BASIS OF CANCER CHEMOTHERAPY PHL 417 Clinical Strategies

BASIS OF CANCER CHEMOTHERAPY PHL 417

Clinical Strategies for Cancer Treatment 1 - Surgery 2 - Chemotherapy 3 - Radiotherapy 4 - Immunotherapy 5 - Hyperthermia 6 - Biological and targeted-therapy 7 - Combined therapy

BASIS OF CANCER CHEMOTHERAPY • CHEMOTHERAPY is the treatment of cancer using specific chemical agents or drugs that are selectively destructive to malignant cells and tissues. • Chemotherapy is the systemic (whole body) treatment of cancer with anticancer drugs. Broadly, most chemotherapeutic drugs work by impairing mitosis (cell division), and effectively targeting fast-dividing cell. • This means that normal fast dividing cells such as those responsible for hair growth and for replacement of the intestinal epithelium lining are also affected. • As chemotherapy affects cell division, tumours with high GROWTH FRACTIONS (such as acute myelogenous leukemia and the lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time.

DETERMINANTS OF TREATMENT PLANNING 1 - Histological Diagnosis: The first and primary determinant of treatment is the histologic diagnosis. Malignant neoplasms occur in over 100 different pathologic forms, each with a characteristic natural history, pattern of progression, and responsiveness to treatment. Thus, the histologic diagnosis, usually made by surgical biopsy or excision of a primary tumor, is of critical importance as a first step in treatment planning

DETERMINANTS OF TREATMENT PLANNING 2 - Staging: The process of determining the extent of disease is termed staging and plays an important role in making therapeutic choices for diseases that are responsive to multiple types of treatment. For example, non. Hodgkin's lymphomas with “indolent” histology are curable with radiotherapy in a majority of cases when the tumor is confined to a single lymph node region (stage I), but are rarely curable, even with aggressive early chemotherapy, when more extensive lymph node involvement or dissemination to extranodal sites is present. Immediate treatment of stage I disease with radiation is indicated, whereas, paradoxically, no immediate therapy may be indicated for patients with advanced disease. 3 - Molecular and immunologic subtype: 4 - Patient's age and baseline health.

TOXICITY OF CHOP REGIMEN FOR TREATING DIFFUSE LARGE CELL LYMPHOMA Drugs Toxicity Risk Factors Cyclophosphamide myelosuppression, hemorrhagic cystitis, secondary leukemia Underlying infection Doxorubicin hydrochloride Cardiomyopathy, myelosuppression, hair loss History of heart disease, prior chest irradiation Vincristine sulfate (Oncovin) Peripheral and autonomic neuropathy other neurotoxic drugs, inherited or acquired peripheral neuropathy Prednisone Glucose intolerance, immune Diabetes, underlying suppression, bone and infection muscle loss

Cancer Chemotherapy and cell cycle 1 - Cell-cycle non specific agents: are cytotoxic in any phase of the cycle even on G 0 phase and so are more effective against large slowly growing tumors. 2 - Cell-cycle specific agents: are cytotoxic on all phases but not on cells out of the cycle (at G 0 ) and so are more effective against rapidly growing tumors. Work better in combination than alone 3 - cell-cycle Phase specific agents: act on specific phase of the cycle

Cancer Chemotherapy and Cell Cycle

TYPES OF CLINICAL CHEMOTHERAPY 1 - Adjuvant chemotherapy (postoperative treatment) refers to giving patients anti-cancer drugs after the primary tumor has been removed by surgery or Radiotherapy and there is no evidence that cancer remains in the body. The intent of adjuvant chemotherapy is to attack microscopic cancer cells that remained after tumor removal.

Types of cancer treatment used as adjuvant therapy 1 - Chemotherapy uses drugs to kill cancer cells. Chemotherapy treats the entire body, killing cancer cells, no matter where they may be located. Adjuvant chemotherapy isn't helpful in all situations, so talk to your doctor about whether this treatment is right for you and how much of a benefit it may provide. 2 -Hormone therapy. Some cancers are sensitive to hormones. For these cancers, treatments to stop hormone production in your body or block the effect of hormones on your cancer may be helpful. Cancers that are commonly hormone sensitive include breast, uterine and prostate cancers. Your cancer will be analyzed to see if it's hormone sensitive. If it is, you might benefit from hormone therapy. Hormone therapy can be used in conjunction with surgery, radiation or chemotherapy.

3 - Radiation therapy uses high-powered energy beams, such as X-rays, to kill cancer cells. Radiation therapy can be given internally or externally. Adjuvant radiation therapy focuses on the area around the original cancer site to reduce the risk that cancer will recur in that area. 4 - Immunotherapy works with your body's own immune system to fight off remaining cancer cells. Immunotherapy treatment can either stimulate your body's own defenses or supplement them. 5 - Targeted therapy aims to alter specific abnormalities present within cancer cells. For example, women with a type of breast cancer that makes too much of a protein called human growth factor receptor 2 (HER 2) may choose a targeted therapy drug that blocks the action of that specific protein. These medications target the specific protein within those cancer cells. More targeted therapies are under development and may one day be available for use as adjuvant therapy

2 - Neoadjuvant (Primary) chemotherapy • Neoadjuvant chemotherapy (preoperative treatment), is the use of anticancer drugs as the main form of treatment or as a treatment prior to Surgery or Radiotherapy. • In some cases, the tumor may be so large that surgery to remove it would destroy major organs or would be quite disfiguring. Primary neoadjuvant chemotherapy may reduce the tumor size, making it possible for a surgeon to perform a less traumatic operation. • Examples of cancers in which primary chemotherapy may be followedup with less extensive surgeries include: anal cancer, bladder cancer, breast cancer, esophageal cancer, laryngeal cancer, osteogenic sarcoma, and soft tissue sarcoma.

3 - Induction Chemotherapy • High-dose, usually combination, chemotherapy given with the intent of inducing complete remission when initiating a curative regimen. This term is usually applied to Hematologic malignancies but is equally applicable to solid tumors. 4 - Maintenance Chemotherapy • Long-term, low-dose, single or combination chemotherapy in a patient who had achieved a complete remission, with the intent of delaying the re-growth of residual tumor cells. 5 - Palliative Chemotherapy • Is given without curative intent, but simply to control symptoms, decrease tumor load and increase life expectancy in a patient in whom cure is unlikely. For these regimens, a better toxicity profile is generally expected.

Drug Schedule in combination chemotherapy • Initiate therapy with cycle-nonspecific drugs followed by cycle-specific drugs. e. g. start with alkylating agents to reduce tumour bulk and recruit slowly dividing tumours into DNA synthetic phase in which antimetabolites as Methotrexate and 5 -Fluorouracil are most active. CAMF Protocol for Breast Cancer Drug Cyclophosphamide Doxorubicin Methotrexate 5 -Fluorouracil Dose Day Mg/m 2 1 750 30 40 500 + + Repeated every 21 days • Comments: - Cytoreduction with cell cycle phase-nonspecific agents on day 1. - S-phase specific agents on day 8 - Methotrexate given before 5 -Fluorouracil on day 8. 8 + +

Kinetic Basis of Chemotherapy The objective of cancer treatment is to reduce the tumor cell population to zero cells. Chemotherapy experiments using rapidly growing transplanted tumors in mice have established the validity of the fractional cell kill hypothesis, which states that a given drug concentration applied for a defined time period will kill a constant fraction of the cell population, independent of the absolute number of cells. Regrowth of tumor occurs during the drug-free interval between cycles. Thus, each treatment cycle kills a specific fraction of the remaining cells. The results of treatment are a direct function of (a) the dose of drug administered and (b) the number and frequency of repetitions of treatment

Kinetic Basis of Chemotherapy Most current chemotherapy regimens are based on cytokinetic considerations and use cycles of intensive therapy repeated as frequently as allowed by the tolerance of dose-limiting tissues, such as bone marrow or gastrointestinal tract. The object of these cycles is to reduce the absolute number of remaining tumor cells to zero (or less than one) through the multiplicative effect of successive fractional cell kills. (For example, given 99% cell kill per cycle, a tumor burden of 1011 cells will be reduced to less than one cell with six cycles of treatment: [1011 cells] × [0. 01]6 <1. )

Rationale for Combination Chemotherapy • Drugs effective as single agent against the particular tumor being targeted should be selected. • Drugs with different mechanism of action should combined. • Drugs with different mechanism of resistance should be combined. • Drugs with different dose-limiting toxicities should be combined. Rational for the use of combination chemotherapy 1 -Synergistic cytotoxcicity 2 -Independent cell kill 3 -Decrease resistance