Principles of cancer therapy

PRINCIPLES OF CANCER THERAPYDr. Samar D. Sarsam

Cancer is an abnormal proliferation of cells which have uncontrolled growth. They have the ability to grow into adjacent tissue and to spread to distant parts of the body. The smallest cancer that can be detected by examination, x-ray or scan is a little less than one fourth inch in diameter. A cancer this size contains between 100,000,000 - 1,000,000,000 cancer cell.

Primary goal is to eradicate cancer. when primary goal is not accomplished → → → →palliation, amelioration of symptoms and preservation of quality of life, while striving to extend life

SURGERY RADIATION THERAPY CHEMOTHERAPY IMMUNOTHERAPY HORMONAL THERAPY

one of challenges of cancer treatment is using various treatment modalities alone and together to maximize chances for patient benefit.


Treatment is determined by: the type of cancer the grade stage location and the biological behavior expected of that particular cancer. Age and overall physical health also need to be considered.

Tumor grade

is the description of a tumor based on how abnormal the tumor cells and the tumor tissue look under a microscope. It is an indicator of how quickly a tumor is likely to grow and spread. If the cells of the tumor and the organization of the tumor’s tissue are close to those of normal cells and tissue, the tumor is called “well-differentiated .” These tumors tend to grow and spread at a slower rate than tumors that are “undifferentiated” or “poorly differentiated,” which have abnormal-looking cells and may lack normal tissue structures.Based on these and other differences in microscopic appearance, doctors assign a numerical “grade” to most cancers.

the following system is generally used: GX: Grade cannot be assessed (undetermined grade) G1: Well differentiated (low grade) G2: Moderately differentiated (intermediate grade) G3: Poorly differentiated (high grade) G4: Undifferentiated (high grade)


Generally, a lower grade indicates a better prognosis. A higher-grade cancer may grow and spread more quickly and may require immediate or more aggressive treatment.

Staging of cancer

Stage refers to the extent of cancer, such as how large the tumor is, and if it has spread. It help us in: Understand how serious cancer is and chances of survival Plan the best treatment A cancer is always referred to by the stage it was given at diagnosis, even if it gets worse or spreads. New information about how a cancer has changed over time gets added on to the original stage. So, the stage doesn't change, even though the cancer might.

Goals of treatment: prevention Cure prolongation of survival and palliation.

The goal of treatment may not necessarily be for cure but for palliation. If there is a significant statistical risk that the cancer will reappear later, then prophylactic treatment is given. Palliation means that treatment is given to remedy a symptom of the cancer without being able to treat the cancer itself.

Principles of Cancer SurgeryFor Cure – Surgery most effective cancer treatment • >40% of cancer is cured by surgery – Complete excision with margin of normal tissue • Other Indications • Diagnosis (excision biopsy) Staging (assess lymph node spread) Local control Palliation (bypass obstruction)

Cancers that can be cured surgically usually must be localized. This means that they are in an early stage and that they are only in one place. The place where they must be removable with a good margin of normal tissue. The cancer must be a type that has little potential to spread to other parts of the body. The regional lymph nodes are also usually removed during the surgery. A cancer of the cervix that is confined to the cervix is an example of a cancer that can be treated surgically. The surgery is a radical hysterectomy and removal of the pelvic lymph nodes. The word radical means that additional surrounding tissue is removed with the cervix.

Surgery may be the initial step in diagnosis and treatment but not be curative itself. Other methods of treatment such as radiation or chemotherapy would be the primary treatment. Ovarian cancer is usually diagnosed surgically. The surgery is seldom sufficient as complete treatment and additional treatment with chemotherapy is then given.

Chemotherapeutic agents and radiation kill cells by first order kinetics; it means a constant proportion of cells are killed for a given dosage. The treatment affects the tumor cells and the normal cells.

Radiation Therapy PrinciplesRadiation therapy is one of the major treatment modalities for cancer. Its effectiveness as a treatment for cancer was first reported in the late 1800s. Advances in equipment, technology, combined with the science of radiology have led to today’s highly sophisticated treatment centers.

Radiation is energy that is carried by waves or a stream of particles. It can change the genes (DNA) and some of the molecules of a cell. To understand how radiation works as a treatment, it is helpful to know about the normal life cycle of a cell. The cell cycle goes through 5 phases.


The Cell Cycle G0 phase (resting stage): Cells have not yet started to divide. Cells spend much of their lives in this phase. Depending on the type of cell, this step can last for a few hours or many years. When the cell gets the signal to reproduce, it moves into the G1 phase. G1 phase: During this phase, the cell starts making more proteins to get ready to divide. This phase lasts about 18 to 30 hours. S phase: In the S phase, the chromosomes that contain the genetic code (DNA) are copied so that both of the new cells to be made will have the same DNA. This phase lasts about 18 to 20 hours. G2 phase: The G2 phase is just before the cell starts splitting into 2 cells. It lasts from 2 to10 hours. M phase (mitosis): In this phase, which lasts only 30 to 60 minutes, the cell actually splits into 2 new cells.

Cellular biology

Mitosis (M) cell division Interphase between successive mitosis it is subdivided into: G1 protein synthesis necessary for DNA synthesis S DNA duplication G2 RNA and protein synthesis occurs *Following mitosis some cells enter the resting phase G0


Radiation used for cancer treatment is called ionizing radiation because it forms ions in the cells of the tissues it passes through as it dislodges electrons from atoms. (Ions are atoms that have taken on an electric charge by gaining or losing an electron.) This can kill cells or change genes.

Other forms of radiation such as radio waves, microwaves, and light waves are called non-ionizing. They don't have as much energy and are not able to ionize cells.

. Non-ionizing radiation includes the spectrum of ultraviolet (UV), visible light, infrared (IR), microwave (MW), radio frequency (RF), and extremely low frequency (ELF). Lasers commonly operate in the UV, visible, and IR frequencies.

Types of radiation: 1-elecromagnetic radiation: visible light Infra red Ultraviolet X-ray Gamma rays 2-particulates radiation: It consist of moving particles of matter The particles include: neutrons Protons Electrons The commonly used particles are electrons.


Alpha (α) radiation consists of Helium-4 (4He) nuclei and is stopped by a sheet of paper. Beta (β) radiation, consisting of electrons, is halted by an aluminium plate. Gamma (γ) radiation, consisting of energetic photons, is eventually absorbed as it penetrates a dense material. Neutron (n) radiation consists of free neutrons which are blocked using light elements, like hydrogen, which slow and/or capture them.

Ionizing radiation can be sorted into 2 major types: photons (x-rays and gamma rays), which are most widely used particle radiation (electrons, protons, neutrons, alpha particles, and beta particles) Some types of ionizing radiation have more energy than others. The higher the energy, the more deeply the radiation can penetrate the tissues. The way a certain type of radiation behaves is important in planning radiation treatments. The radiation oncologist selects the type and energy of radiation that is most suitable for each patient's cancer.

The more common types of radiation used for cancer treatment are: High-energy photons that come from radioactive sources such as cobalt, cesium, or a machine called a linear accelerator This is by far the most common type of radiation treatment in use today. Electron beams that are produced by a linear accelerator. These are used for tumors close to a body surface since they penetrate less into deeper tissues. Protons are a newer form of treatment. Protons are parts of atoms that cause little damage to tissues they pass through but are very good at killing cells at the end of their path. This means that proton beams may be able to deliver more radiation to the cancer while causing fewer side effects to normal tissues nearby. Neutrons are used for some cancers of the head, neck, and prostate. They can sometimes be helpful when other forms of radiation therapy don't work. Their use has declined over the years because of the rather severe long-term side effects they cause.


Biologic Effect Ionizing radiation is defined as energy that causes ejection of an atomic orbital electron when absorbed. Radiotherapy (RT) uses high-energy ionizing radiation to kill cancer cells. It is considered a local therapy because the cancer cells are destroyed only in the anatomical area being treated. Radiation causes a breakage of one or both strands of DNA molecule inside the cells, thereby preventing their ability to grow and divide. While cells in all phases of the cell cycle can be damaged by radiation, the lethal effect of radiation may not be apparent until after one or more cell divisions have occurred. Disruption of plasma membrane is the other form of cell damage that may result from ionizing radiation and it is not linked to cell division. Normal cells can also be affected by ionizing radiation, but they are usually better to repair their DNA damage.


Units of radiation therapyGray the system international unit has now replaced the ‘rad’ (radiation absorbed dose) as the accepted term of radiation dosage.One Gray (Gy) =100 rads

However, the amount of damage done to matter (especially living tissue) by ionizing radiation is more closely related to the amount of energy deposited rather than the charge. This is called the absorbed dose. *The gray (Gy), with units J/kg, is the SI unit of absorbed dose, which represents the amount of radiation required to deposit 1 joule of energy on 1 kilogram of any kind of matter. *The rad (Radiation absorbed dose), is the corresponding traditional unit which is 0.01 J deposited per kg. 100 rad = 1 Gy. Equal doses of different types or energies of radiation cause different amounts of damage to living tissue. For example, 1 Gy of alpha radiation causes about 20 times as much damage as 1 Gy of x-rays.

Principles of treatment The dose of radiation administered is determined by a number of factors: *Radio sensitivity of the tumor *Normal tissue tolerance *Volume of tissue irradiated


Reactions to Radiation Therapy (complications) Acute Reactions It includes the following pathological changes: Cessation of mitosis Swelling Edema Necrosis In gynecological tumors: acute cystitis Proctosigmoiditis Enteritis Bone marrow depression


Late Reactions It occurs 6 to 36 months after completion of radiation Damage to vascular connective tissue stroma that causes an epithelial proliferation with decreased blood supply and subsequent fibrosis. Some stem cells have a limited proliferative capacity and extensive destruction of these cells may result in eventual tissue loss. Common chronic complications: Enteropathy Ulceration Proctosigmoiditis Fistulae Urological injuries Bowel injuries Vaginal vault necrosis


Techniques of Radiation Therapy Radiation treatment can be administered externally or internally depending on the type and the extent of the tumor. *External Beam Radiation uniform dose delivered to a given field *Brachytherapy This may be: Intra-cavitary Interstitial. Intra cavitary using tandem and ovoids, intra-cavitary RT in cancer cervix, vagina Interstitial implants Another form of brachytherapy. The term implies the placement of radioactive source within tissues. Hollow guide needles are placed in a specified geometric pattern that will deliver a known, relatively uniform dose of radiation to a target volume. The position of these guides is checked radiologically and when satisfactory, they can be threaded with the radioactive sources that are left in the tissues; the hollow guides are then removed.


Principles of Cancer Chemotherapy Definition of Chemotherapy: - using chemicals to kill cells in the body - eg. bacteria, fungi, viruses, cancer In contrast, Drug Therapy: - using chemicals to modulate body processes - eg. arterial blood pressure, mood


First Order Kinetics of Tumour Cell Growth and Chemotherapy KillingTumour Growth starts as one malignant cell – divides with constant doubling time –Chemotherapy killing Each dose kills a constant proportion of tumor cells – repeated doses required – Continued after clinical disappearance of disease

Chemotherapy Is the use of chemical substances to treat disease. it refers primarily to cytotoxic drugs used to treat cancer. The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards and folic acid inhibitors. Classification of chemotherapeutic agents: 1-cell cycle specific agent 2-phase specific agent


Principles of chemotherapy: Broadly, most chemotherapeutic drugs work by impairing mitosis (cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells they are termed cytotoxic. Some drugs cause cells to undergo apoptosis (so-called "cell suicide"). Chemotherapeutic drugs affect "younger" tumors (i.e. less differentiated) more effectively, because at a higher grade of differentiation, the propensity to growth usually decreases. Near the center of some solid tumors, cell division has effectively ceased, making them insensitive to chemotherapy. Another problem with solid tumors is the fact that the chemotherapeutic agent often does not reach the core of the tumor. Solutions to this problem include radiation therapy and surgery.

The normal tissues most commonly affected by toxicity are those with the highest intrinsic turnover rate: bone marrow, hair follicles, gastrointestinal tract, and skin. In general, cytotoxic drugs are administered in combination rather than as single agents because simultaneous interference with multiple biochemical pathways may result in more tumor cell kill with a delay in the appearance of drug resistance. To diminish the likelihood of additive toxicity, drugs with non-overlapping side effects are combined.

Combination Chemotherapy• more effective than use of single agents• criteria for combination therapy– some activity as a single agent– differing mechanisms of action– different side-effect profiles

Indications for cancer chemotherapy• Cure – High cure rates achieved in acute lymphoblastic leukaemia, testicular cancer, Hodgkin’s disease • With surgery – Adjuvant chemotherapy for node-positive breast and colorectal cancers • With radiotherapy – Combined modality therapy for Head and neck, cervical cancer etc • Palliation – Improve symptoms and survival time, eg. Lung cancer

Types of chemotherapeutic agents Classification: 1---alkylating agent Alkylating agents are so named because of their ability to cause alkylation to DNA. e.g.: melphalan, cyclophosphamide, chlorambucil. 2---Nitrosoureas Carmustine (BCNU) Lomustine (CCNU)


3---Anti-metabolites* purine antagonists ((azathioprine, mercaptopurine)) *pyrimidine antagonists –as 5-fluorouracilThey block thymidine synthesis Which become the building blocks of DNA they prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. They also affect RNA synthesis. Due to their efficiency, these drugs are the most widely used cytostatics.

Folate antagonists, as methotrexate, they inhibit the enzyme dihydrofolate reductase and deprive the cells of co enzymes essential for synthesis of nucleic acids.3---Plant alkaloids These alkaloids are derived from plants and block cell division by preventing microtubule function. Microtubules are vital for cell division and without them it can not occur. The main examples are vinca alkaloids and taxanes.*Vinca alkaloids Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phase of the cell cycle). The vinca alkaloids include: -Vincristine Vinblastine

Methotrixate mechanism

Podophyllotoxin Podophyllotoxin is a plant-derived compound used to produce two other cytostatic drugs, etoposide and teniposide. They prevent the cell from entering the G1 phase (the start of DNA replication) and the replication of DNA (the S phase). The exact mechanism of its action still has to be elucidated.*Taxanes Taxanes are derived from the Pacific yew tree. As the paclitaxel

Antitumour antibiotics The most important immunosuppressant from this group is dactinomycin, which is used in kidney transplantations. Miscellaneous: Other drugs as cisplatin are one of the important drugs in gynecology. Cisplatin Carboplatin Paclitaxel Docetaxel

Side effects:The treatment can be physically exhausting for the patient. Current chemotherapeutic techniques have a range of side effects mainly affecting the fast-dividing cells of the body, as the cells of bone marrow, intestinal mucosa, and hair follicle. Important common side-effects include (dependent on the agent):Hair loss Nausea and vomiting Diarrhea or constipation Anemia Depression of the immune system hence (potentially lethal) infections and sepsis Hemorrhage Secondary neoplasms Cardio toxicity Hepatotoxicity Nephrotoxicity Ototoxicity

IMMUNOTHERAPY Immunotherapy as a treatment for cancer has been tried in one way or another for about one hundred years. Except for a small number of rare cancers it has not become a major treatment modality. Theoretically it could be a perfect treatment by mobilizing the body's own weapons to kill cancer cells. There is a tremendous amount of research being done, but so far little of clinical value has been produced. Some lymphocytes when properly stimulated can kill other cells. If that other cell is a cancer cell then it can be destroyed by the lymphocyte. The immune system functions primarily by recognizing what is self and what is not self and destroys that which is non-self. If a cancer cell were sufficiently different from a normal cell so as to be recognized as non-self then it would be destroyed.

Hormonal therapy Hormones are chemicals that are naturally produced by the organs making up the body's endocrine system. These chemicals travel throughout the body via the bloodstream, coordinating the functions of various organs from head to toe. Hormones are responsible for regulating the function of just about every cell in the body. Some examples of hormones include: estrogen, testosterone, insulin, thyroid hormone, cortisol, and epinephrine. Researchers have determined that some cancers are "fueled" by hormones, and may rely on them to grow. In those cases, blocking the action of these hormones could possibly stop the cancer from growing. There are a few ways in which this can be achieved:

Block the hormones from acting: Cells have "receptors" on their surface where certain hormones bind and subsequently trigger activity inside the cells. By blocking the receptor with another compound, the hormone is not able to connect to its receptor. The hormone's normal "parking spot" on the cell is already occupied, so the hormone cannot attach to and activate the cell. Prevent the body from producing the hormone: This can be done with medication to block the production of the hormone, or with surgery to remove the organ that produces it. For example, estrogen production can be stopped by surgically removing the ovaries. Eliminate the hormone receptors on cells or change their shape: This makes it impossible for the hormone to properly attach itself to the cell receptor and activate it. Essentially making the hormone unable to function. Hormone therapy is most often used to treat breast and prostate cancers, where its role is well established through numerous clinical studies.

Palliative treatment Palliative cancer therapy is treatment specifically directed to help improve the symptoms associated with terminal cancer. Purpose Palliative care is directed to improving symptoms associated with incurable cancer. Care can include surgery, radiation therapy, chemotherapy, symptomatic treatments resulting from cancer, and side effects of treatment. The primary objective of palliative care is to improve the quality of the remainder of a patient's life. Treatment usually involves a combination of modalities (multimodality approach) and numerous specialists typically are involved in the treatment planning process Pain is one of the common symptoms associated with cancer. Approximately 75% of terminal cancer patients have pain. Pain is a subjective symptom and thus it cannot be measured using technological approaches. Pain can be assessed using numeric scales (from one to 10, one is rated as no pain while 10 is severe) or rating specific facial expressions associated with various levels of pain. T he majority of cancer patients experience pain as a result of tumor mass that compresses neighboring nerves, bone, or soft tissues, or from direct nerve injury (neuropathic pain). Pain can occur from affected nerves in the ribs, muscles, and internal structures such as the abdomen (cramping type pain associated with obstruction, so we start with mild analgesics then add tranquillizers, antidepressants, Patients taking opioids for pain relief can develop tolerance and dependence.

Haemorrhage Treatment is by radiotherapy, packing, embolization Leg swelling Urinary tract symptoms as obstructive nephropathy, they need nephrostomy Incontinence of feces and of urine It is troublesome complication needs regular emptying of the bowel and to douche the vagina.