Principles of Oncology

Cancer refers to a group of diseases in which there is abnormal cell growth with the potential to invade or spread to other parts of the body.

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

Current evidence supports the concept of carcinogenesis as a multistage process that is genetically regulated.

The first step in this process is initiation, which requires exposure of normal cells to carcinogenic substances.

Substances that may act as carcinogens or initiators include chemical, physical, and biologic agents.

Two major classes of genes are involved in carcinogenesis: oncogenes and tumor suppressor genes.

• Tumors may arise from any of four basic tissue types:
  • Epithelial tissue
  • Connective tissue (Muscle, bone, and cartilage)
  • Lymphoid tissue
  • Nerve tissue
• Malignant cells are divided into those of epithelial origin or the other tissue types:
  • Carcinomas are malignant growths arising from epithelial cells.
  • Sarcomas are malignant growths of muscle or connective tissue.
  • Adenocarcinoma is a malignant tumor arising from glandular tissue.

• Tumors have several distinct characteristics:
• Invasion and Tissue Destruction: Tumors have the ability to invade and destroy the surrounding healthy tissue, which can lead to complications.
• Genetic Instability: Tumor cells often exhibit genetic instability, leading to changes in their DNA that contribute to their uncontrolled growth.
• Altered Cell Architecture: Loss of normal cell architecture results in atypical cells that no longer resemble their original tissue of origin.
• Loss of Functional Abilities: Tumor cells lose the ability to perform their usual functions, further compromising the affected tissues and organs.
• Metastasis: Many tumors have the capacity to metastasize, meaning they can spread to distant parts of the body. This often leads to recurrences even after removal or destruction of the primary tumor.

1. Topographic Site: Cancers can be classified based on their specific location within the body, which is important for diagnosis and treatment planning.
2. Histology: Histology refers to the study of the microscopic structure of tissues and cells. It is used to categorize cancers based on the types of cells and tissue patterns involved in the tumor.
3. Anatomic Extent (Staging): Staging involves determining the size of the tumor, its extent within the organ or tissue, and whether it has spread to nearby lymph nodes or distant parts of the body. Staging helps in prognosis and treatment decision-making.

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Reasons for Staging

• To aid the clinician in planning treatment: Staging helps clinicians determine the most appropriate treatment strategies for cancer patients.
• To give some indication of prognosis: Staging provides valuable information about the likely outcome of the disease, influencing decisions about patient care.
• To assist in evaluating the results of treatment: Staging allows healthcare providers to assess the effectiveness of treatments and make adjustments if necessary.
• To facilitate the exchange of information between treatment centers: Standardized staging systems enable consistent communication and collaboration among healthcare institutions.
• To contribute to continuing investigations of human malignancies: Staging data aids in ongoing research to improve cancer diagnosis and treatment.

Anatomic Staging

Anatomic staging is based on three components:

• T (Tumor): This component assesses the extent of the primary tumor within the body.
• N (Node): It evaluates the absence or presence and extent of regional lymph node involvement, which indicates the spread of cancer to nearby lymph nodes.
• M (Metastasis): This component determines the absence or presence of distant metastasis, which indicates whether the cancer has spread to other parts of the body.

Limitations of Cancer Classification:

• Not used in hematologic malignancies: Hematologic malignancies, such as leukemia and lymphoma, often follow different staging systems. For example, the Ann Arbor Staging System is used for lymphomas.
• Rarely used in pediatric cancer: Staging systems are less commonly applied to childhood cancers due to their unique characteristics and treatment approaches.

• Prevention: Strategies to prevent cancer development.
• Screening: Early detection through screening programs.
• Diagnosis: Identifying the type, stage, and extent of cancer.
• Treatment: Medical interventions to manage or eliminate cancer.
• Rehabilitation: Support and therapies to improve the quality of life post-treatment.
• Follow-up Care: Monitoring and support after treatment to detect any recurrence or side effects.
• Palliative Care: Specialized care to improve the comfort and quality of life for patients with advanced cancer.
• Terminal Care: End-of-life care for patients with incurable cancer.

Multidisciplinary Approach for Management

Pretherapy Assessment

• Aim:
  • Establish diagnosis.
  • Assess fitness of the patient.
• Method:
  • Clinical evaluation: History, comorbidities, physical examination to identify the extent of primary disease and metastasis.
  • Laboratory diagnosis: Diagnostic tests to determine cancer type, extent, and baseline data.

Adequate Counselling

• Disease explained in simple terms that can be understood, including:
• Extent of the disease.
• Plan of treatment.
• Expected side effects.
• Fair idea of prognosis.
• Opportunity given to ask adequate questions and get accurate answers.
• A professional counselor/psychologist should be involved.
• Aim of therapy explained and clearly stated as curative or palliative.
• The modalities of treatment (neoadjuvant, adjuvant).
• Informed consent must be obtained.

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Goals of Cancer Treatment

1. Primary Goal:
   • Cure the patient.
   • Render the patient clinically and pathologically free of disease and return their life expectancy to that of healthy individuals of the same age and sex.
2. The Best Alternative Goal:
   • To prolong survival while maintaining the patient's functional status and quality of life.
3. The Third Goal:
   • Relieve symptoms such as pain for patients in whom the likelihood of cure or prolonged survival is very low.

Modalities of Cancer Treatment

• Surgical: Removal of cancerous tissue through surgery.
• Radiotherapy: The use of radiation to destroy or shrink tumors.
• Hormonal: Treatment that alters hormone levels to affect cancer growth.
• Chemotherapy: The use of drugs to kill or slow the growth of cancer cells throughout the body.

Chemotherapy

• Multidrug Regimens: Chemotherapy often involves using multiple drugs with different mechanisms of action and varying toxicities. This approach aims to increase treatment efficacy, reduce dose-related toxicity, and decrease the probability of drug resistance.
• Mechanisms of Action: Chemotherapy drugs act by causing DNA damage, RNA damage, inhibiting cell growth and division, and interfering with vital cellular processes, often referred to as antimetabolites.
• Use Cases (CRAB):
  • Curative: Some cancers, such as leukemia and lymphoma, can be treated with chemotherapy with the intent of achieving a cure.
  • Relief of Symptoms or Partial Remission: In cases where a complete cure is not possible, chemotherapy can be used to alleviate symptoms and achieve partial remission.
  • Adjunct and Basal: Chemotherapy may be used as an adjunct to reduce tumor mass before other treatments like surgery or radiotherapy, especially in solid tumors like Wilms tumor and rhabdomyosarcoma.

Principles of Combination Chemotherapy

• Targeting Different Cell Cycle Phases: Combination chemotherapy aims to target different phases of the cell cycle, maximizing cell kill and reducing the likelihood of drug resistance.
• Drug Selection: Drugs used in combination should individually have activity against the tumor, and those with maximal efficacy are preferred.
• Mechanisms of Action: The chosen drugs should have different mechanisms of action to allow for additive or synergistic effects when combined and should be dosed at their optimal doses and schedules.
• Minimally Overlapping Toxicities: The toxicities of the chosen drugs should be minimally overlapping to reduce the risk of life-threatening toxicity to a single organ system.

Cell Cycle and Chemotherapy

• Cell Cycle Phases: The cell cycle consists of four stages: mitosis, gap 1, synthesis phase (S phase), and gap 2.
• DNA Synthesis: DNA synthesis occurs in the S phase, while mitosis involves chromosome alignment, separation, and cell division.
• Mechanism of Action: Chemotherapy drugs cause cell death by apoptosis, either directly interfering with DNA or targeting key proteins required for cell division.

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Classification of Cytotoxic Agents

• Class I drugs: These are non-phase-specific cytotoxic agents that act on both proliferating and resting (G0) cells. Examples include alkylating agents and cisplatin.
• Class II drugs: These are phase-specific cytotoxic agents that selectively target cells during specific phases of the cell cycle.

Alkylating Agents

• Mechanism of Action: Alkylating agents form covalent linkages with biologically important constituents of the cell cytosol, such as phosphates, amino groups, hydroxyl groups, carbonyl groups, or DNA molecules. This results in the formation of inactive or toxic substances within the cell.
• Class I Agents: Alkylating agents fall under Class I and include examples like nitrogen mustards, cyclophosphamide, ifosfamide, melphalan, busulfan, and chlorambucil.
• Toxic Effects: Alkylating agents can have toxic effects on various tissues, including bone marrow, gut epithelium, hair follicles, bladder, testis, and lungs.

Nitrosureas

• Class I Agent: Nitrosureas belong to Class I cytotoxic agents.
• Examples: Common examples include carmustine and lomustine.
• Mechanism of Action: Nitrosureas act by alkylation.
• Toxic Effects: They can lead to toxic effects such as bone marrow suppression, renal toxicity, and pulmonary toxicity.

Antimetabolites

• Class II Agents: Antimetabolites fall under Class II cytotoxic agents, and they primarily target the S phase of the cell cycle.
• Mechanism of Action: Antimetabolites can act as folic acid antagonists (e.g., methotrexate), purine antagonists (e.g., 6-mercaptopurine, thioguanine), or pyrimidine antimetabolites (e.g., cytosine arabinoside).
• Sites of Toxicity: These agents may lead to toxicity in various tissues, including bone marrow suppression, gastrointestinal tract (resulting in stomatitis and diarrhea), liver, nervous system, and ocular tissues.

Antitumor Antibiotics

• Class I Agents: Antitumor antibiotics belong to Class I cytotoxic agents.
• Examples: Notable examples include dactinomycin, anthracyclines like daunorubicin and doxorubicin, and bleomycin (which arrests cells in G2 phase).
• Mechanism of Action: Antitumor antibiotics act by intercalating with DNA, thereby preventing transcription or causing breaks in DNA.
• Toxic Effects: They can lead to toxic effects such as bone marrow suppression, mucositis, alopecia, skin rash, and cardiotoxicity (in the case of anthracyclines), as well as pulmonary fibrosis (with bleomycin).

Tubulin-Binding Drugs (Vinca Alkaloids and Taxoids)

• Vinca Alkaloids (e.g., vincristine, vinblastine):
  • Class II Agents: Vinca alkaloids are Class II cytotoxic agents that primarily affect the M phase of the cell cycle.
  • Mechanism of Action: They bind to tubulin, causing arrest in mitosis during metaphase by interfering with microtubule assembly.
  • Toxic Effects: Vinca alkaloids can lead to neurotoxicity (paraesthesia, impaired sensation, loss of deep tendon reflexes, ataxia, cranial nerve palsies, muscle wasting), myelosuppression, and gastrointestinal effects.
• Taxoids (e.g., paclitaxel):
  • Mechanism of Action: Taxoids prevent the disassembly of microtubules, thereby inhibiting their normal function.

Plant Alkaloid

• Epipodophyllotoxins (e.g., etoposide, teniposide):
• Mechanism of Action: They act as topoisomerase inhibitors.
• Toxicity: Toxic effects may include myelosuppression, alopecia, mucositis, diarrhea, and allergic reactions, especially if the drug is administered rapidly.

Enzymes

• L-Asparaginase:
• Class II Agent: L-Asparaginase is a Class II cytotoxic agent that primarily affects the G1 phase of the cell cycle.
• Mechanism of Action: It acts by depleting exogenous L-asparagine, leading to the death of neoplastic cells.
• Toxic Effects: Toxic effects may include hypersensitivity reactions (urticarial, bronchospasm, angioneurotic edema, cardiovascular collapse), liver toxicity, hypofibrinogenemia, and central nervous system effects (confusion, somnolence, convulsions, coma).

Synthetic Agents

• Class I Agents: Synthetic agents belong to Class I cytotoxic agents.
• Mechanism of Action: They inhibit DNA synthesis and can act during any phase of the cell cycle.
• Examples: Notable examples include cisplatin, carboplatin, procarbazine, and dacarbazine.
• Sites of Toxicity: These agents may lead to toxicity in the kidney, bone marrow suppression, ototoxicity, and nephrotoxicity.

Hormonal Therapy

• Overview: Hormone therapy utilizes agonists or antagonists to influence the course of cancer.
• Application: It may be used alone or in combination with other therapies.
• Specific Receptor Cancers: Cancers with hormone receptors, such as breast and endometrial cancers, can be controlled by hormone therapy, often involving estrogen receptor binding agents like tamoxifen.

Immune Therapy

Immune therapy can be categorized into two forms:

• Active Immune Therapy
• Adoptive Immune Therapy

Active Immune Therapy

• Mediated by Active Immunity: Active immune therapy is mediated by active immunity, aiming to provoke an anticancer immune response in patients with cancer.
• Examples: Examples of active immune therapy include cancer cell vaccines alone or in combination with adjuvants, which enhance the desired immune response.
• Monoclonal Antibodies: Another approach is using monoclonal antibodies targeting programmed death-1 (PD-1) or PD-1 ligand (PD-1L). These antibodies aim to release a patient's immune system response, which may be suppressed by the cancer through PD-1 or PD-1L mediated mechanisms.

Adoptive Immune Therapy

• Mediated by Passive Immunity: Adoptive immune therapy is mediated by passive immunity.
• Process: It involves administering anticancer antibodies or cells to a patient with cancer.
• Examples:
  • Monoclonal antibodies directed against lineage-specific antigens. These antibodies may be linked to a toxin or radionuclide to increase efficacy.
  • Widely Used Example: Rituximab is a widely used example, particularly in patients with lymphomas.
  • Another approach is to give T cells or natural-killer (NK) cells from a healthy person to someone with cancer.

Targeted Therapy

• Definition: Targeted therapy involves therapies directed against a specific gene or gene product that is thought to be important in the cause or progression of cancer.
• Examples:
  • The use of tyrosine kinase inhibitors, such as imatinib, dasatinib, and nilotinib, in chronic myeloid leukemia, a cancer caused by a specific mutation (BCR-ABL1).

Vaccines

Vaccines are designed to prevent virus-related cancers. Examples include:

• Vaccines against human papilloma virus that can prevent cervical and anal cancers (and possibly and head and neck and tonsil cancers) and
• Hepatitis B vaccine that can prevent liver cancer.

• Cure: Long-term absence of symptoms or signs of a disease, although patients who appear to be cured may still have cancer cells that could eventually cause relapse.
• Complete Remission (Complete Response): No evidence of cancer.
• Partial Response: Substantial (usually > 50%) reduction in the size of cancer.
• Stable Disease: Neither improvement nor worsening.
• Disease-Free Survival: The interval between achieving complete remission and relapse or death, whichever occurs first.
• Progression-Free Interval: The time from the end of treatment to progression.
• Survival Time: The time from diagnosis or the end of an intervention to death.

Supportive therapy in cancer treatment includes the following aspects:

• Optimize Nutrition: Ensuring patients receive proper nutrition to support their health and recovery.
• Control of Infections: Managing and preventing infections that can be especially concerning for individuals with weakened immune systems due to cancer treatment.
• Prevention, Monitoring, and Management of Side Effects: Addressing and handling side effects of cancer treatment such as dehydration, anemia, and oncological emergencies.