Chemotherapy/oral surgery courses by indian dental academy


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Chemotherapy/oral surgery courses by indian dental academy

  3. 3. INTRODUCTION Malignancies of the head and neck region includes cancer of the oral cavity; i.e., of the lip (International Classification of Diseases, ninth revision (code140-ICD9:140), tongue (ICD9:141), and other intra-oral sites (ICD9: 143-145). The salivary glands (ICD9:142) are not normally included when describing oral cancer, i.e., of the oropharynx (ICD9:146), nasopharynx (ICD9:147), and hypophaynx (ICD9:148). Malignancies of these sites are generally clubbed together as head and neck cancer, or mouth/pharyngeal cancer, or oro-pharyngeal cancer, or sometimes just oral cancer, because of the common etiological/risk factors associated with these sites, with the exception of nasopharyngeal cancers.17 The standard line of management depends on the extent of the disease. Radiotherapy or surgery in advocated for the early lesions and combination of both is practiced in advanced lesion. (Vanderval1984).9 The philosophy of combining surgery and radiotherapy in advanced lesions is that surgery fails at the
  4. 4. periphery and radiotherapy at the poorly oxygenated center of the tumour. So combination of both help in total cure. In search of better results, good cosmesis and better quality of life systemic chemotherapy has been incorporated into the treatment modalities along with surgery or radiotherapy. Systemic chemotherapy is usually accepted as standard treatment for palliation in patients with recurrent and metastatic head and neck cancer who have failed the definitive therapy. Recently with the introduction of more active chemotherapy agents and combination systemic chemotherapy, it is being increasingly used before local therapy in previously untreated and locally advanced head and neck cancer. (A1 Sarraf, 1988). Today, the role of chemotherapy in the treatment of Head and Neck Squamous Cell Carcinoma is being intensively reevaluated. The possibility of inducing major tumour shrinkage with chemotherapy before local treatments has led to the enthusiastic expectation that neoadjuvant chemotherapy could have a major effect in improving survival rates in patients with head and neck cancer. Conflicting data have been derived from an analysis of some
  5. 5. single-arm studies, whose results have been compared with those obtained in historical control patients, treated with local treatment alone. The last ten years have witnessed the changing role of chemotherapy in patients with advanced head and neck Squamous cell carcinomas. This is due in part to the introduction of better agents against the disease and to the high over-all objective response and cure rates produced by combination chemotherapy in patients with previously untreated and advanced cancer.15 The aim of this library dissertation is to exhaustively review the literature on chemotherapy from its historical and developmental aspects, basic principles, its effectiveness in improving the cure rate and also to enlighten upon the recent advances in the field of medical oncology.
  6. 6. EPIDEMIOLOGY AND ETIOLOGICAL FACTORS As see from Table, there is an enormous variation in the incidence of mouth and pharyngeal cancer worldwide. The highest, particularly those of South-East Asia. There are also, pockets of high incidence rates in western populations, such as that of the Bas-Rhin in France. Table 1.1 also shown that in males the incidence of cancer – of the tongue varies from a high of 8.0 to a low of 0.4 per 100,000; of the mouth varies from 12.4 TABLE 1.1 CANCER INCIDENCE RATES OF DIFFERENT SITES IN THE HEAD AND NECK REGION (ICD 140-149), EXCLUDING 142 AND 147): GLOBAL VARIATION Site of cancer Sex High cancer incidence Low cancer incidence Population Rate Population Rate Lip (140) Males Australia, South 13.5 China, Shanghai 0.1 Canada, Newfoundland 12.7 Japan, Miyagi 0.2 Spain, Granada 12.0 India, Bangalore 0.2 Females Australia, South 3.2 China, Shanghai 0.0 Thailand, Khon Kaen 2.7 US, Puerto Rico 0.2 Israel: Jews bone in Israel 1.6 India, Bangalore 0.2 Tongue (141) Males France, Bas-Rhin 8.0 Jaban, Yamagata 0.4 India, Bombay, 6.5 China, Tianjin 0.5 US, Connecticut: Black 6.0 Poland, Kielce 0.8 Females India,Karunagappally, 3.7 Belarus 0.2
  7. 7. Philippines, Manila 2.1 Canada, New Brunswick 0.4 US, Cooecticut: Black 1.6 China, Shangai 0.5 Mouth (143- 5) Males France, Bas-Rhin 12.4 Peru, Lima 0.5 India, Trivandrum, 10.8 China, Tianjin 0.8 Italy, Trieste 8.4 Finland 1.0 Females India, Bangalore, 8.9 Spain, Zargoza 0.2 Singapore, India 3.6 Japan, Yamagata 0.3 Philippines, Manila 3.2 China, Tianjin 0.4 Oropharynx (146) Males France, Somme 13.3 Israel: All Jews 0.3 Slovenia, 6.7 China, Shanghai 0.3 US Connecticut: Black 5.7 Finland 0.4 Females Switzerland, Geneva 1.6 China, Shanghai 0.1 US, SEER: Black 1.0 Belarus 0.1 Thailand, Chiang Mai 0.9 Finland 0.1 Hypopharynx Males France, Calvados, 15.0 China, Shanghai 0.1 India, Bombay 8.3 Israel: All Jews 0.2 Switzerland, Vaud 6.8 Philippines, Manila 0.3 Females India, Madras 2.4 China, Shanghai 0.0 Switzerland, Vaud 1.0 Finland 0.1 US, Atlanta: Black 0.8 Japan, Miyagi 0.2 Notes: Numbers given are age-standardized (world) annual incidence rates per 100,000 population. Source: Parkin et al.(1997) SEER: Surveillance, Epidemiology and End Results (Program of NCI, US). to 0.5 per 100,000; of the oropharynx varies from 13.3 to 0.3 per 100,000; and hypopharynx varies from 15.0 to 0.1 per 100,000. Lip cancer is particularly common in Australian and Canadian
  8. 8. populations with its incidence in males going up to 13.5 per 100,000. It is not so common in the South-East and East Asian countries. For example, in Japanese, Chinese, and Indian populations, its incidence is barely 0.2 per 100,000. The incidence of cancer of the mouth and pharynx is universally higher in males than in females, except in some countries of South-East and East Asian countries. For example, in Japanese, Chinese, and Indian populations, its incidence is barely 0.2 per 100,000. The incidence of cancer of the mouth and pharynx is universally higher in males than in females, except in some countries of South-East Asia. In Bangalore (in Indian), for example, the incidence of cancer of the mouth (ICD9:143-145) in males is lower, at 2.8 per 100,000, as compared to the incidence rate of 8.9 per 100,000 in females (PArkin et al., 1997). Globally, almost haft-a-million cancers of the mouth and pharynx (ICD9:140-149) are diagnosed every year, and three- fourths of these are from the developing world (Parkin et al., 1993). A similar picture emerges as regards deaths from these cancers. Currently, over 400,000 individuals die from this
  9. 9. disease every year, and again, over 80 per cent of these deaths are from the developing world (Pisani et al., 1993). Thus, cancer of the head and neck region is an important cancer globally. For the developing world it is certainly of great significance, and ranks fourth in frequency. In males, however, it is the third most common cancer, and in females it ranks fourth (Parkin et al., 1993). In countries like India, it is in fact the leading cancer site as reported by the various cancer registries in the country (Biennial Report, 1992). However, in western countries also, cancer of the mouth and pharynx is now gaining importance. There is evidence that the incidence of and mortality rates due to this cancer has started to increase in recent decades particularly in men (Johnson, 1991; Moller, 1989; Hakulinen et al., 1986). Va Vacchia et al. (1997) has compared the mortality rates of the cancer of the head and neck region (ICD9: 140-149) at two different time periods for thirty-two European countries and found that in males of age group 35 to 64 years the mortality rate in the early 1990s were two-to-eight- fold higher than that reported in the late 1950s, except in Finland. An increase in the
  10. 10. risk of tongue was particularly noted in young adult (Davis and Severson, 1987; Coleman et al., 1993). The ratios of high and low incidence rates reported world- wide shown in Table 1.1, vary from twenty-five-fold to over a hundred-fold. These high ratios indicate that a tremendous potential for successful implementation of preventive strategies exists, once the risk/protective factors have been identified. These are likely to be more prevalent in males than in females in view of the pattern of distribution of the disease in the two sexes.17 ETIOLOGY The association of betal quid chewing with oral cancer was observed in India as early as 1902 by Niblock and confirmed by Orr (1933) in an excellent epidemiologic study. Niblock (1902) described oral cancer in Madras and Travancore and attributed it to the habit of chewing arecanut and betel leaf and often a lime rich paste with tobacco. Orr (1933) in his study concluded that the use of shell lime and Vadakkan or Jaffna tobacco along with a low
  11. 11. vitamin content in the diet due to tapico consumption, was primarily responsible for the prevalence of oral cancer. Sanghvi and his colleagues (1955) demonstrated for the first time, the association of beedi smoking in addition to chewing with oral cancer in a case-control study at the Tata Memoriral Hospital, Mumbai, India. Besides these risk factors, diet has been implicated in the etiology of oral cancer (Notani 1987) also alcohol usage has been shown to be an independent risk factor (Notani 1988).9
  12. 12. CHEMOTHERAPY, HISTORY OF DEVELOPEMENT AND CLASSIFICATION The word ‘chemotherapy’ can be defined as the use of chemical compounds in the treatment of infection diseases, so as to destroy off evolving parasites or organisms without damaging the host, tissues. The use of the term to cover all drug, or synthetic drug, therapy needlessly removes a distinction which is convenient to the clinician and has the sanction of long usage. By convention the term is used to include therapy of cancer.11 This method of treating cancer has been used in head and neck tumours for palliation and in a curative role, both as integral part of a planned regime involving surgery or radiotherapy or both, and on its own. Certain tumors have been found to respond well to chemotherapy and in management of these it is an accepted part of total treatment. In the context of head and neck malignancies how ever such tumours are rarities and it is the value of chemotherapy in the common tumours such as squamous carcinoma and the salivary tumours which is of real interest to the oral and maxillofacial surgeon.18
  13. 13. History of drug Discovery Chemotherapy has its origin in the work of Paul Ehrilich who coined the term in reference to the systemic treatment of both infection diseases and neoplasia. Many of the Ehrlich’s concepts regarding the experimental evaluation of new therapies using murine or rat models have survived to the present day and have provided a number of important biologic insights that have been applied successfully to the clinical setting. Gilman and Philips conducted the first clinical trial of nitrogen mustard in patients with malignant lymphomas at Yale university in 1947. The results, initially published in 1946, could be said to mark the beginning of modern chemotherapy.13 HISTORICAL OUTLINE OF DEVELOPMENT OF CANCER CHEMOTHERAPY A. Period 1946-1960
  14. 14. - Development of single-drug chemotherapy mainly on empirical basis. - Establishment of critical criteria for the clinical development of new drugs: criteria of response; toxicity; performance status; optimum tolerated dose. - First results from the treatment of leukemias and malignant lymphomas. Generally poor results in the treatment of advanced solid tumours. B. PERIOD 1960-1970 - Development of knowledge of cell kinetics and application of kinetic concepts to the design of chemotherapy schedules. - Broadening of the experimental basis for clinical chemotherapy. - Introduction of pharmacokinetic concepts into clinical chemotherapy. - First developments in the field of combination chemotherapy.
  15. 15. - Introduction of the concept of the controlled randomized clinical trials into clinical chemotherapy assessment. - Further improvement of treatment results in leukemias and lymphomas and significant progress in the results obtained in the treatment of certain solid tumours. C. PERIOD 1970 TILL DATE - Development of the concept of the combined modality approach; improved cooperation between the onco- surgeon, radiotherapist and chemotherapist. - First indication of definitive role for adjuvant chemotherapy. - Recognition, in long-term survivors, of the late toxicities of anti-cancer drugs particularly when combined with radiotherapy. - Development of the concepts of immunotherapy in man. Disappointing results despite widespread application.14
  16. 16. Classification of chemotherapeutic agents 3 Major Classes Examples Malignancies Used in Toxicities 1.Alkylating agents Nitrogen mustard Chlorambucil Ifosfamide Melphalan Thiotepa Cisplatin Carboplatin Lymphomas Chronic lymphoblastic leukemia Sarcomas Myeloma Breast cancer Ovarian cancer Head and neck cancer Leucopenia Anemia Thrombocytopenia Nausea and vomiting Neurotoxicity Alopecia II.Antimetabolites Methotrexate 5-Fluorouracil Ara-C Hydroxyurea Fludarabine Breast and gastrointestinal cancer Acute myeloblastic leukemia Chriocarcinoma Genitourinary cancer Head and neck cancer Lymphoma Mucositis Diarrhea Leucopenia Anemia Thrombocytopenia Alopecia III. Antibiotics Actinomycin-D Doxorubin (Adriamycin) Daunorubicin Mithramycin Mitomycin Bleomycin Mitoxantrone Acute myeloblastic leukemia Germ cell cancer Gastrointestinal, lung, Breast cancer Head and neck cancers Sarcomas Lymphoma Leucopenia, anemia, and thrombocytopenia Mucositis Diarrhea Skin disturbances Alopecia Nausea and vomiting Cardiac and pulmonary toxicity IV. Plant alkaloids Vincristine Vinblastine VP-16 Taxol Testicular, lung, breast and bladder cancers Lymphoma Leukopenia Anemia Thrombocytopenia Alopecia Nausea V.Micellaneous DTIC M-AMSA Sarcomas Acute myeloblastic Leucopenia Anemia
  17. 17. Procarbazine Hexamethylmel amine Asparaginase leukemia Hodgkin;s lymphoma Ovarian cancer Acute lymphoblastic leukemia Thrombocytopenia Nausea Bleeding
  18. 18. PHARMACOKINETICS AND INNOVATION OF NEWER AGENTS Pharmacokinetic of cancer chemotherapy Because there are such narrow margins between effective and toxic dosages for many antineoplastic agents, rational therapy should be assisted by the ability to maintain drug concentrations in specified therapeutic ranges. Thorough pharmacokinetic analyses have been performed for a number of anticancer drugs in a variety of clinical situations. Modeling The classical pharmacokinetic device for describing the disappearance of drugs from plasma is the two-compartment open model. The concept assumes that a drug is instantaneously injected and distributed in Compartment 1(with concentration, C1, and volume, V1) and that all elimination of the drug from the system occurs from this “central” compartment. Immediately after injection the drug may distribute into compartment 2(concentration, C2, and volume, V2) at a rate defined by k12. Drug may move from Compartment 2 (the “peripheral”
  19. 19. compartment) at the rate k21 into the central compartment, thence to be eliminated. The elimination rate is indicated as kel. Movement of drug into and out of either compartment is a first- order process and the rate constants k12, k21, and kel have dimensions of inverse time (e.g., min-1 , hr-1 ). A typical two- compartmental curve for plasma disappearance of a drug is depicted in fig which plots concentrations on a logarithmic ordinate and time on a linear abscissa. This smooth curve can be divided into two discrete exponential terms. Ae-at and Be-t , indicated by hatched lines. The concentration, C, at any time is the sum of these terms. Dividing the curve allows for definition of the earlier portion as the distribution phase of drug disposition, and of the later portion as the elimination phase. Five parameters are commonly found in pharmacokinetic descriptions of antineoplastic agents, and can be calculated from the relationship, C= Aeot + Be- . The concentration at the moment of injection, C0, is usually the peak concentration during rapid intravenous bolus injections and equals the sum of the constants A and B: C0 = A+B. The terminal elimination half life, t1/2, is determined by the
  20. 20. elimination rate constants, : t1/2 = 0.693/. The initial volue of distribution of the drug, Vd, is related to the initial (peak) concentration, Co, and the dose given: dose = Vd x Co, or Vd = dose/Do (dimensional units of dose and Co must be similar, e.g., mg and mg/ml or nmol and nmol/ml). The area under the plasma concentration-time plot provides a measures of the exposure of the body or of a particular tissue to a drug over a period of time. This quantity, often referred to as the area under curve (AUC) or concentration x time product (C x t) of a drug, is calculated by integrating the equation C = Ae-nt + Be- . Because e-t approaches zero at very late times of observation, this integral can be reduced to C x t (or AUC)=A/ + B/. The C x t can be estimated equally well by the trapezoidal rule. Finally, the clearance of a drug Cl =kel x V1. In practice kel and V1 are difficult to determine and clearance values can be estimated as Cl =  x Vd.2
  21. 21. New Chemotherapy Agents To date, the combination of cisplatin and 5-FU represents standard polychemotherapy in association with RT in HN cancers.5 Recently, pre-clinical studies have demonstrated an enhanced activity of RT with new cytotoxic agents such as taxol, which has radiosensitizing properties and anti-cancer activity. A phase I study was conducted with 24-hours paclitaxel infusion and simultaneous RT in locally advanced, recurrent metastatic Head andNeck malignancies. The dose limiting toxicity was febrile granulocytopenia and the maximum tolerated dose of paclitaxel was 75 mg/m2 . All the patients with locally advanced disease demonstrated either a complete or a partial response, and at a median follow-up of more than 1 year only 9 per cent of patients had progressed (Seinberg et al., 1977). The results were confirmed by an additional preliminary report in a study using concurrently taxol at 60 mg/70 per cent showing complete response. Mucositis was the main toxicity (Amrein et al., 1998).
  22. 22. A potentially synergistic activity between RT and gemicitabine has been suggested in recent trials. A pilot study performed at the Institute of Cancer Research, Genoa, Italy and Croce General Hospital, Cuneo, Italy demonstrated a high response rate (90 per cent) in advanced, inoperable Head and Neck cancer patients, treated with alternating RT and a combination of gemcitabine and cisplatin (Benasso et al., 1997; 1998). A complete response was observed in 85 per cent of the patients, of which more than 70 per cent are alive and disease-free after a median follow-up of 1 year. However, modifications to the schedule are mandatory in light of the heavy toxicity observed, but the high anti-tumour activity obtained suggests further investigations on the combination of RT and gemcitabine.17
  23. 23. INTERFERENCE AND MECHANISM OF ACTION ARRESTING IMMATURE CELL PROLIFERATION General Chemotherapy is planned on the basis of observed differences between normal and tumour cells in response to anti- tumour agents used both as single and in combination. Part of the difference between normal and neoplastic cells can be emphasized that cell kinetics cannot explain all the consequences of tumour- cell exposure to a drug, since these are also dependent upon pharmacokinetics, biochemistry and tumour biology. The proliferation of tumour cells is not entirely autonomous, neither is it constant; it varies with the size of the tumour and is related to its blood supply. Animal studies show that the characteristics of tumour cell proliferation have an important influence on the response to chemotherapy. Skipper (1971) has reviewed some of the principles concerned and the following generalizations can be made for experimental tumours.14 |
  24. 24. The Cell Cycle An understanding of cell-cycle kinetics is essential for the proper use of the current generation of antineoplastic agents. Many of the most potent cytotoxic agents act at specific phases of the cell cycle and, therefore, have activity only against cells that are in the process of division. Accordingly, human neoplasms that are currently most susceptible to chemotherapeutic measure are those with a large growth fraction, that is, a high percentage of cells in the process of division. Similarly, normal tissues that proliferate rapidly (bone marrow, hair follicles, and intestinal epithelium) are subject to damage by some of these potent antineoplastic drugs, and such toxicity often limits the usefulness of drugs. On the other hand, slow –growing tumors with a small growth fraction (for example, carcinomas of the colon or lung) are often unresponsive to cytotoxic drugs. Although difference in the duration of the cell cycle occur between cells of various types, all cells display a similar pattern during the division process. This cellcycle may be characterized as follows : (1) there is a
  25. 25. presynthetic phase (G1); (2) the synthesis of DNA occurs (S); (3) an interval follows the termination of DNA synthesis, the postsynthetic phase (G2); and (4) mitosis (M) ensues – the G2 cell, containing a double complement of DNA, divides into two daughter G1 cells. Each of theses cells may immediately reenter the cell cycle or pass into a nonproliferative stage, referred to as G0. The cells of certain specialized tissues may differentiate into functional cells that are no longer capable of division. On the other hand, many cells, especially those in slow-growing tumors, may remain in the G0 state for prolonged periods, only to be recruited into the division cycle again at a much later time. Most antineoplastic agents act specifically on processes such as the synthesis of DNA or of the mitotic spindle. Other block the synthesis of DNA precursors or damage the integrity of DNA. While most of the known anticancer drugs are G1 is the period between mitosis and the beginning of DNA synthesis. Resting cells (cells that are not preparing for cell division) are said to be in subphase of G1, G0. S is the period of DNA synthesis; G2 the premitotic interval; and M the period of mitosis. Example of cell-
  26. 26. cycle-dependent anticancer drugs are listed in blue below the phase in which they act. Drugs that are cytotoxic for cells at any point in the cycle are called cycle – phase-nonspecific drugs. (Modified from Pratt et al., 1994 with permission.) most effective against actively proliferating cells, some (called – cell cycle phase-specific, such as cytosine arabinoside and methotrexate) affect cells only during the S phase or during mitosis (e.g., pactiaxel and vinca alkalids) and will not kill nondividing cells. Damaged cells that cross the G1/S boundary will undergo apoptosis, or programmed cells death, if the p53 gene is intact and exerts its normal checkpoint function. If the p53 gene is mutated and the diversion down the apoptotic pathway does not take place, the damaged and potentially mutated cells will proceed through S phase and emerge as a drug-resistant population.8 All tissues are basically composed of three populations of cells. The first of these consist of cells that are continuously traversing the cell cycle. The second population is composed of cells that leave the cell cycle after a certain number of divisions to
  27. 27. differentiate and later never to divide again, and die. In the third population group, the cells remain dormant and leave the cell cycle temporarily to return when a stimulus or other environmental conditions dictates their re-entry into the cell cycle. An example of these populations is seen in the bone marrow. The marrow is composed of a sub-set of cells which are continuously traversing the cell cycle by dividing and producing more blast cells from precursors.
  28. 28. The second population consists of cells such as granulocytes which have differentiated and are destined to perform a specific function, not undergo further mitosis, and finally to die. Cells in the third population include stem cells which do not cycle until marrow depletion causes them to re-enter the cell cycle and proliferate again. In terms of tissue growth in both normal and abnormal situations, 3 factors regulate the population: 1. The cell cycle and its duration, 2. The growth fraction, 3. The rate of cell loss. The cell cycle time refers to the interval between mitoses. The faster that the cell cycles, the faster the increase in the total number of cells. The growth fraction refers to the subset of the population of cells which are actually traversing the cell cycle. The larger the number of cycling cells, the more cells will be produced. The rate of cell loss refers to the number of cells that die or leave the cell loss population by migrating to other tissue. In an adult organism where growth has ceased to exist, there is a steady state produced where cell loss is equal to cell production. Growth of both normal
  29. 29. and neoplastic tissue occurs as a results of an increase in the total cell number.1 Host-Tumor-Drug Relationship and the response to Chemotherapy. A number of pharmacokinetic parameters such as activation, inactivation, binding to carrier proteins, excretion, and delivery of drug have obvious impact in the clinical response to even the most active agents. As well, the response to an agent given in an appropriate schedule seems to depend heavily on the proliferative status of tumor cell populations, which in turn seems to vary as a function of tumor burden. Thus, understanding the host-tumor relationship with the purpose of designing more effective schedules might be profitable. The early pioneering work of Skipper et al in the L1210 leukemia model led to their statement of the log-kill hypothesis in 1964. This holds that a constant fraction of the tumor cells will survive a given level of effective therapy irrespective to the size of the tumor. Thus, the greatest number of cells will be killed in large tumors, while small tumors should be curable if the same level of therapy is repeatedly applied until virtually every cell is killed.
  30. 30. In 1977 Norton and Simon suggested that tumor killing for a given level of effective therapy varies with the growth rate of the tumor. For L1210 or other tumors which follow logarithmic growth, growth fraction (GF) is large and stays constant. Thus, growth rate accelerates as the tumor grows, rendering large tumors sensitive. In contrast, for Gompertzian tumor growth, which probably more accurately describes human tumors, GF is large initially, but progressively diminishes. Growth rate progressively increases reaching its maximum at about 37% of total volume and subsequently decreases, as decreased GF become significant. Consequently, large tumors, as well as very small tumors, have low growth rates wand are relatively resistant to effective treatment.16 - The doubling time of a tumour increases with the tumour mass up to a critical point while the thymidine labeling index decreases. The growth of most experimental tumours can be described as Gompertzian
  31. 31. (after the statistician who first described the mathematics) rather than linear. - The response to chemotherapy is reflected by the change in the thymidine-labelling index (the number of cells synthesizing DNA). - The shorter the doubling time at the onset of treatment, the better the initial response to chemotherapy is likely to be. - As the tumour volume increases the disease becomes less easy to eradicate by single modality therapy. - Non-phase dependent agents are theoretically more effective than phase-dependent agents against tumours with long times and low thymidine-labelling indices. Gompertzian growth curve
  32. 32. Animal tumours do not grow in a linear manner. As they become larger the growth rate slow. Though few data are available for human tumours, there are suggestions that the above generalizations may apply to human cancer, and proliferation studies may come to be helpful in the choice of chemotherapy and in predicting duration of remission and survival. Phase-specificity / Phase dependency of cytotoxic drugs Phase dependent agents exert an increasingly toxic effect with prolonged exposure of the cells to an effective concentration
  33. 33. while in the sensitive phase. This results from an accumulation of cells in that phase (provided the drug does not prevent entry). Given over a short period, even at high dose level, these agents are not very toxic. Cells not in the sensitive phase, at the time of the brief exposure, will be minimally affected. The toxicity of cycle-dependent or non-phase-dependent drugs for both malignant and normal cells depends on the drug concentration and the duration of exposure. To achieve maximum effect it is therefore logical to administer the drugs intermittently at the highest dose. Some drugs interfere with progression from one phase of the cell cycle to another. Cytosine arabinoside and hydroxyurea, for example, inhibit the progression of G1 cells into S and therefore cells not is S are protected. This protective effect can be overcome by giving the drug intermittently at intervals that permit the non-S phase cells to enter S during the drug-free period. Diagrammatic presentation of the phase specificity of some of the cytotoxic drugs
  34. 34. Relationship between cell kill dosage of cytotoxic agent (Clarysse, Kenis and Mathe, 1976) A. Drugs that kill cells exponentially with increasing dosage B. Drugs that kill exponentially at lower dosages but reach a plateau at higher doses R = Rapidly proliferating cells S = Slowly proliferating cells
  35. 35. Note that for both A and B rapidly proliferating cells are more sensitive than slowly proliferating cells Classification of anti-tumour agents according to their effect on the cell cycle Predominantly non-phase dependent Predominantly phase- dependent Alkylating agents Vinca alkaloids Nitrosoureas Hydroxyurea Anthracyclines Cytosine arabinoside Imidazole carboxamide (DTIC) Methotrexate Mitomycin C 6-Mercaptopurine Actinomycin D 6-Thioguanine Procarbazine Podophyllotoxins - VM26 - VPP 16-213
  36. 36. Drug metabolism Most anti-cancer agents are metabolized in the body, usually to products which are inactive having lower lipid solubility. These are then excreted. In some instances, active metabolites are produced (e.g. cyclophosphamide). Drug absorption, distribution and excretion Anabolic activation is particularly important in the case of anti-metabolites. The role of anabolic and catabolic activation and deactivation is of great importance since it may form the basis of selective activity in different cell types (normal and malignant). Usually, drug metabolism occurs in two phases: EXCRETION Renal and extra-renal Biotransformation to active or inactive product(s) Free drug in plasma ABSORPTION Plasma protein binding Tissue binding (specific and non-specific) tumour and normal tissues
  37. 37. A. Biotransformation – involving hydroxylation, oxidation, reduction or hydrolysis B. Conjugation – e.g. with sulphate, acetyl or a glucuronyl group. Drug metabolism occurs chiefly in the liver but may also take place in the plasma, gastro-intestinal tract, kidneys and lungs. For this reason, hepatic function is an important consideration in the choice of dose of some anti-tumor agents. The anthracyclines (e.g. Adriamycin and Daunorubicin) are excreted mainly in the bile and these drugs produce enhanced toxicity in patients with hepatic failure or biliary obstruction. EXCRETION Most anti-tumour agents are excreted in the bile and urine. Drugs not bound to albumin are filtered by the glomerulus. The proximal tubule possesses two pump systems which transport drugs from plasma to urine, one for the secretary mechanism and probenecid can be used to reduce the elimination of acidic drugs (e.g. penicillins and, possibly, anti-cancer agents such as
  38. 38. Methotrexate). Passive reabsorption of lipid-soluble drugs and the non-ionized fraction of drugs which are weak electrolytes takes place in the renal tubule. Elimination of weak acids by the kidney is increased by alkalinizing the urine. The reverse is true for weak bases. Active tubular reabsorption of ions and various solutes can also take place in the proximal tubule. Excretion in tears, sweat, saliva and in the breath is relatively unimportant but may be the cause of unusual toxicity such as the conjunctivitis seen following the use of high dose Methotrexate. Several host dependent factors have important influences on drug absorption, distribution, metabolism and excretion. Illness which affects renal and hepatic function, bone- marrow reserve or gastro-intestinal function may well have a marked influence on the efficacy and toxicity of a drug. Methotrexate, for example, is largely excreted in the urine and its toxicity may be markedly enhanced in patients with renal failure.14
  39. 39. AGENT WHICH PONTENTIATE THE FUNCTION OF CHEMOTHERAPEUTIC AGENTS Chemosensitization Hypoxic cell Chemosensitizers In the animal model the hypoxic cell sensitizers misonidazole and SR-2508 enhance of the cytotoxicities of alkylating agents and nitrosoureas. However, the optimal method of administration is not known. Dose-response curves for the different sensitizers and alkylating agents are needed to optimize efficacy and reduce toxicity. A randomized trial using intravenous melphalan with or without misonidazole in metastiatic non-small-cell lung cancer showed a small, but statistically significant, improvement in response rate with misonidazole. Other single-arm trials of misonidazole and alkylating agents have been negative or inconclusive. Perfluorochemicals as Chemosensitizers Fluosol-DA and carbogen breathing increased the antitumor efficacy of bleomycin and cyclophophamide in the animal model. With cyclophosphamide when the Fluosol dose was increased
  40. 40. from 0.1 to 0.3 ml and carbogen breathing extended from 6 hr the tumor growth delay tripled. Similar effects were seen with bleomycin. Chemosensitization by Vasocative Drugs Several vasoactive drungs can selectively reduced blood flow and increases the percent of hypoxic areas in experimental tumor systems. By promoting hypoxia in the tumor, the cytotoxicity of drugs which are active in hypoxic conditions is potentiated. When hydralazine was given prior to or after the alkylating agents melphalan, melphaln’s antitumour activity increased by a factor of 2 and 3, respectively. However, systemic toxicity was only increased by a factor of 1.2. Additional animal studies have shown that hydralazine cause a dose-dependent decrease in tumour energy metabolism (measured by PNMR spectroscopy). PH, and perfusion pressure in tumors. Despite these alternations in tumor metabolism, toxicity is minimal in the treated animals. These data suggest that hydralazine might be beneficial combined with therapy which is specifically toxic by hypoxic cells (e.g., hyperthermia, mitomycin C, and perhaps after
  41. 41. alkylting agents). Verapamil and other calcium chemotherapeutic agents also potentiate the efficacy of certain chemotherapeutic agents by preventing drug efflux and altering tumor blood flow . Agents That Are Toxic to Hypoxic Cells The bioreductive alkylating agents mitomycin and porfiromycin may target to hypoxic cells. In a randomized trial of radiation with or without mitomycin in head and neck cancer, improved disease-free survival was observed in the patients treated with mitomycin . SR-4233 is a new benzotriazine which is 15-to 50-fold more toxic to anoxic than to well-oxygenated human tumor cells in vitro. However, the invivo results with SR-4233 were less impressive. A new analog, SR-4482 is more toxic than SR-4233 in vitro, and less toxic in vivo.Several important effects of the nitroimidazole compounds (hypoxic cytotoxicity, thiol depletion, and chemosensitization) are felt to be due to reduction of the parent compound. The benzotriazines are activated by enzymatic reduction. The differential activity of various reductases in
  42. 42. normal and malignant tissues may lead to the logical selection of the appropriate sensitizer in this class. NONHYPOXIC RADIATION SENTIZIERS Halogenated pyrimidines Bromodeoxyuridine (BUdR) and iododeoxyuridine (IUdR), are halogenated pyrimidines, which were designed as thymidine analogs. The initial hypothesis was that these drugs could be incorporated into the DNA of actively dividing cells and act as radiosensitizers. Clinical trails should attempt to achieve sustained plasma levels of 10m IUdR for optimal radiosensitization. Early clinical trials using the halogenated pyrimidines demonstrated excessive normal tissue reactions without increased antitumor efficacy in patients with head and neck cancer. Since the halogenated pyrimidines are absorbed preferentially in actively dividing cells, it is not surprising that severe mucosal toxicity was encountered. Since BUdR is associated with photosensitivity, recent interest has focused on IUdR. More encouraging results may be observed in the Phase II trials
  43. 43. combining halogenated pyrimidine with radiotherapy for gliomas and sarcomas, since the irradiated, surrounding normal tissues have lower mitotic rates . Two clinical studies of continuous intrahepatic artery infusions of IUdR have shown that human colon cancer cells absorb almost six times the amount of IUdR compared with adjacent normal liver. Regional infusion also decreases systemic IUdR leves 50-78% . DNA repair inhibitors Inhibitors of DNA repair may act as radiosensitizers. Inhibitors of DNA replications which act by inhibiting DNA- dependent DNA polymerases can decrease the radiation damage at the chromosome level. However, the effectiveness of inhibiting both replication and repair of DNA does not always correlate with clinical response. In human cervical cancer cell lines, the DNA repair inhibitors reduced radiation survival. Various DNA repair inhibitors have been studies in the laboratory. Hydroxyurea reduced survival at both high and low
  44. 44. radiation doses. Beta-ARA-A and caffeine are more effective in reducing all survival at low doses. Nicotinamide In several animal models nicotinamide has bee shown to preferentially radiosensitize tumors, perhaps by reducing hypoxia. The radiation enhancement ratio ranged from 1.2 to 1.7 in animal tumors and 1/0 to 1.3 in normal tissues. Platinum analog Cis-plantinum is one of the most active chemotherapeutic agents. However, its radiosensitizing properties have not been exploited with fractionated radiation because cis-plantinum’s normal tissue toxicity. The less toxic transiomer trans-platinum and other platinum analogs interact with radition in vitro. Trans- platinum might be an ideal sensitizer for most radiation fractionation schedules used in clinical practice. Thiol Depletors As the thiol content in cells increases, most cells are protected from the cytotoxicity of radition of alkylting agents. In vitro, thiol depletion leads to radiosensitization. When BSO
  45. 45. depletes cellular glutathione in vitro, radiation injury increases. However, the presence of other reducing agents (such as ascorbic acid or -tocophero) blunts the sentizing effect of BSO in vivo. Lowering glutathione levels in tumours might potentiate the effect of hypoxic radiosensitizers. However, glutathione depletion’s major likely role will be in chemosensitization.4 Chemoprevention The most effective methods of preventing oral cancer are avoidance of the major etiological factors, tobacco and alcohol. However patients with premalignant conditions in the mouth have a high risk of developing carcinoma, and patients successfully treated for oral cancer have a high risk of developing seconds primary neoplasms. Accordingly there is now a considerable interest in measures to prevent the development of cancer in this high risk group, including the use of chemical agents. Retinoids Vitamin A and related compounds have several properties which suggests that they may be useful as chemopreventive agents in oral squamous cell carcinoma. They are modulators of
  46. 46. epithelial cell differentiation, both in vitro and in vivo. They probably act by regulating gene expression. Cell nuclei contain retinoic acid receptors that mediate the biological effects of retinoids. The ligand for these receptors is probably all-trans- retinoic acid, to which retinoids must be metabolized to exert their biological effect. In experimental animals vitamin A deficiency causes squamous metaplasia similar to that induced by chemical carcinogens. It has been found that vitamin A and related retinoids can reverse the metaplsia in vitamin A deficient animals. They have also been shown to inhibit the growth of squamous carcinoma cell lines in vitro. There have been several studies of treatment of oral dysplastic leukoplakia by retinoids. Hong et al. used isotretinoin in a dose of 1-2 mg/kg per day for 3 months in a placebo- controlled trail involving 44 patients. The drug produced major clinical responses in 67 per cent of patients compared with 10 per cent who received placebo (P=0.0002) and reversed the dysplastic change in 56 per cent. At this dosage isotretinoin has appreciable toxicity, with peeling of the skin, chelitis, facial erythema and
  47. 47. hypertriglyceridaemia in about 75 percent of patients, headaches and dyspepsia also occasionally occur. The leukoplakic changes recur after stopping treatment. However a subsequent study demonstrated that low dose maintenance treatment (0.5 mg/kg) after the end of the 3 months of high dose therapy was well tolerated and prevented recurrences. Vitamin A in high dosage was shown to reverse premalignant change in Indian betel chewers. Vitamin A is generally less loxic than isotretinoin, but effective dose levels, i.e.300 000 IU per day, produce similar if less severe side effects. In both of the above studies -carotene was also tested as maintenance treatment because of its lower either vitamin A or isotretinoin, probably because it is less easily metabolised to the active ligand. Experience with isotretinoin in the treatment of leukoplakia has led to being tested as adjuvant treatment in patients with oral and laryngeal carcinoma who were disease-free after primary treatment. There was no influence on recurrence rates of the original tumours, but there was a significant reduction in the
  48. 48. incidence of second primary tumours. This experience led to the setting up of larger multicentre chemopreventive trails in cured head and neck cancer patients, for examples the Euroscan trail using vitamin A. Antioxidants Agents with antioxidant properties can inhibit the effects of many toxins including carcinogens. N-acetylcysteine, a precursor of intracellular glutathione, inhibits the mutagenic effect of carcinogens such as benzpvrene in vitro.10
  49. 49. CLINICAL APPLICATION AS PRIMARY TREATMENT AND AS ADJUVANT IN MALIGNANT LESIONS One of the most important factors in selecting chemotherapy is the incidence of clinical and histological cure rate achieved by such treatment. Present chemotherapy regimes do not produce cure rate in all patients treated and considerable improvement is required in this area. Also, it is very important to mention that after clinical cure rate is achieved, the additional number of courses of chemotherapy administered is critical in determining the frequency of histological cure rate and duration of overall survival. A clinical cure rate occurring after one course of chemotherapy, when additional courses of the same chemotherapy are planned, is a more favorable prognostic factor than clinical cure rate occurring at the end of the last planned course of chemotherapy. It is important in evaluating chemotherapy as part of multimodality treatment that in addition to the minimum number of courses needed to achieve clinical cure rate.
  50. 50. The goals of including chemotherapy as part of the multimodality treatment in patients with locally advanced head and neck cancers are better overall survival and/or quality of life. When our best chemotherapy is proven to be of value as part of multimodality therapy, then the possibility of delaying or performing less extensive surgery can be studied. The main purpose would be to lessen the cosmetic and/or functional morbidity caused by radical surgical procedures without jeopardizing the survival of the patients. Induction (initial) chemotherapy To investigate the effectiveness of chemotherapy as part of multimodality treatment, the drugs must be administered before definitive surgery and/or radiotherapy when gross and measurable disease in present. As with most new therapies patients with more advanced disease (stage III and IV) are usually selected for trials. The use of chemotherapy as initial treatment started in the mid 1970s because of the increased local toxicities of simultaneously administered chemotherapy and radiotherapy and lack of benefit of the combined approach at that time.
  51. 51. Initially high dose methotrexate with leucovorin rescue as utilized. In general, the overall response rate to this agent alone in previously untreated patients with locally advanced disease was poor, with no clinical cure rate and no evidence of improved survival of these patients as compared with historical controls. With the demonstration that cisplatin was effective as a single agent in patients with recurrent cancer of the head and neck, many trails were initiated with cisplatin containing combinations in patients with previously untreated and locally advanced disease, summarizes the overall results of trials with cisplatin alone or in combination with other agent(s) that are known to be effective against head and neck cancers. More than sixty such trials were reported up to 1985. All except two trials were single arm pilot studies. Because of patient heterogeneity and marked variation in the doses and schedules of drug administration it is difficult to draw conclusions. It does seem that cisplain combinations are superior to cisplatin alone in achieving clinical cure rate and in overall response rate. The most common agent(s) combined with cisplatin
  52. 52. are bleomycin alone or with other agents like methotrexate, vinblastine or Oncovin. The overall clinical cure rate rate seems high with cisplatin and 5-FU infusion than with any of the cisplatin and bleomycin combinations. Also, the incidence of histological cure rate in those clinical cure rate patients who underwent surgical resection is high after cisplatin and 5-FU infusion than with any cisplatin and bleomycin combinations. The side effects of these combinations are acceptable and reversible. From the clinical trails, patients achieving clinical cure rate to the initial chemotherapy had significantly superior survival than those patients with less than cure rate to the treatment regardless of the subsequent definitive therapy. More important those cure rate patients who were found to have no histological disease after surgical resection have statistically superior survival when compared with those clinical cure rate patients who had residual disease at surgery. Oral cancers constitute about 10% and 6% of all cancer cases in males and females respectively in India (ICMR 1989). Carcinoma of buccal mucosa is more commonly seen among
  53. 53. females than males with a 3:1 incidence. About 80% of these tumors are locally advanced (Stage III and IV) at the time of presentation, inspite of oral cavity being easily accessible for examination and early identification. Buccal mucosa is made up of stratified squamous epithelium covering the internal surface of lips and cheeks. Pathologically buccal mucosal cancers vary from verruccous exophytic indolent types with well demarcated borders to deeply infiltrating ulcerative painful tumor with poorly defined margins. More than 90% of these tumors are squamous cell carcinomas and the remaining make up for minor salivary gland tumors, melanoma, sarcoma etc., (Strong and Spiro 1987). Million and Cassissi (1984) reported that 95% of oral cancers were squamous cell carcinomas. The standard line of management of buccal mucosa cancer depends on the extent of the disease. Radiotherapy or surgery is advocated for early lesions (Stage I & II) and combination of both practiced in advanced lesions (Stage III & IV) (Vanderwaal 1984). The philosophy of combining surgery and radiotherapy in
  54. 54. advanced lesions is that surgery fails at the periphery and radiotherapy at the poorly oxygenated center of the tumor. As seen earlier, majority of the patients present with advanced lesions and even combination of surgery and radiotherapy may not be possible in most of the patients, as the tumors either will be unresectable or the patient will not be fit to undergo surgery due to associated medical conditions. Over the years the results with surgery and radiotherapy has not improved much and has reached a plateau (RTOG, 1980, Perez). The locoregional recurrence with the above modality is as high as 60% (Vikram, 1984; Kramer, 1985). The combined modality of surgery and radiotherapy in advanced cases has given better results only when surgery was very extensive and cosmetically inacceptable (Pinsolle, 1992). In search of better results, good cosmesis and better quality of life systemic chemotherapy has been incorporated into the treatment modalities along with surgery or radiotherapy. Systemic chemotherapy is usually accepted as standard treatment for palliation in patients with recurrent and metastatic head and neck
  55. 55. cancers who have failed the definitive therapy. Recently with introduction of more active chemotherapy agents and combination systemic chemotherapy is being increasingly used before local therapy in previously untreated and locally advanced head and neck cancers (Al Sarraf 1988). Systemic chemotherapy has been used in various forms as detailed below. Induction chemotherapy: This is other wise called as neoadjuvant chemotherapy. This started being used from mid 1970’s because of increased local toxicities seen with simultaneously administered chemotherapy and radiotherapy and lack of benefit of combined approach during 1960’s (Al Sarraf 1988). The drugs are administered prior to start of definitive therapy. The rational for neoadjuvant chemotherapy is that a) ability to deliver drug to untreated tumors with intact vascularity, b) Better tolerance to chemotherapy, c) to enhance the efficacy of planned definitive local therapy after cytoreduction and eradication of sub clinical metastasis and d) for better overall survival and quality of life.
  56. 56. Concurrent chemotherapy: The drugs are used simultaneously with definitive therapy (Radio Therapy or Surgery). Chemotherapy after surgery and before radiotherapy (“Sandwich”) Sandwich method: Here chemotherapy is administered after surgery and before delivering radiotherapy. Various agents have been used either singly or in combination as chemotherapy. The agents used are Methotrexate, bleomycin, 5-flurouracil (5-Fu), vinblastine and cisplatinum. The commonly used combinations being methotrexate and 5-Fluorouracil (Tarpley 1975; Al Sarraf 197; Alan Coates 1984; Ervin 1987; Jaulerry 1991) and Cisplatinum and 5-Fluorouracil (Singhal 1993). Ten years of clinical trails have not yet identified the best chemotherapy regimen to be combined with definitive treatment (Al Sarraf 1988). Methotreaxate and –Fluorouracil has been used in combination in advanced head and neck cancers as neoadjuvant chemotherapy agents (Alan Coats 1984; Jacobs 1982; Pitman 1983; Mackintosh 1988) with varying success. Oral cancers are common tumors presenting in advanced stages. The effect of treatment is easily assessable in oral cancers. Neoadjuvant chemotherapy has shown its effectiveness in head and neck cases. So we want to assess the effect of combined
  57. 57. neoadjuvant chemotherapy with definitive radiotherapy in carcinoma of buccal mucosa. In patients with previously untreated respectable and operable, locally advanced head and neck cancer, the timing and sequence of effective chemotherapy as part of multimodality treatment is important and needs to be investigated. The following problems existed with induction chemotherapy when given as the initial treatment in combined modality therapy: 1. Patients refuse surgical resection or any further therapy, especially those achieving the best response to chemotherapy. 2. The planned surgery after initial successful chemotherapy is not the same as that done in previously untreated patients with identical tumors. 3. The results of surgery after three courses of chemotherapy, even with achievement of up to a 50% clinical cure rate, are no different than adequate surgery without preoperative treatment. 4. Chemotherapy yields higher objective response rates in patients with smaller tumor masses (stage III v stage IV). Thus a higher effectiveness is expected of the same chemotherapy when it is given to patients with minimal residual disease
  58. 58. after surgery (microscopic) rather than gross bulky disease present before surgery. Because of the above, a pilot study for patients with locally advanced but respectable cancer in which three courses of cisplatin and 120 hour 5-FU infusion were given after surgery and before radiotherapy. Following the demonstration of the feasibility of this approach two pilot studies were activated by the RTOG in 1981, one using induction chemotherapy followed by surgery and postoperative radiotherapy in respectable patients, while the second uses the same chemotherapy after surgery and before radiotherapy. The side effects of chemotherapy were the same regardless of the sequence of chemotherapy in relation to the definitive treatments. Survival favored chemotherapy in the middle “sandwich”, in spite of more stage IV patients and poorer performance status in this group. This led to a phase II trail RTOG 83-22, Head and Neck Cancer Inter Group I-0034) in which after surgical resection patients are stratified and randomized to receive radiotherapy or three courses of cisplatin and 5-FU infusion followed by radiotherapy.
  59. 59. Combined chemo-radiotherapy Since the late 1960s several efforts were made to commune chemotherapy with radiotherapy. The concept of combining chemotherapy and radiation in the treatment of locally advanced squamous cell carcinoma of the head and neck, particularly unresectable or inoperable lesions, is attractive. Many single agents or combinations of drugs were used with radiotherapy . The most common single agents selected for combination with irradiation were, hydroxyurea, methotrexate or bleomycin. The efficacy of these agents combined with radiotherapy has not been established in randomized oral cancer, which often results in interruption of therapy. The search for better and safer agents to combine with radiotherapy led to the administration of Cisplatin. Cisplatin is an active agent in squamous cell cancers of the head and neck. It does not produce mucositis of the oral cavity and should not interfere with the delivery of radiotherapy. Cisplatin possesses properties of radiosensitization that have been observed both in vitro and in vivo. It has been suggested that the cytotoxic activity of cisplatin is
  60. 60. independent of cellage, and that radiation enhancement is both dose and cell cycle phase dependent. The combination of cisplatin and radiotherapy produced high CR rates when given preoperatively in resectable stage III head and neck malignancy and IV head and neck cancer or as the total treatment in unresectable and/or inoperable disease. Also, this combination is being tested as postoperative treatment at Wayne State University in Detroit. Because of the high complete response rate obtained with the combination of cisplatin and 5-FU, this two drug regimen was added to radiotherapy, and resulted in improved local control. The combination of the cisplatin and radiotherapy is being compared to radiation alone in phase III randomize trails by ECOG, RTOG, and SWOG. We feel that chemo-radiotherapy may play an important role in the treatment of patients with locally advanced head and neck cancer and clinical investigation in this area continues.
  61. 61. Chemotherapeutic agents used concurrently with radiotherapy in advanced cancers Methotreaxate Hydroxyurea 5-Fluorouracil Bleomycin Cisplatin Combined Agents Bleomycin, vincristine, and methotrexate (BVM) Bleomycin, and methotrexate Bleomycin, Adriamycin,* and 5-FU Bleomycin, and cytoxan Bleomycin, cytoxan, and vincristine Mitomycin-C, and 5-FU Cisplatin, and 5-FU  Adrimycin (Adria Laboratories, Columbus, OH) Chemotherapy After Radiotherapy It has been reported that chemotherapy is most effective in animal models when used for the eradication of small tumor masses. Thus, chemotherapy administered after the definitive
  62. 62. treatments of surgery and/or radiotherapy may be efficacious in eradicating minimal residual disease. Randomized trails of single agent chemotherapy (methotrexate or cisplatin) post definitive treatments of surgery and/or radiotherapy were initiated in many cooperative groups. In the NCI head and neck contract trial one of the experimental arms required that six doses of cisplatin be administered following one course of cisplatin plus bleomycin, surgery and postoperative radiotherapy. Only about 10% of the patients finished the total six courses while about 30% either progressed or died, or refused therapy respectively. Chemotherapy postdefinitive treatment is an important concept that needs further evaluation.15
  63. 63. DRUG SENSITIVITY TO VARIOUS LESIONS, THERAPY REGIMES Chemotherapy for recurrent or metastatic SCC H&N When a patient relapses after extensive surgery or radiation therapy, treatment options are limited. Traditionally, chemotherapy has been used in this patient population, with chemotherapeutic single agents and combination chemotherapy being evaluated for their response as well as their impact on the patient’s quality of life. Four drugs have been noted to have major activity in recurrent and metastatic SCC H&N. They are (1) methotrexate, (2) cisplatin, (3) belomycin, and (4) 5- fluorouracil. Other chemotherapeutic agents are noted to have activity but are not as frequently used. Methotrexate Include in the antimetabolite class of agents, methotrexate exerts its cytotoxic effect through inhibition of the enzyme dihydrofolate reductase. This enzyme is responsible for
  64. 64. maintaining the intercellular pool of folates in reduced state, which is required for the synthesis of the purine nucleotides. For most oncologists, this is the standard chemotherapeutic agents to which other single agents and combinations are compared. The overall response rate using methotrexate as single agents approximately 31%, with predominantly partial response seen and few complete response noted. The initial dose is 40mg/m2 , given intravenously weekly until toxicity is noted, usually in the form of mucositis or leucopenia. Various doses and schedules have been used, including leucovorin as a bone marrow protector in the higher doses. Nevertheless, pooled response rates are very similar between the moderate and high doses of methotrexte, and toxicity plus cost are more appreciable at the higher doses. Cisplatin Cisplatin is considered a heavy metal compound and is believed to exert its activity by causing DNA cross-linking. This agent has been extensively evaluated for patients with recurrent SCC H&N, with single-agents activity in the range of 28%.
  65. 65. Cisplatin has been evaluated when given on a weekly basis, every 3 weeks as an intravenous bolus, or by continuous infusion. All schedules have shown similar response rates. The issue of dose intensity has also been addressed, with dose-realted toxicity being a limiting factor, particularly involving renal toxicity and neurotoxicity. The typical dose used has been between 80 and 100mg/m2 , with no clear advantage see when higher doses are used. Cisplatin is usually given every 3 to 4 weeks, with pre and post-hydration plus mannitol infusion to protect renal function. Bleomycin Bleomycin is a mixture of glycopeptides considered in the class of antibiotic considered in the class of antibiotic neoplastic agents with activity in the G2 and mitotic phases of the cell cycle. It has been one of the more frequently used agents for head and neck cancer and has a single agent response rate of approximately 21%. Bleomycin has been administered as a bolus or by continuous infusion, with equal activity in both continuous infusion, with equal activity in both schedules but with a suggestion of an improved toxicity profile when the continuous
  66. 66. infusion, with equal activity in both schedules but with a suggestion of an improved toxicity profile when the continuous infusion schedule is used. The dose-limiting toxicity of bleomycin is its cumulative effect on pulmonary function, making it difficult to administer after several courses. The single-course dosage frequently used is 10 to 15 mg/m2 daily for 3 to 4 days every 3 to 4 weeks. 5-Fluorouracil One of the most frequently used chemotherapeutic agents for head and neck cancer, 5-FU is usually used in combination with cisplatin. 5-FU is pyrimidine antimetabilite that is converted intracellularly to fluorodeoxyuridine monophosphate (5-F- DUMP); a potent inhibitor of thymidylate synthetase, thereby inhibiting DNA synthesis. Another way -5-FU mediates its activity is by forming fluorouridine triphosphate (FUTP), which is incorporated into a interferes with the function of RNA. Single-agent response rate with 5-FU is approximately 15%. 5-FU has been extensively used with cisplatin because of preclinical synergy noted.
  67. 67. Recently, it has been observed that 5-FU can be potentiated when used in conjunction with leucovorin, which is the reduced form of folate. Leucovorin stabilizes the 5-FU and thymidylate synthetase tenary complex. When 5-FU is administered as a bolus daily for 5 days, the dose-limiting side effect is predominalty bone marrow suppression. If the schedule is altered to a continuous venous infusion over 24 hours daily for 4 to 5 days, the limiting toxicity changes to mucositis, diarrhea, and cutaneous erythema. Cardiac toxicity has also been noted. The continuous infusion schedule was used in an effort to reduce myelosuppression, but, indeed, it seems to have improved the activity of this drug in SCC H&N. The dosage most frequently used has been 800 to 1000 mg/m2 by continuous intravenous infusion for 72 to 96 hours. Other single agents, not as widely used but with reported activity in SCC H&N in the range of 15% to 36%, are the following: (1) carboplatin, an analogue of cisplatin whose dose- limiting toxicity is myelosuprresion, specifically thrombocytopenia (2) cyclophosphamide and its analogue, ifosfamide, and hydroxyurea; (3) general classes of drugs with
  68. 68. limited single – agent activity, including the anthracylines (doxorubicin), the vinca alkaloids, mitomycin, and the nitrosureas. Combination chemotherapy for recurrent or metastatic SCC H&N In the 1970s, the many trails using combination chemotherapy for patients with recurrent or metastatic SCC H&N combined the active single agents cisplatin, bleomycin, and methotrexate. The response rates noted were encouraging, with the cisplatin-based combination thought to be superior to the non- cisplatin-based regimens. In the 1980s, investigators at Wayne State University combined cisplatin with 5-fluorouracil, both as a bolus and by continuous intravenous infusion for 96 hours. The initial results were very encouraging, with an objective response rate of 78% noted; more importantly, a 29% complete response rate was obtained for patients with recurrent and metastatic disease. Other investigators have used the cisplastin/5-FU combination with the same dose and schedule but have obtained overall response rates,
  69. 69. usually in the range of 25% to 30%, with approximately 10% achieving a complete response. Efforts have been made over the past several years to improve the response rates of the cisplatin 5-FU combination. Some of this research efforts has focused on (1) substituting the analogue carboplatin for cisplatin, (2) modulating 5-FU with leucovorin, and (3) dose escalating the cisplatin combined with the use of chemoprotectors to try to prevent cisplatin-related toxicities. Unfortuanately, these efforts have failed to significantly improve the response rate of this combination, and no overall improvements have been seen with these approaches. Eleven randomized trails have looked at comparing single agents, such as cisplain, 5-FU, and methotrexate, versus combination chemotherapy, including cisplatin and 5-FU, for patients with recurrent or metastatic SCC H&N. Review of these studies reveals that, although slightly higher response rates have been noted using combination chemotherapy, this has not translated into an improved disease-free or overall survival advantage. In addition, combination chemotherapy has added
  70. 70. toxicity and cost for the patient when compared with single agents. Although higher responses and, in particular, complete responses, can be obtained with the use of cisplatin and 5- fluororuacil, more toxicity is noted with this combination than with single agents. Primary Chemotherapy Primary chemotherapy refers to the use of chemotherapy, given either before local therapy, concurrent, with radiation, or after local treatment has been completed. The rationale for using chemotherapy prior to local treatment is based on factors such as (1) an improved patient performance status, (2) an intact vascular supply to the tumor bed, and (3) the eradication of micrometastasis to prevent regional and distant metastases. Induction (Neoadjuvant) The initial observation made was that response rates using single agents, such as cisplatin, bleomycin, and methotrexate, were higher for patients who had not received prior local therapy than for patients in whom disease recurred. In the 1970s,
  71. 71. Randolph et al combined cisplatin and bleomycin for two cycles prior to local treatment. In this study, the combination of cisplatin and bleomycin as induction chemotherapy yielded an overall objective response rate of 71%, with a 20% complete response rate. Subsequently, investigators at Wayne State University combined cisplatin and infusional 5-FU for three cycles prior to local treatment and reported an 88% overall response rate, with 54% of the patients achieving a complete response. Other investigators have also used the cisplatin and 5-FU regimen for three courses prior to local therapy with less favorable results. Parts of the disparity can be explained by patients selection factors, because patients with N2 or greater disease have been noted to obtain a complete response rate in the range of 20%. The pilot feasibility studies pointed to an improved overall and complete response rate obtained with induction chemotherapy, without compromising local therapy. Concurrent Chemoradiation Therapy Although there have been no new agents developed to add to the response rate of combination chemotherapy for patients
  72. 72. with locally advanced, unresectable SCC H&N, the concurrent use of single agents, such as bleomycin, 5-FU, methotrexate, hydroxy- urea, mitomycin-C, and cisplatin, with radiation therapy has been investigated. The rationale for combining these two modalities is based on preclinical data suggesting the radiation-sensitizing effects of certain chemotherapeutic agents. Also, combining these two modalities of treatment simultaneously applies the concept of dose-intensity – administering the largest amount of treatment per unit time in an effort to over-come any inherent drug or radition resistance. Adjuvant Chemotherapy Chemotherapy given after local therapy has been tried with the rationale of eradicating micrometastases and thereby possibly reducing the local, regional and distant metastatic rate. Unfortunately, of the six randomized trials using chemotherapy in this fashion, none has shown a survival advantage. Nevertheless, one large study showed a statistically significant decrease in distant metastases for patients receiving chemotherapy after local
  73. 73. therapy, even though overall survival rates in both arms were not different. Nasopharyngeal cancer Standard treatment for nasopharyngeal carcinoma worldwide has been radiation therapy because of this tumor’s known radiation sensitivity and poor anatomic location, making surgical intervention difficult. In fact, early-stage disease is well controlled with radiation therapy alone, but in advanced stage disease, survival is considerably less. For example, for Stage III disease using radiation therapy alone, 5-year survival has been reported in the range of 15% to 40% and for Stage IV disease, it is only 0% to 30%. Patients with nasopharyngeal carcinoma have a high likelihood to developing distant metastasis, which seems to correlate with the amount of cervical adenopathy. In patients with bilateral neck involvement, there is an established 80% chance for developing distant metastases at a later date, usually involving the lung, liver, or bone.
  74. 74. Nasopharyngeal carcinoma is believed to be a chemosensitive tumor; in fact, multiple single agents, such as cisplatin, 5-FU, methotrexate, bleomycin, the vinca alkaloids, and doxorubicin, have known activity in this disease. Various studies have reported rate, of which less than 20% are complete responders, with the use of cisplatin and non-cisplatin-based regimes for patients with recurrent or metastatic nasopharyngeal carcinoma. Salivary gland carcinoma Salivary gland carcinomas make up approximately 5% to 10% of all head and neck malignancies. These tumors demonstrate very diverse anatomic, histologic, and biologic behaviour. Traditionally, treatment for these tumours has been surgery with or without radiation therapy. Chemotherapy has been reserved for patients with recurrent and/or metastatic disease, and the benefits of chemotherapy have been predominantly palliative for this group of patients. A number of single agents have shown activity in this disease, but the most active and
  75. 75. frequently used are cisplatin, doxorubicin, 5-FU, cyclophosphamide, and methotrexate. Depending upon the histologic type of the tumor, methotrexate, for example, has been shown to have a single-agent response rate of approximately 36% in mucoepidermoid cancer, which is similar to the activity seen for this agent in SCC H&N. However, for other histologic types of salivary tumours, the response rate with methotrexate is much lower, approximately 6%. In contrast, doxorubicin is relatively inactive in mucoepidermoid carcinoma but is active in other salivary gland histologic types. Single-agent cisplatin has also been extensively used with a wide range of response rates from 17% to 70%. Multiple combinations of the most active agents have been tested, with the most frequent combination being cisplatin and doxorubicin, with or without 5-FU or cyclophosphamide. The responses with doxorubicin-based combinations have been in the range of 35% to 100% with a median response of approximately 50%.
  76. 76. Miscellaneous groups A number of diverse histologic tumors present less commonly in the head and neck area for which chemotherapy has been utilized. These include sarcomas, lymphomas, esthesioneuroblastomas, neuroendocrine carcinomas, and Merkel cell carcinomas. Sarcomas Sarcomas can arise from either the bone or soft tissues in the head and neck but are rare. When they d occur, the most common of these tumors are the osteogenic sarcomas, malignant fibrous hitiocytomas, rhabdomyosarcomas, fibrosarcomas, synovial sarcomas, and angiosarcomas. Surgery and radiation therapy remain the treatment of choice for local disease, but depending upon the extent of disease, grade and location, local and regional recurrences can be significant, with distant metastases predominantly involving the lung, liver and bone. Chemotherapy, particularly with doxorubicin-based regimens, has been used and can provide palliation. Response
  77. 77. rates with chemotherapy are similar to those seen for other sites and are largely partial response. For one particular subtype, rhabdomyosarcoma, chemotherapy added to surgery and radiation therapy has been reported to improve 5-year survival compared with that seen with surgery and/radiation therapy alone. Lymphomas Both Hodgkin’s and non-Hodgkin’s lymphomas can present in the head and neck area. When the disease is localized to the head and neck, the treatment usually consists of radiation therapy only. However, this disease is frequently found in multiple areas, and chemotherapy and radiation therapy are used with substantial success. The most commonly used chemotherapeutic agents for the lymphomas are the alkylating agents (i.e., cyclophosphamide) in combination with doxorubicin and vincristine. Prednisone is also incorporated into these regimens.3
  78. 78. MULTIDISCIPLINARY APPROACH TO ADVANCED SQUAMOUS CARCINOMA OF THE HEAD AND NECK 21 STAGING MEDICAL ONCOLOGY RADIOTHERAPY SURGICAL ONCOLOGY DENTISTRY Chemotherapy No treatment Adjuvant chemotherapy If response to chemotherapy Radiotherapy and/or surgery If no response to chemotherapy
  79. 79. Price-Hill Schedule A For Head and Neck Cancer 19 Hydrocortisone 500mg IV Hydrocortisone 500mg IV 5FU 500mg IV MTX 100mg IV MTX 100mg IV MTX 100mg IV BLEOMYCIN Vincristine 2mg IV 15mg 15mg 15mg 15mg FOLINIC ACID
  80. 80. Combination chemotherapy regimens in metastatic head and neck carcinoma with >40% response rates (15 or more patients) 16 Investigator† Drugs DeWell (1975) CTX, VCR, MTX, PDN, 5FU Richman (1976) BLE, ADR, CCNU, VCR, HN2±BCG Eisenberger (1980) BLE, HOU Huang (180) BLE, MTX, VBL, CCNU Yagoda (1975) BLE, MTX Cortes* (1980) MTX, 5FU, BLE Costanzi* (1976) BLE, MTX, HOU Pitman (1979) MTX, CDP Livingston (1976) MTX, ADR, MCCNU, CTX, VCR, BLE Kaplan (1979) MTX, BLE, CDP Price* (1975) 6MP, BLE, VCR, ADR, MTX, HOU Adapted from Khandekar and Dewys. *”Kinetci” design CTX-Cyclophosphamide; VCR-Vincristine; MTX-Methodologies blastine; 6MP-6 Mercaptopurine; HOU-Hydroxyurea; CDp-Cis-diammine dichloroplatinum; BCG-Bacillus Calmette-Guerin.
  81. 81. Drug Combination Effective in head and neck cancer (Clarysse, Kenis and Mathe, 1976) Drug combinations No. evaluated No. with 50% regression Methotrexate + bleomycin 4 2 15 8 Methotrexate + vincristine 28 15(53%) Dibromodulcitol + bleomycin 20 5(25%) Adriamycin + bleomycin 8 4 MeCCNU + cyclophosphamide + bleomycin + vincristine (COMB) 32 11(35%) Methotreaxate + 5-fuorouracil + cyclophosphamide + vincristine (modified COMF) 10 8 Methotrexate + cyclophosphamide + vincristine+prednisone (Cooper’s regimen) 18 4(22%) CCNU+HN-2+ adriamycin + bleomycin + vincristine (BACON) 13 7 Methotrexate+6-mercaptopurine + procarbazine + chlorambucil + thio-tepe + streptonigrin + rufochromomycin + vinblastine 82 45(55%)
  82. 82. Results of the Combination of Cisplatin I and 5-FU In Patients With Recurrent Head and Neck Cancer 15 Authors Year Drug Schedule No. of Patients Response % CR Overall Kish, et al. 1984 C 1000 mg/m2 d1 5-FU 1.0 g/m2 /24 h d1-4 30 27 70 Rowland, et al. 1984 C 1000 mg/m3 d1 5-FU 1.0 g/m2 /24 h d1-4 21 24 71 Creagan, et al. 1984 C 1000 mg/m3 d1 5-FU 1.0 g/m2 /24 h d1-4 20 - 25 Merlao, et al. 1984 5-FU500 mg/m2 /6 h d1-4 Leucovorin 200mg/m2 /dd1-4 C 50 mg/m2 d5 17 0 6 Sridhar, et al. 1984 C 100 mg/m2 d1 5-FU 40 mg/m2 /h d2-6 20 17 72 Kish, et al. 1985 C 100 mg/m2 d1 5-FU 1.0 g/m2 24 h d1-4 18 22 72 Kish, et al. 1985 C 100 mg/m2 d1 5-FU600mg/m2 bolus d1&8 20 10 20 Merlano, et al. 1985 C 20 mg/m2 d1-5 5-FU400-200/m2 bolusd1&5 27 15 59 Dasmahapatra, et al. 1985 C 100 mg/m2 d1 5-FU 1.0 g/m2 /24 h d1-5 18 - 11 Amrein, Waitzman 1985 C 80 mg/m2 /24 h d1 5-FU 800 mg/m2 24 h d2-6 39 18 46 Raymond, Cyman 1985 C 100 mg/m2 d1 5-FU 1.0 g/m2 24 h d1-5 16 Not Stated 75 Fosser, et al. 1985 C 100 mg/m2 d1 5-FU 1.0 g/m2 /24 h d1-5 21 19 62
  83. 83. SINGLE AGENT ACTIVITY 22 Drug Dose Schedule Evaluable Patients Responsea Cyclophosphamide 8-10 mg/kg IV 56 2 CE, 35 improved 4 mg/kg/dy IV 4-60 mg/kg single dose 150-300mg/dy; then 100-200 mg/day PO 15 2 improved 2g in divided doses for 8 days; then 100 mg/day PO 6 3 PR, 3 improved Cyclophosphamide IV, PO, IP, or intrapleural ranging from 100mg daily PO to 8g IV loading dose preceding PO therapy 4 2 excellent and 2 moderate responses Cyclophosphamide 50-200 mg/day PO 1 Improved 30mg/kg IVP; then 10- 15 mg//kg q1-2 wks Cyclophosphamide Various IV and PO doses 4 1 improved Chlorambucil 0.2 mg/kg/day X 42 days PO 34 1 CR, 4 PR Nitrogen mustard Total dose, 0.5-0.8 mg/kg 2 None 0.6mg/kg in 3 divided doses 41 5 improved 5-FU 15mg/kg/day X 5 IV; then 7.1mg/kg every other day until toxicity. Maximum loading dose per day, 1,000 mg 84 1 CR, 4 PR, 20 improved 5-FU 1,000 mg/day X 5; then 500mg every other day until toxicity 2 2 improved 5-FU 4-8mg/kg/day X 14-42 days 17 3 improved 5-FU 15-20 mg/kg/wk 12 1 CR, 1 PR
  84. 84. Drug Dose Schedule Evaluable Patients Responsea Hydroxyurea 80mg/kg q 3 days X 6 wks and 40 mg/kg PO in 2 divided doses per day X 21 days; escalated to 60 mg/kg/day after 21 days if not toxic 1 10 1 improved 3 improved Vinblastine 0.1 mg/kg/wk to a maximum of 0.3 mg/kg/wk IV 23 4 PR 7, improved Procarbazine 150-400mg/day PO or 250-1,250mg single dose IV 31 3 improved Adriamycin 60-75 mg/m2 IV q 3 weeks 12 0 Adriamycin Review of various IV dose schedules, i.e., 60- 90 mg/m2 , q 3 weks; 20-30 mg/m2 /day X 3, q 3 wks; 0.4mg/kg day 1, 2, 7, 8, 9, 10, q 2 wks; 1 mg/kg/day, q 7 days and 75 mg/m2 : IA over 7 2 h 76 11 PR Mitomycin C 50mg/kg/day X 6; then 50 mg/kg every other day until toxicity 4 0 a CR = Complete response; PR = Partial response (50% or more in tumor measurements); Improved = Less than a PR not quantitated
  85. 85. Selected Multidrug Combination in recurrent and Metastatic Disease22 Investigator Treatment Evaluable Patients CR + PR Response Rate (%) Median Duration (months) Wittes et al. CDDP 2 mg/kg IV q 3 wks 24 3 13 4 Bleo 0.25 mg/kg IV daily until toxicity, 1-2 mg daily maintenance Moran et al. (1982) CDDP 50-60 mg/m2 IV q 22 days (day 2) MTX 30 mg/m2 IV (day 1) 23 8 35 4 Medenica et al. Bleo 15 mg IV wk 26 13 50 8.5 (mean) Vogl and Kaplan (1979) MTX 40 mg/m2 IM day 1 & 15 31 19 61 CR 7+ Bleo 10 mg/m2 IM day1, 8, 15 PR3 CDDP 50 mg/m2 IV day 4; 3- wk cycles Caradonna and Paldine (1979) Bleo 15 mg/m2 IV day 1 17 14 74 4 MTX 20 mg/m2 IV day 1 CDDP 120 mg/m2 IV day 2 Murphy et al. (1980) CDDP 100 mg/m2 IV day 2 24 11 46 5 MTX 30 mg/m2 IV days 1&15 Bleo 30 mg ± day 1 weekly X 6 Von Hoff et al. (1981) CDDP 50 mg/m2 5 X day 1 26 9 35 3 Bleo 6 U/m2 SC q 8 h X 12, days 1-4 MTX 7.5mg/m2 IM days 4-6 Pitman et al. (1983) MTX 124-250 mg IV 23 15 65 PR3 5-FU 600 mg/m2 IV 1h later CR6 Leucovorin 10 mg/m2 q 6 h X 6 given weekly Ringborg et al. (1983) Same as above: MTX + 5-FU + leucovorin 16 9 52 Not available
  86. 86. Investigator Treatment Evaluable Patients CR + PR Response Rate (%) Median Duration (months) Huang et al. (1980) Bleo 10 U SCC days 1 and 4 38 Jacobs (1982) Same as above: MTX + 5- FU+ leucovorin 30 517 MTX 20 mg PO days 1 and 4 Vinblastine 8 mg/m2 IV day 1 CCNU 175 mg/m2 PO day 1 Hydroxyurea 2 g PO days 1 and 4 Woods et al. (1979) Vincristine 2 mg IV day 1 33 8 24 4 MTX 200 mg/m2 24-h IV infusion with leucovorin rescue, day 1 Bleo 15 mg/day 48-h IV infusion day 2 Creagan et al. (1981) Adriamycin 40 mg/m2 day 1 25 16 64 7 Cyclophosphamide 400 mg/m2 day 3 CDDP 40 mg/m2 every 21 days cycle Kish et al. (1982) CDDP 100 mg/m2 day 1, q 3 wks 30 21 70 PR6.5 5-FU 1,000 mg/m2 days 1-4 by continuous IV infusion CR11
  87. 87. ROUTE OF ADMINISTRATION OF VARIOUS CHEMOTHERAPEUTIC AGENTS The administration of chemotherapy has not always been as it is today. As recently as the 1950s, the physician administered the medications and the nurse was left to care for any side effects (Lind and Bush 1987). The first chemotherapy drug. A nitrogen mustard (mechlorethamine), was discovered in the 1940’s and in comparison to other areas of medicine, the field of oncology was still in its infancy. As the number of available drugs increased and the technology of chemotherapy administration became more complex. ROUTES OF ADMINISTRATION The goal of chemotherapy administration is to optimize drug availability. In an attempt to deliver drugs in high concentrations to areas of greatest clinical need and to improve the antitumor effects, many diverse routes of drug administration have been developed (Haskel 1980). The current routes of administration include: intrathecal (IT)
  88. 88. intra-arterial (IA) intracavitary (IC) subcutaneous (SQ) intramuscular (IM) topical (TOP) oral (PO) intravenous (IV) The following three routes of administration allow for high drug concentrations in the disease area while minimizing the systemic concentrations, and thus the side effects: intrathecal intra-arterial intracavitary Administering chemotherapy intrathecally allows the drugs to reach the central nervous system to prevent or treat local disease. The majority of chemotherapy agents do not cross the blood-brain barrier, so they must be delivered directly into the cerebrospinal fluid. This is accomplished by either:1) a lumbar puncture or 2)utilizing an indwelling subcutaneous cerebrospinal
  89. 89. fluid reservoir, such as the Ommaya reservoir (Heyer-Schulte del Caribe, Anasco PR). The benefits and risks to the patient must be determined before either method of administration is chosen. To put it concisely, include: 1) having a lumbar puncture performed for each treatment (weighing the pain and potential complications that procedure involves) or 2) the potential complications of surgically inserting and Ommaya reservoir, but utilizing a consistent port for each treatment. The Ommaya reservoir is a mushroom-shaped, reusable, self-sealing, silicone port which is connected to a catheter placed in the ventricle (Figure ). The reservoir is accessed by inserting a hypodermic needle, usually a small-gauged butterfly needle with an attached three-way stopcock and syringe, directly into the dome. During the procedure an amount of cerebrospinal fluid, equal to the amount of medication to be injected, is removed. The medication is injected into the reservoir and, once the needle is removed, the domed reservoir is manually compressed and released to mix the medication with the cerebrospinal fluid (Brown 1987). This
  90. 90. procedure is usually performed by a physician using strict aseptic technique. Cerebrospinal fluid reservoir and mode of use Intra-arterial infusions treat an isolated organ or inoperable tumor. The chemotherapy agents are administered through a catheter inserted into an artery usually in the liver, head, neck, or brain. The celiac artery is used to treat the liver, the external carotid artery for the head and neck area, and the internal carotid artery for brain tumors (Johnston and Pratt 1981). The catheters are inserted into the artery surgically with general anesthesia or using angiographic catheterization and a local anesthetic. The
  91. 91. catheters are then connected to either an implanted or portable pump. There are two impantable pumps currently being used: the Infusaid pump (Shiley Infisaid Inc, Norwood, MA), and the Medtronic pump (Medtronic, Minneapolis). The Autosyringe Division, Hooksett, NH), is an example of a portable systems used for intra-arterial infusions. Portable infusion pump Three other modes of drug administration are used less frequently: subcutaneous
  92. 92. intramuscular topical Many of the antineoplastic agents are irritating or damaging to body tissue, so it is inadvisable to give a subcutaneous or intramuscular injection of these agents. Some drugs that can be given by the subcutaneous route are cytosine arabinoside (ARA-C) and the interferons, while bleomycin and methotrexate can be given intramuscularly. L-asparaginase is one drug that may be given either by the subcutaneous or intramuscular route. Topical administration has limited usefulness with only mechlorethamine and 5-fluorouracil cream having this method as one of their routes of administration, (Dorr and Fritz 1980). Occasionally, a specific protocol or drug may be administered using one of the methods. The last two routes of chemotherapy administration are the most common: Oral Intravenous
  93. 93. The oral route is usually preferred but absorption can be unpredictable. Several factors must be considered before choosing the oral route: patency and functioning of the GI tract, presence of nausea, vomiting, or dysphagia, the patient’s state of consciousness, the patient’s willingness to comply to the schedule, and the availability of the medication in oral form. The intravenous (IV) route of administration is the most common method used to deliver chemotherapy. It allows absorption of the drug thus providing predictable blood levels (Brown 1987). Intravenous drugs may be administered through a peripheral access, a vein in the patient’s arm or hand, or through a central venous access device, such as a silicone, silastic catherter, or an implanted infusion port. The three major adviser reactions to the intravenous route of administration are: phlebitis, venous flare, and extravasation (Troutman 1985). There are four methods of intravenous administrations: push (IVP) piggyback (IVB) sidearm
  94. 94. infusion, continuous or intermittent Intravenous push refers to directly administering the medication into the intravenous cannula, through either an angiocath or a butterfly needle. A piggyback method denotes there is a main line of intravenous fluid connected into the intravenous cannula. The solution to be piggybacked is connected, usually in the port closest to the patient, into the main intravenous line. The sidearm method of administration is the route of choice for chemotherapy with vesicant properties. Again, a main line of intravenous fluid, freely flowing, is connected into the intravenous cannula. The physician directly administers the medication, slowly, into the part closest to the patient while continually assessing the peripheral IV site for complications and extravasation. This method, as could the piggyback method, allows for further dilution of the chemotherapeutic agent with the main fluid. The two solutions must be compatible. The infusion method may last from several minutes (bolus infusions) to several days, 24 hours a day (continuous infusions).
  95. 95. Selecting a Vein Assess veins in both arms and hands. Do not use veins in compromised limbs/lower extremities Criteria for Vein Selection Appropriate Choice of Venipuncture Site Ideal Vein/Best Location forearm Large, soft resilient veins in forearm, hand Ideal Vein/Undesirable Location Large, soft, resilient veins in hand/antecubital fossa; small, thin veins in forearm hand Satisfactory Vein/Best Location Small, thin veins in forearm/hand forearm Satisfactory Vein/Undesirable Location hand small thins veins in hand; veins in forearm not palpable or visible Unsatisfactory Vein/Undesirable Location Consider central venous line* small, fragile veins, which easily rupture, in hand/forearm Unsatisfactory Vein/Undesirable Location Consider central venous line* veins in forearm/hand not palpable or visible *In some situations, central venous lines are inserted before the patient is started on a chemotherapy protocol.
  96. 96. Dealing with the “veinless” patient One of the most common dilemmas facing oncology nurses is trying to administer chemotherapy to the “veinless” patient (described by Lokich 1978). With the variety of central venous access devices, both catheters and subcutaneous ports, this issue doesn’t have to be a problem. 1. In an attempt to dilate the veins, apply moist heat to the arms for 5-10 minutes (Johnston Early, Cohen and White 1981). 2. Once the soaks are removed, work efficiently while the veins are dilated. 3. Local vein manipulation may also aid dilation: a. Appropriate use of a tourniquet or blood pressure cuff to encourage pooling of venous blood. b. “Milking” the veins from proximal to distal (elbow to hand) c. Gently striking the surface of the vein
  97. 97. 4. Catheter selection is very important in this setting. The veins may well be small and an appropriately sized needle will decrease trauma. 5. Perform the actual techniques and preparation for venipuncture according to the institution’s policies and procedures. Controversial Issues in Chemotherapy Administration Issue Solution Rationale Administration site Use antecubital fossa Larger veins permit more rapid infusion and administration of drugs Larger veins permit more rapid circulation of potentially irritating drugs Avoid antecubital fossa Mobility of arm restricted Risk of extravasation increased due to patient mobility Ealry infiltration and extravasation difficult to assess due to subcutaneous tissue Repair of infiltration would be difficult and debilitating for the patient Needle size Larger gauge (#19- 21 scalp vein needles) Potentially irritating drugs reach circulation sooner, with less irritation to peripheral veins Small gauge (#23- 25) Smaller gauge needles less likely to puncture wall of vein; less scar tissue at insertion site; and less pain on insertion
  98. 98. Increased blood flow around needle increases dilution of the drug Reduced incidence of mechanical phlebitis Slower infusion rate – may reduce side effects, i.e., nausea and vomiting Sequencing of medications Administer vesicant first Vascular integrity decreases over time, i.e., more stable and less irritated at the beginning of treatment Initial assessment of vein patency is most accurate Irritating agents may cause venous spasm and pain Administer vesicant last Vesicants are irritating, may increase vein fragility, and cause spasm at onset of drug administration. The nurse must assess whether the spasm and complaint of pain is an infiltrate or not Particular intravenous method of administration Use sidearm method Freely running intravenous lines allow for dilution of drugs Use direct IV push method Integrity of the vein can be more easily assessed Extravasation can be noted earlier
  99. 99. DRUG DELIVERY SYSTEMS One of the fastest growing areas in the oncology setting today is the area of drug delivery systems – catheters, implantable ports, and infusion pumps. By the time this book is published, numerous new products will be available that were only a thought at the time the authors were formulating this section. Previously, a venous access device was only indicated when the patient had unsatisfactory veins for further cancer therapy. Now there are several indications for early placement of a venous access device (Simon 1987). Patients receiving continuous infusions of chemotherapy, nutritional supplements, or antibiotics either at home or in the hospital are also ideal candidates for such devices. Two central venous access devices will be discussed in this section: silastic right atrial catheters and implantable venous access ports (VAP).
  100. 100. Silastic Catheters The Broviac silastic catheter (Davol Inc., Cranston, R.I.) was first reported in 1973. It was a small-bore, 18-gauge catheter that as originally described as being safe for infusing Total Parenteral Nutrition (TPN) on a long-term basis (Simon 1987). In 1979, the larger bored, 16-gauge Hickman catheter (Davol Inc., Cranston, R.I.) was reported to be sage for intravenous infusions including blood transfusions and blood samples (Simon 1987). The Hickman-Broviac catheters became the front runners for not only a type of central venous access device but also for a surgical technique of inserting such catheters. The Hickman-broviac technique for catheter insertion was designed to reduce an undesirable complication in the long-term use of these catheters: infection (Raaf 1985). Implantable Venous Access Ports (VAPs) Venous access ports (Vaps) consist of two main features: the port housing made of either plastic, stainless steel, or titanium with the resealable silicone septum, and the silastic catheter which
  101. 101. is either preattached to the housing or comes as a separate piece needing attachment during the insertion procedure. A “tunnel” is made under the skin toward the collarbone for the catheter. The catheter is inserted into the subclavian or internal jugular vein (Lawson and Finley 1988). Both the port and the catheter are sutured into place, including closing the pocket containing the port. Once this is completed, the VAP is completed under the skin.12
  102. 102. MARKERS USED TO INTERFERE WITH CELL GROWTH TO STUDY THE PERFORMANCE OF THE DRUG Biologic markers of prognosis Although certain clinical parameters such as disease stage, tumor histology and grade, site of origin, nodal metastasis, and perineural spread generally correlate with the prognosis of patient with cancer of the salivary glands, there is still a great deal of heterogeneity in outcome among patient with similar clinical parameters. The inability of clinical parameters to consistently predict the outcome of patients with cancer of the salivary glands has led to the recent extensive study of various biologic markers as predictors of prognosis in patients with cancer of the salivary glands. Tumor suppressor Genes and Oncogenes Cancer is disease of altered cellular genes. These altered genes, in turn, initiate or promote the malignant phenotype by inducing changes in key events involved in regulation of the cell
  103. 103. cycle. Examples of such altered gene expression include inactivation of tumor suppressor genes and or overexpression of oncogenes. Several such alterations have been investigates as potential prognostic indicators in patients with salivary gland cancers. Point mutation of TP53 (formally known as p53), a tumor suppressor gene, was associated with an increased likelihood to tumor recurrence in patients with ACC. More recent studies emphasize the prognostic value of TP53 alteration as an independent prognostic marker and its association with radiotherapy and chemotherapy resistance in patients with ACC. TP53 expression was detected in more than one third of patients with high-grade cancer of the salivary glands, and it has been implicated in carcinogenesis of tumors of salivary glands origin. Loss of wild-type TP53 and activation of C-MYC and RAS p21 proto-oncogenes may play important roles in the malignant transformation of salivary gland pleomorphic adenoma. Another example of a tumour suppressor gene is p27 (Kipl), a cyclin-dependent kinase inhibitor negatively that regulates the
  104. 104. G1 phase progression of the cell cycle by binding to the cyclin E/cyclin-dependent kinase 2 complex. A recent study of the expression of p27 in patients with MEC indicated its usefulness as a marker of tumour progression aggressiveness and prognosis. Significant correlation was found between low p 27 expression and tumour with high-grade, advanced T-stages, positive nodal status, and advanced clinical stages (p=0.01). Multivariate analysis indicated that p27 expression was a significant predictor of overall survival among these variables poor prognosis. DNA Ploidy Several studies have suggested a potentially important prognostic role for flow cytometric measurement of DNA content in salivary neoplasms. Significant statistical correlation between DNA content and tumour size, histologic grade, lymph node metastasis and survival was found in patients with malignant tumors of the salivary glands. High grade tumours such as undifferentiated carcinoma, adenocarcinoma, salivary duct carcinoma, squamous cell carcinoma, and pleomorphic adenoma were more likely to have aneuploid DNA stem lies, and the survival time of patients
  105. 105. with aneuploid tumours was considerably lower than for patients with diploid tumours. Aneuploid tumors are also more likely to be present with TP53 abnormalities. These data emphasize the potential usefulness of DNA measurements as a prognostic indicator in patients with malignant tumours of the salivary glands. Markers of Cellular Proliferation Several markers of cellular proliferation were recently reported to bear prognostic significance in patients with cancer of the salivary glands. The Ki-67 index, a marker of cellular proliferation, was found to be significantly higher in malignant than benign neoplasms of the salivary glands. The Ki-67 index also correlated significantly with malignant tumour grade and patient survival. Among patients with ACC, expression of Ki-67 was related to the morphologic type – the solid subtype had the highest frequency of Ki-67-positive cells. Because this subtype is recognized as the most aggressive of these tumours. Ki-67 may have the potential for providing an indication of the clinical behavior of ACC.
  106. 106. Argyrophilic Necleolar Organizer Regions Several studies have found a positive correlation between the argyrophilic nucleolar organizer region (AgNOR) count and the aggressive clinical course of malignant salivary gland tumors. Vuhahula and colleagues measured Ag NOR counts in 34 patients with ACC to determine (1) whether AgNOR count correlates with histologic grade and (2) whether AgNOR count can offer any additional prognostic advantage over histologic grading. All unfavourable cases had high AgNOR counts regardless of histologic grade, suggesting that the metabolic alterations associated with the degree of malignancy of ACC may be partly portrayed by the AgNOR count, irrespective of histologic appearance. Hormone Receptors A variety of hormone receptors, including estrogen, progesterone, and androgen receptors, have been identified in and correlated with the clinical behavior of salivary gland tumors. Shick and coworkers confirmed the presence of progesterone