Module 4

• Epidemiology:

  • 1 in 285 or approximately 300 children will develop cancer
  • Children now develop cancer, no longer exclusive to adults
• • Biologic agents have a small role in treating cancers in children due to lack of studies on effectiveness and tolerable side effects
• Primary Modalities of Therapy:

  • Three approved methods to treat cancer: Cut (Surgery), Burn (Radiation), Poison (Drugs)
  • Side effects especially with drugs
  • Survivor patients need monitoring for potential secondary malignancies like AML, Sarcomas, etc.
  • Children are usually treated with chemotherapy, brain tumors not very sensitive to chemotherapy
  • Try to avoid radiotherapy in very young children (<3 years old) due to negative effects on the growing nervous system
• Basic Principles of Chemotherapy:

  • Goal is to cure patients by eradicating all cancer cells
  • Principles include: Combination chemotherapy, Adjuvant Chemotherapy, Maximum Tolerated Dose Intensity
• Combination Chemotherapy:

  • Overcomes drug resistance to individual agents
  • Prevents or delays development of acquired drug resistance
  • Contains drugs with single agent activity against tumor, non-cross-resistant, non-antagonistic mechanism of action, nonoverlapping toxicities
• Adjuvant Chemotherapy:

  • Most effective when administered to patients without overt evidence of residual disease after local therapy
  • Prevents metastatic recurrence by eliminating micrometastatic tumor deposits
  • Should begin as soon as possible after definitive local therapy
• Multimodal, Multidisciplinary Approach to Treatment of a Child with Cancer:

  • Treatment involves a multimodal, multidisciplinary approach
  • Chemotherapy is using drugs to treat any disease, usually connotes cancer treatment
  • Chemotherapy has a systemic effect to cure, control, or palliate symptoms
  • Chemotherapy works by stopping cancer cells from growing and multiplying at different points in their life cycle
• The Cell Cycle:

  • Phases of Cell Cycle: G1, S, G2, M
  • G1 phase: Cells increase in size
  • S phase: Copying of DNA material
  • G2 phase: Preparation for division
  • M stage: Mitotic stage
  • G0 phase is a resting phase where cells are quiescent and not dividing or preparing to divide
• Cells in the G0 phase may not be affected by chemotherapy because they are already resistant to chemotherapeutic drugs
• Chemotherapeutic agents are historically divided into phase-nonspecific agents and phase-specific agents
• Phase-nonspecific agents can act in any phase of the cell cycle
• Phase-specific agents require the cell to be at a particular cell cycle phase to cause the greatest effect, especially in the M phase
• Phase-specific agents are usually given repeatedly to introduce cells at specific cell cycle stages
• Cells may progress to checkpoints in the cell cycle after the agent has acted, where drug-related damage may be assessed and repaired or lead to apoptosis
• Tumor-suppressor genes like p53 may modulate checkpoint function
• Alkylating agents damage the DNA of cancer cells to prevent replication
• Alkylating agents attach to the guanine base of DNA at the #7 nitrogen atom of the purine ring
• Alkylating agents are non-cell cycle specific
• Antimetabolites are structural analogues of normal cell substances that interfere with nucleic acid or nucleotide synthesis
• Antimetabolites are cell-cycle specific and attack cells at specific phases in the cycle
• Antimetabolites are classified based on the substances they interfere with
• Antitumor antibiotics interfere with DNA and mRNA production and act during multiple phases of the cell cycle
• Antitumor antibiotics are considered cell-cycle non-specific
• Plant alkaloids are derived from specific plants and have different mechanisms of action
• Plant alkaloids can be mitotic spindle inhibitors or topoisomerase inhibitors
• Other agents used in chemotherapy include ribonucleotide reductase inhibitors, adrenocortical steroid inhibitors, enzymes like asparaginase, antimicrotubule agents, and retinoids
• Monoclonal antibodies are laboratory-produced molecules that target specific antigens of tumors
• Tyrosine kinase inhibitors block tyrosine kinases to stop cell growth
• Tyrosine kinases are important mediators that transmit signals for cellular functions
• Examples of tyrosine kinase inhibitors include Imatinib, Dasatinib, Nilotinib, and Bosutinib
• Immunomodulatory cytokines like interferon, interleukin, tumor necrosis factor, and colony stimulating factors are used in cancer treatment
• Interferon was previously used for CML treatment
• 1. CSF can be given to patients with leukopenia secondary to chemotherapy
• Erythropoietin is used in cases of anemia secondary to end-stage renal disease
• ERYTHROPOIETIN:

  • Good cytokine
  • Indicated for chronic anemia
  • Takes time for RBCs to increase (usually 2 weeks)
  • Given subcutaneously
• CAR-T CELL THERAPY:

  • T-lymphocytes are a major component of adaptive immunity involved in killing infective host cells
  • T-cells are taken from a patient and a specific receptor gene is added in the laboratory
  • T-cells are introduced to a retroviral vector producing a gene found on the tumor of the patient
  • Retroviral vector introduces the protein or antigen found on the cancer cell to the T-cell
  • Forms Chimeric Antigen Receptor (CAR-T cell) which kills tumor cells
• RECENT DISCOVERIES:

  • Professor Tasuku Honjo won the Nobel prize in 2018 for his contribution to cancer therapy
  • Discovered PD-1 on T-cells and PDL-1 receptor on cancer cells
  • Cancer cells can block PD-1 receptors on T-cells, leading to T-cells being ineffective
  • Discovery led to antibodies against the receptors, like Anti-PD-1 antibody
• OTHER TYPES OF CHEMOTHERAPY:

  • Neoadjuvant: given before primary treatment to shrink tumor
  • Adjuvant: given after primary procedure like surgery
  • Concurrent: given simultaneously with radiation therapy
  • Sequential: given in sequence with radiation therapy
  • Palliative: given to alleviate pain when cancer cannot be cured
• ROUTES OF ADMINISTRATION:

  • Intravenous: thin needle inserted into a vein or catheter in a larger vein
  • Infusion: given over a few days or weeks using pumps
  • Oral: taken by mouth
  • Subcutaneous: injected into the space between skin and muscle
  • Intramuscular: deposited in muscle tissue
  • Intrathecal: used in leukemia treatment to reach cerebrospinal fluid
  • Topical: applied to the skin
  • Catheter: ensures delivery of drugs to specific areas
  • Pump: external or internal pump
• SIDE EFFECTS:

  • Anticancer drugs target fast-growing cells, affecting normal cells like hair follicles, skin, GIT lining, and blood
  • Most side effects disappear after treatment ends
  • Nausea and vomiting are common side effects, can be controlled with medications like Ondansetron
  • Alopecia (hair loss) can occur due to rapid growth of hair follicles