Chemo for head&neck ca

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Chemotherapy in head & neck cancer:

Chemotherapy in head & neck cancer Dr.Ashkarali


Introduction Toxic action of nitrogen mustards Cells of the haematopoietic system 50 years ago Research into the development cytotoxic agents Current chemotherapeutic agents As a result of screening compounds In vitro against murine and/or human cancer cells in vivo against rodent tumour models


Introduction Molecular basis of cancer Target directed drug therapies. The aim being to develop agents that can modulate or inhibit specific molecular targets identified as being essential for tumour growth .


PRINCIPLES OF CHEMOTHERAPY Chemotherapy are targeted at the process of cell division. The rationale being that cancer cells are more likely to be replicating than normal cells. Their action is not specific, they are associated with significant toxicity. An understanding of the principles of tumour biology and cellular kinetics is helpful to appreciate the mechanisms of action of cancer chemotherapy

Principles of tumour biology:

Principles of tumour biology Cellular kinetics Cell cycle Normal nondividing cells are in GO. When actively recruited into the cell cycle they then pass throug four phases: Gl : S (synthesis): G2: M (mitosis): Uncontrolled cell division is a result of interference in the normal balance of the cell cycle. The cell cycle is divided into a number of phases governed by an elaborate set of molecular switches. the growth phase in which the cell increases in size and prepares to copy its DNA; which allows doubling of the chromosomal material; a further growth phase before cell division; where the chromosomes separate and the cell divides.


TUMOUR GROWTH The kinetics of any population of tumour cells is regulated by the following: Doubling time: Growth fraction: Cell loss: Death, desquamation, metastasis and migration. the cell cycle time, which varies considerably between tissue types the percentage of cells passing through the cell cycle at a given point in time which is greatest in the early stages which can result from unsuccessful division

Cell signalling:

Cell signalling Cells respond to their environment via external signals called growth factors. These interact with cell surface receptors that activate an internal signalling cascade. This ultimately acts at the DNA level through transcription factors that bind to the promoter regions of relevant genes, stimulating the cell cycle and influencing many important processes including cell division, migration, programmed cell death (apoptosis).


ONCOGENES Proto oncogenes are involved in controlling normal cell growth. Mutated forms, known as oncogenes , Inappropriate stimulation of the cell cycle and excessive cell growth. Alternatively, malignancy can also arise secondary to abnormal activation of a normal gene. The consequences of gene activation associated with tumour growth include 1) Excess growth factor production 2) Alteration of growth factor receptor genes so that they are permanently switched on 3) Alteration of the intracellular cascade stimulating proliferation


TUMOUR SUPPRESSOR GENES These act as a natural brake on cell growth. This can have several important effects, which include: Impairment of the inhibitory signals influencing receptor genes or intracellular signalling 2) loss of the counter signals controlling protooncogene function Inhibition of apoptosis, often as a consequence of a mutation of p53, the protein associated with DNA repair Metastatic spread A tumour is considered malignant when it has the capacity to spread beyond its original site and invade surrounding tissue. Normally cells are anchored to the extracellular matrix by cell adhesion molecules, including the integrins . Abnormalities of the factors maintaining tissue integrity will allow local invasion and ultimately metastases of the tumour cells.

Mechanism of cell death:

Mechanism of cell death Two types of cell death: apoptosis and necrosis. Apoptosis is a regulated form of cell death that may be induced or is preprogrammed into the cell (e.g. during development) and is characterized by specific DNA changes and no accompanying inflammatory response. It can be triggered if mistakes in DNA replication are identified. Necrotic cell death is caused by gross cell injury and results in the death of groups of cells within a tissue. Loss of this protective mechanism would allow mutant cells to continue to divide and grow, thereby conserving mutations in subsequent cell divisions. Many cytotoxic anticancer drugs and radiotherapy act by inducing mutations in cancer cells which are not sufficient to cause cell death, but which can be recognized by the cell, triggering apoptosis.


FRACTIONAL CELL KILL HYPOTHESIS AND DRUG DOSING Clinical responses to antitumour therapies are defined by arbitrary criteria that have been used as part of the evaluation process in assessing the potential utility of novel agents. Tumour size: complete response is defined as the apparent disappearance of the tumour; Partial response represents a reduction of more than 50 % Progression is defined as an increase in tumour size by more than 25 % 4) Stable disease is anintermediate between partial response and tumour progression. Tumour products: biochemical or other tests can be used to assess response, including circulating tumour markers


CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS Target cells in a particular phase of their growth cycle more toxic to cells that are actively dividing rather than cells in both the proliferating and resting phases. PHASE SPECIFIC CHEMOTHERAPY Methotrexate and vinca alkaloids, kill proliferating cells only during a specific part or parts of the cell cycle. Antimetabolites , such as methotrexate , are more active against S-phase cells (inhibiting DNA synthesis) vinca alkaloids are more M-phase specific (inhibiting spindle formation and alignment of chromosomes) .

Classification of chemotherapeutic agent:

Classification of chemotherapeutic agent Cell cycle non specific chemotherapy These drugs, for example alkylating agents and platinum derivatives, have an equal effect on tumour and normal cells whether they are in the proliferating or resting phase. They have a linear dose-response curve; that is, the greater the dose of the drug, the greater the fractional cell kill. Classification according to metabolism Alkylating agents These highly reactive compounds produce their effects by covalently linking an alkyl group (R-CH2) to a chemical species in nucleic acids or proteins. The cell then either dies or is physically unable to divide or triggers apoptosis. The damage is most serious during the S-phase, as the cell has less time to remove the damaged fragments.

Alkylating agents:

Alkylating agents Nitrogen mustards (e.g. melphalan & chlorambucil ); Oxazaphosphorenes (e.g. cyclophosphamide,ifosfamide ) Alkyl alkane sulphonates ( busulphan ); Nitrosureas (e.g. carmustine , lomustine Tetrazines (e.g. dacarbazine , mitozolomide & temozolomide ) Aziridines ( thiopeta , mitomycin C); Procarbazine .

Heavy metals:

Heavy metals These include carboplatin , cisplatin and oxaliplatin Cisplatin is an organic heavy metal complex. Chloride ions are lost from the molecule after it diffuses into a cell allowing the cross-link with the DNA strands, mostly to guanine groups. This causes intra- and interstrand DNA cross-links, resulting in inhibition of DNA, RNA and protein synthesis. Carboplatin has the same platinum moiety as cisplatin,but is bonded to an organic carboxylate group. This leads to increased water solubility and slower hydrolysis that has an influence on its toxicity profile. It is less nephrotoxic and neurotoxic , but causes more marked myelosuppression . Oxaliplatin belongs to a new class of platinum agent. It contains a platinum atom complexed with oxalate and a bulky diaminocyclohexane (DACH) group. It forms reactive platinum complexes that are believed to inhibit DNA synthesis by forming interstrand and intrastrand cross-linking of DNA molecules


ANTIMETABOLITES Antimetabolites are compounds that bear a structural similarity to naturally occurring substances such as vitamins, nucleosides or amino acids. They compete with the natural substrate for the active site on an essential enzyme or receptor Folic acid antagonist Pyrimidine analogues Purine analogues


CYTOTOXIC ANTIBIOTICS Most antitumour antibiotics have been produced frombacterial and fungal cultures (often Streptomyces species).They affect the function and synthesis of nucleic acids in different ways. Anthracyclines (e.g. doxorubicin, daunorubicin,epirubicin ) intercalate with DNA and affect the topoiosmerase II enzyme. 2) Actinomycin D intercalates between guanine and cytosine base pairs. 3) Bleomycin consists of a mixture of glycopeptides that cause DNA fragmentation. 4) Mitomycin C inhibits DNA synthesis by cross-linking DNA, acting like an alkylating agent. Spindle poisons Vinca alkaloids The two prominent agents in this group are vincristine and vinblastine that are extracted from the periwinkle plant. They are mitotic spindle poisons that act by bindingto tubulin , the building block of the micro tubules


LIMITATIONS OF CYTOTOXIC AGENTS Cytotoxics predominantly affect rapidly dividing cells so They also only influence a cell's ability to divide and have little effect on other aspects of tumour progression such as cytotoxics are associated with a high incidence of adverse effects .. do not specifically target cancer cells in the resting phase. tissue invasion, metastases or progressive loss of differentiation bone marrowsuppression , alopecia, mucositis , nausea and vomiting


CHEMOTHERAPY IN HEAD AND NECK CANCER Worldwide, squamous cell cancer of the head and neck accounts for an estimated 500,000 new cancer cases per year. One-third of these patients present with early stage disease that is amenable to cure with surgery or radiotherapy alone Currently, surgery or radiotherapy are the standard curative options for early stage head and neck cancer. Chemotherapy in combination with surgery, radiotherapy or both is employed for loco regionally advanced disease. A llowed improved organ preservation when combined with radiotherapy and has led to a reduction in rates of"distant metastases Chemotherapy


CHOICE OF CHEMOTHERAPY IN HEAD AND NECK CANCER The single agents active in head and neck cancer with response rates between 15 and 40 percent methotrexate , cisplatin , carboplatin , fluorouracil, ifosfamide,bleomycin,paclitaxel and docetaxel . Cisplatin is particularly popular for use either as a single agent or in combination with other drugs because for a long time it was viewed as one of the most active drugs in squamous head and neck cancer Taxoids and gemcitabine are now gaining favour and are being incorporated into many current drug trials

Chemotherapy strategies:

Chemotherapy strategies Combination chemotherapy : Combinations of cytotoxic agents are widely used for many cancers and may be more effective than single agents Possible explanations for this include: Exposure to agents with different mechanisms of action and nonoverlapping toxicities 2) Reduction in the development of drug resistance The ability to use combinations of drugs that may be synergistic In practice, the predominant dose-limiting toxicityty of many cytotoxic drugs is myelosuppression and this limits the doses of individual drugs when used in combination

Adjuvant chemotherapy:

Adjuvant chemotherapy This is the use of chemotherapy in patients known to be at risk of relapse by virtue of features determined at the time of definitive local treatment (e.g. tumour grade, lymph node status, etc .). The intention of adjuvant chemotherapy is therefore the eradication of micrometastatic disease . Randomized trials assessing the use of adjuvant chemotherapy for the patients with head and neck squamous carcinoma do not suggest a significant benefit

Neoadjuvant chemotherapy:

Neoadjuvant chemotherapy Neoadjuvant , or induction chemotherapy, is the use of chemotherapy before definitive surgery or radiotherapy in patients with locally advanced disease. The intention of this strategy is to improve local and distant control of the disease in order to achieve greater organ preservation and overall survival. Numerous phase III trials have considered the benefit of neoadjuvant chemotherapy followed by definitive surgery,by surgery and radiotherapy, or by radiotherapy alone as compared to definitive management without chemotherapy. Unfortunately, these studies have not demonstrated a survival advantage The role of neoadjuvant chemotherapy therefore continues to remain controversial and further studies are planned, particularly looking at more effective drug combinations

Concurrent chemoradiation:

Concurrent chemoradiation This involves the synchronous use of chemotherapy & radiotherapy . Multiple randomized trials comparing concurrent radiotherapy and chemotherapy with radiotherapy alone have shown significant improvement in loco regional control , relapse-free survival and overall survival rates in patients with locally advanced, unresectable disease These results may reflect the influence of chemotherapy on micrometastatic disease or its ability to enhance tumour radiosensitivity Some chemotherapy agents are recognized to be more active in certain radioresistant cell types . Other drugs may act synergistically with radiotherapy by hindering the repair of radiation-induced DNA damage ( cisplatin ), by synchronizing or arresting cells during radiosensitive phases ( hydroxyurea , paclitaxel ) or by hindering regrowth between fractions of treatment.


Chemoprevention This is a novel approach with the aim of reversing or halting carcinogenesis with the use of pharmacologic or natural agents. Retinoids have been tested in head and neck carcinogenesis both in animal models and against oral premalignant lesions and in the prevention of secondary tumours in humans, with initial encouraging results. Studies are also looking at the benefit of using cyclo-oxygenase 2 (COX-2) inhibitors in a similar role

High dose chemotherapy:

High dose chemotherapy H igh doses is limited by myelosuppression . This may be overcome by using bone marrow or peripheral stem cell infusions. While highdose chemotherapy appears to have a role in the Management of leukaemias , myeloma and certain lymphomas, Little benefit has been demonstrated in common solid tumours.


NOVEL THERAPIES FOR THE FUTURE Despite the introduction of new cytotoxic drugs, such as antimetabolites ( capecitabine ) and topoisomerase I inhibitors , the management of advanced head and neck cancer remains challenging Targeted therapy aims to specifically act on a welldefined target or biologic pathway that, when inactivated, causes regression or destruction of the malignant process . The main strategies of research have looked at the use of monoclonal antibodies or targeted small molecules Monoclonal antibodies

Monoclonal antibodies:

Monoclonal antibodies There are several proposed mechanisms of action of monoclonal antibodies direct effects: - Induction of apoptosis; Inhibition of signalling through the receptors needed for cell proliferation/function ; Anti- idiotype antibody formation , determinants amplifying an immune response to the tumourcell ; indirect effects: Antibody-dependent cellular cytotoxicity (ADCC, conjugating the 'killer cell' to the tumour cell) Complement-mediated cellular cytotoxicity (fixation of complement leading to cytotoxicity ). 1)wide distribution on tumour cells; 2) High level of expression ; 3) Bound to tumour, allowing cell lysis ; 4) Absent from normal tissues ; 5) Trigger activation of complement on MAb binding ; 6) Limited antigenic modulation of target. A desirable target for MAbs would have the following properties


OTHER NOVEL TREATMENTS There are now a large number of new types of agents entering all phases of clinical trials. To date, they have met with variable success 1) Trastuzumab : A humanized monoclonal antibody against the HER-2 receptor, both locally advanced and metastatic breast cancer . 2) Imatinib mesylate : An adenosine triphosphate binding selective inhibitor of bcr-abl that has been shown to produce durable complete haematologic and cytogenetic remissions in early chronic phase CML 3) Ritiximab : The rituximab antibody is a genetically engineered chimeric murine /human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes .. 4) Bortezomib : is the first of a new class of agents called proteasome inhibitors and the first treatment in more than a decade to be approved for patients with multiple myeloma.

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