Cancer treatment and chemotherapy 11 Cancer treatment and chemotherapy

Cancer Cancer is a group of more than 100 different diseases, characterized by uncontrolled cellular growth, local tissue invasion, and distant metastases.

Etiology of cancer A cancer, or neoplasm, is thought to develop from a cell in which the normal mechanisms for control of growth and proliferation are altered.

Carcinogenesis Substances that may act as carcinogens include chemical, physical, and biological agent. Exposure to chemicals may occur by virtue of occupational and environmental means, as well as lifestyle habits. For example Exposure to aniline dye cause bladder cancer Exposure to Benzene cause some leukemia. Some drugs and hormones used for therapeutic purposes cause cancer in human include

Drug or Hormone Type of cancer caused Alkylating agents ( e.g. chlorambucil, mechlorethamine, carmustine) leukemia Anabolic steroids Liver Analgesic containing phenacetin Renal , urinary bladder Antiestrogen ( tamoxifen) Endometrium Coal tars ( topical) Skin Nonsteroidal Estrogens (diethylstilbestrol) vagina/ cervix, endometrium , breast , testes Steroidal ( estrogen replacement therapy, oral contraceptive ) Endometrium, breast, liver Epipodophyllotoxins ( etoposide, teniposide) Leukemia Immunosuppressive drugs ( cyclosporine, azathioprine) lymphoma, skin Nitrogen mustard derivatives ( cyclophosphaide, ifosfamide) Urinary bladder , leukemia

Physical agents that act as carcinogens include ionizing radiation and ultraviolet light. Viruses are biologic agents that are associated with certain cancers. Example Epstein- Barr virus is an important factor in the initiation of African Burkitts lymphoma. Infection with hepatitis B virus is known to be a major cause of hepatocellular cancer.

Genetic basis of cancer There are two major classes of genes involved in carcinogenesis: Activation Oncogenes Inactivation Tumor- suppressor genes Another group of genes important in carcinogenesis is the DNA repair genes. The normal function of these genes is to repair DNA that is damaged by environmental factors, or errors in DNA that occur during replication. If not corrected, these errors can result in mutations that activate oncogenes or inactivate tumor suppressor genes.

Pathogenesis of cancer

Invasion and metastasis Metastasis is the spread of neoplastic lesion cells from the primary tumor site to distant sites. The two primary pathways of metastasis are 1- hematogenous 2- lymphatic

Types of tumors Tumor may be either benign or malignant. Benign tumor Malignant tumor Rate of growth/ slow Rapid localized Invades and destroy the surrounding tissue These masses rarely metastasize, and once removed they rarely recur metastasize Cells of benign tumors resemble the cells from which they developed. The cells of malignant tumors are genetically unstable, and loss of normal architecture results in cells that are atypical of their tissue or cells of origin.

Tumor origin Tumors may arise from any of four basic tissue types: Epithelial tissue Connective tissue Lymphoid tissue and hematopoietic cells Nerve tissue

Cancer classification by tissue type Tissue of origin Malignant Epithelial/ Surface epithelium Glandular tissue Carcinoma ( squamous, epidermoid) Adenocarcinoma Connective tissue / Fibrous tissue Bone Smooth muscle Striated muscle Fat Fibrosarcoma Osteosarcoma Leiomyosarcoma Rhabdomyosarcoma liposarcoma Lymphoid tissue and hematopoietic cells/ Bone marrow elements Lymphoid tissue Plasma cell Leukemia Hodgkin s and non Hodgkin s lymphoma Multiple myeloma Neural tissue/ Glial tissue Nerve sheath melanocytes Glioblastoma multiforme, astrocytoma Neurofibrosarcoma Malignant melanoma

Staging of cancers The most commonly applied staging system for solid tumors is the TNM classification, where T= tumor, N= node, and M= metastases. The designated rating for tumor describes the size of the primary mass and ranges from T1 to T4. Nodes are described in terms of the extent and quality of nodal involvement ( N0 to N3). Metastases are generally scored depending on their presence or absence (M0 or M1).

The staging process, most cancers are classified according to the extent of disease by a numerical system involving stages I through IV. Stage I usually indicates localized tumor Stages II and III represent local and regional extension of disease. Stage IV denotes the presence of distant metastasis.

Signs and symptoms Early cancer no symptoms Change in bowel habits or bladder functions A sores that do not heal Unusual bleeding or discharge Lumps or thickening of breast or other parts of the body Indigestion or difficulty swallowing Recent change in wart Persistent coughing or hoarseness

Diagnosis of cancer Self examinations Biopsy involves histological examination by a pathologist of a piece of tissue. Imaging techniques X-rays, CT scan , MRI, ultrasound, bone scans Laboratory test Tumor markers(produced by cancer) Example: PSA in patient with Prostate cancers. alpha fetoprotein in patient with testicular cancer

Treatment Four primary modalities are employed in the approach to cancer treatment: Surgery (localized therapies) Radiation (localized therapies) Chemotherapy Biological therapy

Systemic disease such as leukemia can not treated by localized modality. Chemotherapy ( including hormonal therapy) accesses the systemic circulation and can treat the primary tumor and any metastatic disease. Solid tumors can be treated by surgery or radiation. But because most patients with cancer have metastatic disease at diagnosis, localized therapies often fail to completely eliminate the cancer.

Adjuvant therapy Adjuvant therapy is defined as the use of systemic agents to eradicate micrometastatic disease following localized modalities such as surgery or radiation or both.

Neoadjuvant therapy Chemotherapy given before surgery or raidotherapy in order to reduce the volume of large primary neoplasm and to determine response to chemotherapy/ hormone therapy in vivo therapy.

Purposes of chemotherapy Cancer chemotherapy may be indicated as a primary, palliative, adjuvant, or neoadjuvant treatment modality.

Cell cycle

Both cancer cells and normal cells reproduce in a series steps known as the cell cycle. The first phase is mitosis M phase (mitosis): In this phase, which lasts only 30 to 60 minutes, during this phase, cell division occur. G0 phase (resting phase): The cell has not yet started to divide. Some stimulus results in the cell entering the first gap phase (G1). G1 phase : During this phase, the cell prepares for DNA synthesis by manufacturing necessary enzymes.

S phase: In the S phase DNA synthesis occur .It lasts 10 to 20 hours. The percentage of cells in the S phase can be measured by cytometry and is an indicator of the rate of tumor cell proliferation. Tumors with high percentage of S phase cells are aggressively growing. Second gap or premitotic G2 phase: during this gap , the cell prepares for mitosis by producing RNA .This phase lasts from 2 to 10 hours.

Classification of anticancer drugs Cell cycle specific agents 1- S phase A- Antimetabolites Fluorinated pyrimidines Fluorouracil Oral fluoropyrimidines ( Capecitabine) Cytidine analogs Cytarabine Gemcitabine

Purines and purine antimetabolites 6- mercaptopurine and 6- thioguanine Fludarabine monophosphate Cladribine Antifolates Methotrexate B- Miscellaneous agents Hydroxyurea C- alkylating agent Procarbazine C- Steroids

2- G2 phase A- Miscellaneous agents Bleomycin B- Microtubule- targeting drugs Topoisomerase II inhibitors Etoposide Teniposide

3- M phase Microtubule- targeting drugs Vinca alkaloids Vincristine Vinblastine Vinorelbine Taxanes paclitaxel Docetaxel

4- G1 phase A- Steroids B- Miscellaneous agents Asparaginase

Cell cycle phase- non specific agents 1- Alkylating agents - Classic alkylating agents (Cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, mechlorethamine) Nitrosoureas ( Carmustine, lomustine) - Non classic alkylating agents ( Dacarbazine)

2- Microtubule- targeting drugs Anthracene derivatives ( doxorubicin, daunorubicin, idarubicin) 3- Miscellaneous agents ( Mitomycin C, dactinomycin) 4- Heavy metal compounds (cisplatin, carboplatin)