic acid. Some of them are described below: Alkyl Sulfonate BusulfanIt is highly specific for myeloid elements, granulocyte precursors being most sensitive, followed by those of platelets and RBCs. UseIt is the drug of choice of chronic myeloid leukemia. Dose2-6 mg/day orally.

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Nitrogen Mustards
Mechanismit has two chloroethyl side chains. One of them forms a cyclical highly reactive ammonium ion which binds to nucleic acids, i.e. 7-nitrogen group of guanine. The other chloroethyl sides of nitrogen mustards can crosslink with DNA strands, either within a strand or between strands. Although alkylating agents may bind to variety of cellular components like cytoplasmic proteins and RNA at therapeutic doses, impairment of DNA replication is the major mechanism of cytotoxicity of these drugs. Damage to DNA is more serious during the 'S' phase of cell cycle probably because the cell has less time to excise the damage to DNA Page 51 fragment.

Mustine HClIt is the first nitrogen mustard, highly reactive and local vesicant. Dose 0.4 mg/kg IV in 1-4 days. Cyclophosphamideit has prominent immunosuppressant property. Dose2-3 mg/kg/day orally, 10-15 mg/kg IV every 710 days. Chlorambucilit is the slow acting alkylating agent, especially active on lymphoid tissue. It is drug of choice for chronic lymphatic leukemia. Dose4-10 mg daily for 3-6 weeks, then 2 mg daily for maintenance. Melphalanit is very effective in multiple myeloma. Dose10 mg daily for 7 days or 6 mg/day for 2-3 weeks and after 4 weeks' gap, 2 -4 mg daily for maintenance orally.Page 52

Nitrosoureas
Mechanismthey act partly as alkylating agents linking to an alkyl group or carbonyl group of cell proteins and form compounds which are unstable in water and decompose to form alkylating groups, which are able to damage the cell proteins.

DoseBCNU50-200 mg/m2, CCNU100-130 mg/m2, methyl CCNU100-200 mg/m2.

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Triazine
Dacarbazineit is different from other alkylating agents in having primary inhibitory action on RNA and protein synthesis. It is activated in the liver. It is used in malignant melanoma. Dose3.5 mg/kg/day IV for 10 days, repeat after 4 weeks.
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Ethylenimine
Thio-TEPAit does not require formation of an active intermediate. It has high toxicity and seldom used today. Dose0.3-0.4 mg/kg IV at 1-4 weeks intervals.

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Antimetabolites
Purine antagonist - 6-Mercaptopurine, 6-Thioguanine -Folate antagonist Methotrexate

-Pyrimidine antagonist 5Fluorouracil, Cytarabine (cytosine arabinoside).

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Purine Antagonist
Mechanism of actionMercaptopurine and thioguanine are highly effective anticancer drugs. It inhibits conversion of inosine monophosphate to adenine and guanine nucleotides. Usethey are useful in childhood acute leukemia and choriocarcinoma Toxic effectmain toxic effects of antipurines are bone marrow depression which develops slowly. Dose6-Mercaptopurine (2.5 mg/kg/day) and 6-Thioguanine (2 mg/kg/day).

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Folate Acid Antagonist

ActionMost commonly used folic acid antagonist methotrexate. It inhibits the conversion of dihydrofolate to tetrahydrofolic acid which in turn is converted to a variety of coenzymes. It blocks thymidylate monophos-phate synthesis and thus inhibiting RNA synthesis and so methotrexate is 'S' phase specific Absorptionit is well absorbed from the gut at low doses (up to 100 mg) but higher doses should be given intravenously. After IV injection, there is a rapid early half life of 45 minutes, a slower phase of renal excretion: of about 3 hours and then a very long terminal halt Methotrexate does not penetrate the CSF at conventional doses. To ensure adequate levels in CSF, methotrexate may be given intrathecally at a dose of 10 mg/m2. Page 58

 Toxicitythe prolonged clearance of

methotrexate is responsible for the toxicity to marrow gut and mucous membrane which leads to bone marrow depression, diarrhea and oral ulceration. The toxicity of methotrexate can be reversed by folic acid.

Contraindicationsit should be avoided in patients with ascites or pleural effusion as the drug may accumulate in fluid reservoirs and will release slowly causing toxicity.
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IndicationsUsed in treatment of acute leukemia, non-Hodgkin's lymphoma, breast cancer and osteogenic sarcoma. Dosein choriocarcinoma 1 5-30 mg/day for 5 days orally or 20-40 mg/m2 IM or IV twice a week. In maintaining remission in children with acute leukemias. 2,5-15 mg/day is useful.

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Pyrimidine Antagonists
Actionmost commonly used are 5fluorouracil and cytarabine. It interferes with nucleic acid synthesis by antagonizing or mimicking pyrimidine metabolites. Absorptionit may be given orally but its absorption is unpredictable. So, the IV route is often used because the plasma clearance is rapid.

Toxicitynausea, vomiting, stomatitis, alopecia and myelosuppression.

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 Indicationsit is given in the treatment of breast and GIT cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute leukemia to induce remission, Dosefluorouracil1 gm orally on alternate day for 6 days followed by 1 gm weekly or 12 mg/kg/day IV for 4 days. Cytarabine1.5-3 mg/kg IV BD for 5-10 days.
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Antibiotics
-Actinomycin-D

-Mitoxantrone -Bleomycin -Daunorubicin -Doxorubicin -Mithramycin -Mitomycin C

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Antibiotics
Practically all of the antibiotics intercalate between DNA strands and interfere with template functioning

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Actinomycin-D
It is isolated from streptomyces. It is intercalated with guanine and cytosine base pairs and blocks the transcription of DNA and DNA related RNA Synthesis. It inhibits division of rapidly dividing cells. It is given intravenously and plasma clearance is within a few- minutes.

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Toxicitynausea, vomiting, mucositis, diarrhea and myelosuppression. Indicationsit is active against rhabdomyosarcoma, Wilm's tumor ,Ewing's sarcoma, and teratoma. Doseit maybe given as a single injection of 15 g/kg IV daily for 5 days or in combination with cyclophosphamide and vincristine. Page 66

Mitoxantrone
Actionit binds to DNA and is given intravenously and has a long terminal half life of 36 hours. -Toxicityit may cause myelosuppression, cardiomyopathy and alopecia.

Indicationsacute non-hemolytic leukemia, chronic Myelogenous leukemia, non-Hodgkin lymphoma and Carcinoma of breast:12 mg/m2 single IV dose repeat at 3 weeks Page 67

Bleomycin
ActionIt consists of a mixture of closely related glycopeptide antibiotics. It inhibits DNA synthesis and causes a break in DNA and is active in G2 phase of the cell cycle AbsorptionIt is given by parenteral, subcutaneous,intramuscular route because it is non-vesicant. It has initial half life of 30 minutes and elimination from plasma takes 2-9 hours. It is excreted by kidney and does not cross the CSF.

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Toxicityskin pigmentatic , erythema, vesiculation or fibrosis. Indicationsit is used in combination with other chemotherapeutic drugs in testicular carcinoma, head and neck cancer and Hodgkin's lymphoma. Dose30 mg per injection twice weekly IV

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Doxorubicin and Daunorubicin

ActionThese are antitumor antibiotics and are produced by streptomyces fungus. They are capable of causing breaks in DNA strands by activating topoiso-merase II and generating quinone type radicals.

Absorptionthey are given by IV route and cleared from plasma, metabolized in liver and excreted in bile. So should be taken while prescribing in liver dysfunction patients.

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 Toxicitynausea, vomiting, alopecia and diarrhea occur. Cardiotoxicity can occur which manifests as ECG changes, arrhythmias and hypotension. Indications-doxorubicin is given in lymphoma (Hodgkin's disease), small cell cancer, breast cancer and daunorubicin is given in acute myeloid and lymphatic leukemia. Daunorubicin used is limited to acute leukemia. Dosedoxorubicin60-75 mg/m2 IV every 3 weeks and daunorubicin30-60 mg/m2 IV daily
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Mitramycin
Actionits use is restricted to embryonal testicular tumor, disseminated cancers, especially those with bony metastasis and hypercalcemia. It reduces serum calcium levels, probably by direct action on bone inhibiting calcium release.

Dose25 g/kg by slow IV infusion daily or on alternate days.

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Mitomycin-C
Action-it is derived from streptomyces species and inhibits DNA synthesis by both cross linking and alkylating DNA. Toxicitymyelosuppression, cumulative thrombocytopenia and renal toxicity. Indicationsused in combination in cancer of breast, stomach, cervix, pancreas and those of head and neck. Dose10 mg/m2 IV.

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Plant Extracts
Vinca alkaloids -Vinblastine -Vincristine Taxanes - Paclitaxel - Docetaxel

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Epipodophyllotoxin -Etoposide - Teniposide

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The Vinca Alkaloids

They are mitotic inhibitors, which bind to 'tubulin' (proteins of the cellular microtubules) to cause disruption of mitotic spindle and interfere with cytoskeletal function.

The vinca alkaloid blocks assembly of A and B subunit of the tubulin preventing the formation of the microtubules.

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Vinblastine
-Absorptionthese drugs are given IV and are vesicants if extravasated. Plasma clearance occurs in 3 phases with half life of 4 minutes, 1 hour and 16 hours. -Tissue binding is extensive and prolongs the actions and the drug binds to platelets, red cells and plasma proteins.
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 Indicationsit is used in combination for treatment of testicular tumors and lymphoma. Toxicityit causes alopecia, neurotoxicity and myelosuppression. Dose0.1-0.15 mg/kg IV weekly in 3 doses.

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Vincristine
Use.it is a rapidly acting drug, very useful for inducing remission in childhood acute leukemia. Toxicityit causes peripheral neuropathy, alopecia. Indicationsit is medicated in lymphoma (Hodgkin's disease), acute lymphatic leukemia, small cell cancer of bronchi and breast cancer. Dose1.5 mg/m2 IV weekly.
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Taxanes
Paclitaxel Actionit is a complex diterpin taxane from bark of the Western yew tree. It enhances polymerization of tubulin. The microtubules are stabilized and their depolymerization is prevented.
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Indicationsit is used in metastatic ovarian and breast carcinoma after failure of first line chemotherapy and in relapse cases. It can be used in head and neck cancer, small cell lung cancer. Dose175 mg/m2 by IV infusion over 3 to 24 hours repeated every 3 weeks

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Docetaxel
It is a congener of paclitaxel with the same mechanism of action. It has been found to have efficacy in metastatic breast cancer refractory to first line drugs. Major toxicity is neutropenia.

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Epipodophyllotoxin
Actionthese are phase specific and prevent cells from entering mitosis from G2 phase. Absorptionthe drugs are absorbed erratically from the gut with the plasma availability up to 50%, rapid clearance from plasma occurs when given intravenously followed by a slower phase. Etoposideit is highly protein bound and is excreted in the urine in 72 hours. Teniposideit is active as a single agent in small cell lung cancer.
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Toxicitythey cause alopecia, myelosuppression, mucositis and neuropathy. Indicationsit is used in treatment of testicular tumors, leukemia and lymphoma. Dose100 mg in 5 ml injection or 120 mg/m2 IV infusion for 30 minutes.

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Others
Enzymes:
L-Asparaginase
Miscellaneous:
- Hydroxyurea

- Procarbazine - Cisplatin -Hexamethylamine -Carboplatin

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Enzymes
L-Asparaginasethis enzyme is produced by E. coli. Actionit acts by removing asparagine from the circulation, thus depressing those tumor cells which are unable to synthesize asparagine due to lack of or have very low levels of asparagine synthetase. Route of administrationdrug is usually given intravenously after a skin test for hypersensitivity.

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 Indicationsit is used in the remission period in acute lymphocytic leukemia. Toxicityanaphylaxis, pancreatitis, hypoglycemia, hypoproteinemia, encephalopathy and nausea. Dose50-200 KU / kg IV daily for 2-4 weeks

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Miscellaneous Agents
Hydroxyurea Actionit blocks the conversion of ribonucleotides to deoxyribonucleotides by inhibiting the enzyme ribonucleoside diphosphate reductase interfering with DNA synthesis. It is'S' phase specific. It is well absorbed orally and crosses the CSF. Toxicityit causes neutropenia and gut disturbance. There is also myelosuppression.

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 Indicationsit is used in
chronic granulocytic leukemia, polycythemia vera. Dose20-30 mg/daily for 8 weeks.

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Procarbazine
Actionthis is a weak monoaminoacid oxidase inhibitor which inhibits action of DNA and RNA and depresses proline synthesis. It also causes chromosomal damage. Absorptionit is well absorbed from the gut and is one of the few drugs which penetrate the CSF.
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 Indicationsit is used mainly in Hodgkin's disease and brain tumor. Toxicityit includes nausea, vomiting and leukopenia. Dose: 100 -300 mg orally daily for 2 weeks.

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Cisplatin Actionthis drug is the only active cytotoxic agent in its cis form. Chloride ions are lost from the molecule after it diffuses into the cell and the compound crosslinks mainly to guanine groups like an alkylating agent. It should be protected from light and is given intravenously with an early half life of about 40 minutes with a later slower phase of clearance i.e. about 60 hours. Absorptionabout 90% of cisplatin bound to plasma protein is taken up in the kidney, gut, liver, testis and ovary, but it does not cross the blood-brain barrier. It is excreted by the kidney.

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 Toxicityit is nephrotoxic, ototoxic and may cause severe nausea and vomiting. Renal damage may be cumulative. Magnesium wasting may occur as a result of renal damage. If it is given in large doses it is associated with peripheral neuropathy, predominately affecting sensory nerve endings. it is very effective in testicular tumors and ovarian cancer. It is also effective in bladder, head neck tumors, small cell cancer of bronchi and Htensarcoma. DMP50-100 mg/m2 every 3-4 weeks.
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Hexamethylamine
Indications-it is active against ovarian and cervical cancer Absorption-it is well absorbed from the gut. Toxicity it causes abdominal cramps, diarrhea and leucopenia. CNS toxicity includes altered mental state aid convulsions. DOSE it is given orally at a dose of 12 mg/kg/day for 14 days
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Carboplatin Action it is a less reactive

second generation platinum compound that is better tolerated.
Toxicity nephrotoxicity, ototoxicity and neurotoxicity are low. The dose limiting toxicity is thrombocytopenia, aids less often, neutropenia.

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Indications it is primarily indicated in ovarian carcinoma of epithelial origin, squamous cell carcinoma , head and neck, small lung cancer and seminoma. Dose 400 mg/m2 as an IV infusion over 15-60 minutes to be repeated only after 4 weeks

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COMPLICATIONS
Many cytotoxic drugs are associated with side effects at commonly used therapeutic doses. Long term side effect of chemotherapy result in an increased risk of secondary malignancy and infertility in some cases.
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Local Toxicity
Some cytotoxic drugs cause severe local reaction when extravasated, e.g. daunorubicin, mitomycin and mustine HCl. The use of trained personnel for injection of cytotoxic drugs reduces the hazards of administration

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Hematological Toxicity
Bone marrow suppression is the most important dose limiting toxicity. Myelosuppression is expected to be maximum in 10-14 days after treatment. Certain drugs such as mitomycin and nitrosoureas have a delayed effect at 4-5 weeks. Hence, these drugs cannot be given more than once in week. Some of the alkylating agents have a cumulative effect on the bone marrow stem cells, e.g. chlorambucil, busulphan and melphalan. So the count may fall gradually for several weeks and recovery is slow.

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Gastrointestinal Toxicity
The precise cause of nausea and vomiting which is commonly seen with cytotoxic drugs is uncertain; but it is probably due to a combination of stimuli from the chemoreceptor trigger zone. The timing of onset of vomiting varies and may occur within 2 hours. Prophylactic anti-emetics are used to abolish vomiting and reduce nausea. Vinca alkaloids may cause constipation and paralytic ileus which will usually resolve spontaneously

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Alopecia
Generally, the head hair is lost but the whole of the body hair may be affected. The hair follicles are affected because of the high rate of cell turnover. Hair loss due to daunorubicin may be reduced by scalp cooling "which by causing local vasospasm reduces the amount of drug reaching the follicles.

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Pulmonary Toxicity
It is associated with only a few cytotoxic agents such as bleomycin, busulphan, cyclophosphamide and methotrexate. The pulmonary changes with infiltrate may be transient or may progress to pulmonary fibrosis

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Cardiac Toxicity
Cadiomyopathy may be seen with certain drugs. The exact cause is uncertain. Cardiac arrhythmias maybe seen during or recently after the injection of daunorubicin

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Renal and Bladder Toxicity

Cisplatin may cause nephrotoxicity leading to fall in glomerular filtration rate and tubular dysfunction with subsequent hypocalcemia and hypomagnesemia. High doses of methotrexate may cause renal damage. The damage may be avoided by treating only those patients with satisfactory renal function.

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Neurological Toxicity
The most common toxicity associated with cytotoxic drugs is peripheral neuropathy as seen with vinca alkaloids. Loss of tendon reflexes, paresthesia and numbness in the finger and toes may be noted only and are an indication to reduce the dosage. Development of myalgia, neuritic pain and peripheral sensory loss is an indication to stop the treatment. Drowsiness, confusion and encephalopathy may be seen with cyclophosphamide, procarbazine and dacarbazine.
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Complication

Direct Risk Factor

Indirect Risk Factors

Oral mucositis

-Mucosal cytotoxicity -Physical/chemical trauma -Re-activation of HSV

-Decreased local/systemic immunity -local infections

-Decreased systemic immunity -Decreased systemic immunity -Salivary gland dysfunction -Altered oral flora (decreased bacterial flora)

Oral infections Viral Fungal

Bacterial

-Inadequate oral hygiene -Mucosal breakdown -Acquired pathogens Taste receptor toxicity -Salivary gland toxicity

-Decreased systemic immunity -Salivary gland dysfunction -Anticholinergic drugs

Taste dysfunction Xerostomia

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Neuropathies

Vinca alkaloid drug use

Gastrointestinal mucositis

Nausea and vomiting

Hemorrhage

Oral mucositis

Thrombocytopenia

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Cancer Chemotherapy Agents Which Cause Mucositis

Amsacrine Bleomycin Busulfan Carboplatin Chlorambucil Cisplatin Cyclophosphamide Cytarabine Dacarbazine Dactinomycin Daunorubicin Docetaxel Doxorubicin Epirubicin Etoposide 5-Fluorouracil Fludarabine Gemcitabine Idarubicin Irinotecan Hydroxyurea Lomustine Mechlorethamine Mercaptopurine Methotrexate Mitoxantrone Mitomycin Paclitaxel Procarbazine Vinblastine Vincristine Vinorelbine Page 108

MANAGEMENT
Current management of mucositis in patients includes an emphasis on good oral hygiene, the use of frequent oral rinses for wetting the surfaces and diluting oral contents, avoidance of irritating foods and oral care products, avoidance of tobacco products, and the use of benzydamine (in countries where available). The management of oropharyngeal pain in cancer patients frequently requires systemic analgesics, adjunctive medications, physical therapy, and psychological therapy, in addition to local measures, oral care, and topical treatments.
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 Topical antimicrobials, including chlorhexidine and systemic antimicrobials, have little effect in preventing mucositis in patients but may be used for effect upon plaque levels, caries and gingivitis risk, and candidiasis. Amifostine provides salivary gland protection but requires further study to document a potential role in prevention of oral mucositis. Innovative new products are in clinical trials and low-energy lasers and (possibly) anti-inflammatory medications require further study.
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 Amifostine, administered by the intravenous or intramuscular route prior to radiation exposure, has been approved by the PDA for prevention of salivary gland dysfunction and may reduce the severity of oral mucositis; however, additional study is needed to determine its impact on mucositis and its cost effectiveness

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Hyposalivation STIMULATION OF SALIVARY FUNCTION

For patients with residual gland function, high fluid intake and the use of sugarless gum or candies also may assist the stimulation of residual gland function. Systemic sialagogues offer the advantage of stimulating saliva secretion that includes all normal components and protective functions of saliva. Measurement of saliva flow rates to determine the amount of residual function should be conducted before prescribing a sialagogue. If no saliva is collected under resting or stimulated conditions, it is unlikely that a systemic agent will be effective.
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 Pilocarpine is the best studied sialagogue. Pilocarpine is a parasympathomimetic agent and has its major effects at the muscarinic cholinergic receptor of salivary gland acinar cells. In doses of 5 to 10 mg tid, increased secretion of saliva occurs, and few cardiovascular side effects have been noted.
Other agents have been studied, including bethanechol and civemiline. Bethanechol (75-200 mg/d in divided doses), which stimulates the parasympathetic nervous system, has been reported to have potential benefits without causing gastrointestinal upset. Anetholetrithione (not available in the United States; Paladin Laboratories Inc, Montreal, Canada) has been reported to be beneficial in the management of dry mouth . Page 113

 .The mechanism of action may be due to an increase the number of cell surface receptors on salivary acinar cells. Because pilocarpine stimulates the receptors and because anetholetrithione may act by stimulating the formation of receptor sites, synergistic effects may result with the combined use of these drugs

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SYMPTOMATIC TREATMENT
Mouth-wetting agents or saliva substitutes may be used when it is not possible to stimulate salivary function. Frequent sipping of water and a moist diet are mandatory. The desired characteristics of saliva substitutes are excellent lubrication, surface wetting, inhibition of overgrowth of pathogenic microorganisms, maintenance of the hardness of dental structure, pleasant taste, long duration of effect, extended shelf life, and low Page 115 cost.

 The majority of products currently available are based on carboxyl ethyl cellulose. Complex molecules and animal mucins have been incorporated into some products. Most commercial products are more viscous than saliva and do not simulate the viscoelastic properties of saliva. They also do not contain the complex enzyme systems and antibodies of natural saliva. Many of the commercial products being marketed have not been subjected to controlled clinical study
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 Patients who receive radiation therapy/chemotherapy can be managed with topical antifungals because oral candidiasis produces oral discomfort but does not lead to systemic infection unless the patient is immunocompromised. Systemic azoles are used for infection that occurs while using topicals and if compliance with topical oral therapy is poor. When prescribing topical antifungal drugs, the presence of sucrose in the product must be known because frequent use of sucrose-sweetened products may promote caries, particularly in patients with dry mouth.

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CARIES
Caries associated with hyposalivation typically affect the gingival third and the incisal cusp tips of the teeth . The etiology is related to a lack of production of saliva, loss of remineralizing potential, loss of buffering capacity, reduced pH, and change in the bacterial flora. Treatment of each component of the caries process must be addressed to prevent demineralization and rampant caries.

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MANAGEMENT
The tooth structure may be hardened by the use of fluorides, and remineralization may be enhanced by the use of fluorides and remineralizing products The effects of topical products maybe enhanced by increased contact time on the teeth, which can be achieved by applying them with occlusive vacuform splints or gel carriers, which should extend over the gingival margins of the teeth. Custom vinyl trays are useful for the application of fluoride to prevent and control caries in high-risk patients.

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 However, until controlled studies are available, treatment should remain fluoride application in gel carriers; for those who do not comply with carrier application, high-potency brush-on fluoride dentrifice may be suggested as it is simpler and may reduce demineralization and caries. Continuing reinforcement of topical fluoride use is needed and will enhance patient compliance.

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 Topical fluorides and chlorhexidine rinses may reduce levels of Streptococcus mutans. A 2% chlorhexidine gel applied in mouth guards demonstrated an enhanced ability to control cariogenic flora in cancer patients with xerostomia

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Taste and Smell impairment

Zinc supplementation (zinc sulfate, 220 mg twice daily) may be useful for some patients who experience taste disturbances. Nutritional counseling in which the focus is on the maintenance of caloric and nutrient intake may be required during and following cancer therapy. Long-term complications include hyposalivation, altered ability to chew, difficulty in forming the food bolus, and dysphagia. Consideration must be given to taste, texture, moisture, and caloric and nutrient content.
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Drug Resistance

De novo Resistance

Acquired Resistance Multidrug Resistance (MDR)

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De novo resistance:

De novo resistance can be de novo genetic (i.e. the cells are initially inherently resistant), or can arise because drugs are unable to reach the target cells because of permeability barriers such as the bloodbrain barrier.
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Acquired Resistance: Acquired drug resistance may result from genomic mutations, such as the induction or deletion of enzymes involved in drug inactivation or drug activation, respectively.

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Multidrug Resistance (MDR):

P-glycoprotein transports many naturally occurring drugs out of neoplastic cells, and its induction may lead to multidrug resistance.
As scientific understanding of the mechanisms of drug resistance increases, new treatments may be developed to counteract resistance
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Current concepts for the management of head and neck cancers in chemotherapy

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Locoregionally advanced squamous cell carcinoma of the head and neck

Two-thirds of the SCCHN are in a LA stage at time of diagnosis. Treatment paradigms in that setting include various forms of curative combined modality therapies, including concurrent chemoradiation (or biochemoradiation), induction chemoradiation followed by irradiation and sequential therapy (induction chemotherapy followed by concurrent chemoradiation).

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Concurrent chemoradiation
Concurrent chemoradiation was widely adopted as standard of care for LA-SCCHN after thepublication of a large meta-analysis based on individual data of 10,741 patients in 63 randomized trials. The meta-analysis was recently updated and extended to 6,640 patients treated in 87 trials.a Concurrent chemoradiation conferred an absolute survival benefit of 8% at 2 and 5 years.
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 Chemotherapy even improves survival when added to hyperfractionated or accelerated racliotherapy which itself is superior to conventional radiation alone. The best studied and most widely used regimen, which can be considered the standard comparator for randomized trials, is cisplatin 100mg/m2 0n days 1,22 and 43

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A survival benefit in single randomized trials has also been suggested with daily low dose cisplatin weekly intermediate dose of cisplastin 20 mg/m2 day 1-5 and day 29-33 and 5flurouracil combined with either cisplatin,carboplatin or mitomycin C. Promising results in non-randomized studies were reported with multiple single agents including weekly low dose gemcitabine,weekly docetaxel,weekly paclitaxel,carboplatin and with combinations as TFHX (paclitaxel, 5 fluorouracil and hydroxyurea).

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Induction chemotherapy
Rationale Induction chemotherapy has some appealing theoretical advantages such as optimal drug delivery to the tumor through undisrupted vasculature, early eradication of micrometastases and improved tolerance of cytotoxic drugs. Moreover, induction chemotherapy offers the opportunity of assessing tumor response and thereby selecting the patients for organ preservation.

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Combination of cisplatin, (7 5- 1 00 mg/m2 ) and 5-flurouracil (5-FU, 750 - 1000 mg/m2) every three weeks is the most commonly used regimen (pF) for induction treatment. the pF regimen yields a 5% improvement in 5year survival There have been three randamised trial adding taxans to standard approach In one trial by Hitts Et al paclitaxel added to cisplastin and 5Fu in exp arm Although the response rates were better in the experimental arm there was no significant difference in the ovetall survival (51% versus 43%p=0.063). In the two recently published studies (EORT24971/TAX323 and TAX324 study), docetaxel was added to cisplatin and 5-FU (TPF) in the experimental arm for induction treatment

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 Post operative induction chemotherapy has also been investigated the Radiotherapy Oncology Croup(RTOG) study , a Phase II study of paclitaxel followed bv paclitaxel and cisplatin for CRT in resected SCCHN patients showed comparable toxicity and improved outcome compared to historical controls (RTOG study 9501) receiving postoperative CRT alone.

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 In spite of the published evidence, induction chemotherapy is not considered the standard of care There are several reasons The induction therapy delays CRT which is thought to be the definite treatment in advanced SCCHN. The toxicity resulting from induction chemotherapy may preclude the delivery of adequate doses of chemotherapy and radiation during CRT In some cases chemotherapy did deliver concomitant chemotherapy if they did it was thought to be sub-optimal Randamised studies of induction chemotherapy followed by CRT verses CRT alone are ongoing

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Recurrent disease
While the vast majority of the patients presenting with stage I and II SCCHN will remain disease free after surgery and/or radiotherapy, the majority of patients presenting in a more advanced disease stage will eventually relapse either locoregionally and/or at distant sites. A few patients with a locoregional recurrence can be salvaged by surgery or reirradiation.

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 However, most patients with recurrent or metastatic disease only qualify for palliative treatment. Treatment options in these patients include supportive care only, single agent chemotherapy, combination chemotherapy or targeted therapies either alone or in combination with cytotoxic agents. Treatment choice - hormone status, comorbidity, prior treatment, symptoms and patient preference.

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Single agent cytotoxics

The 4 most extensively studied single cytotoxic agents are - bleomycin, methotrexate. 5-fluorouracil ancl cisplatin

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Combination chemotherapy
Standard combinations The PF combination gradually emerged as the most commonly used combination chemotherapy regimen in SCCHN,

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 The combination of cisplatin, bleomycin and methotrexate was compared to weekly methotrexate in a randamised prospective trial in 163 patients combination - 48% response to 35% for methotrexate Median survival was the same (5.6 months) both arms

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SOME OTHER STUDIES

Cirauvergne et al. reported that cisplatin can be alone or in combination with vincristine, bleomycin and methotrexate. The response rate was higher with combination(30% vs, 15%). however, the tolerance was significantly better with cisplatin alone.
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 The Liverpool Head and Neck Oncology Groups-reported that in a randomized study of 200 pts,were made to receive either cisplatin alone or methotrexate alone or cisplatin plus methotrexate or PF. No difference in the response rates was found. They reported a survival benefit for the cispiatin alone arm compared with metotrexate alone

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REFERENCES
Current concept in the management of head and neck cancer, pol Specenier, oral oncology,2009.(49)400-415 Oral cancer treatment: developments in chemotherapy and beyond British Journal of Cancer (2002) 87, 933 937 Advances in chemotherapy for head and neck cancerS.A. Bhide, C.M. Nutting Oral Oncology 46 (2010) 436-438

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 Textbook of Radiation Oncology,Principles and practice ,Gaura K Rath,Bidhu Mohanti,Third edition,2007 Internet

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THANK YOU

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