Chemotherapy, Hormonal, and Targeted Therapy (ONRT120) - Nov 15, 2024 PDF

Principles of Treatment: Chemotherapy, Hormonal, and Molecular Targeted Therapy Nathaniel So, MRT(T) Radiation Therapist Princess Margaret Cancer Centre [email protected] ONRT120/MRS144H1 November 15, 2024  Lecture Objectives After this lecture, you will...

Principles of Treatment: Chemotherapy, Hormonal, and Molecular Targeted Therapy Nathaniel So, MRT(T) Radiation Therapist Princess Margaret Cancer Centre [email protected] ONRT120/MRS144H1 November 15, 2024  Lecture Objectives After this lecture, you will be able to: Describe the various types of systemic therapy and how they work to kill cancer cells Outline the roles of each type of treatment Explain how the response to each treatment is evaluated Describe the limitations and toxicities of each type of treatment Become familiar with terminology associated with systemic therapy 2  Local vs. Systemic Therapy Local therapy: Treatment that is directed at a specific area of the body – E.g. Surgery, radiation therapy, cryotherapy, laser therapy, topical therapy Systemic therapy: Treatment using substances that travel through the bloodstream and affect cells all over the body – E.g. chemotherapy, hormonal therapy, targeted therapy 3  What is Chemotherapy? Chemotherapy: treatment that uses drugs to stop the growth of cancer cells – Also called: cytotoxic (cell-killing) or antineoplastic (anti-cancer) drugs First used as cancer treatment in the 1940s – Nitrogen mustard, derived from mustard gas – Treatment for lymphoma 4  How does chemotherapy work? Kills cancer cells Prevents effective DNA replication and cell division Works at the DNA level at various phases of the cell cycle – Chemo works best on cells that grow and divide rapidly NOT specific to cancer cells → SIDE EFFECTS! QUESTION: What types of normal cells grow and divide rapidly? 5 REVIEW: The Cell Cycle G0 (resting phase): cells are not considered to be in the cell cycle G1: RNA, protein, and enzyme synthesis; preparation for DNA synthesis S: DNA synthesis G2: RNA and protein synthesis, DNA check M: mitosis (nuclear division) + cytokinesis (cell division) Interphase: G1 + S + G2 6 Classification of Chemotherapy Agents 7  Classification of Chemotherapy Agents Vinca Alkaloids Cell Cycle Non-Specific: Cell Cycle Phase-Specific: Taxanes Nitrosureas (e.g. carmustine) Bleomycin G0 Etoposide M G2 Cell Cycle Phase Non-Specific: 1) Alkylating agents 2) Anthracyclines G1 3) Miscellaneous S Antimetabolites Steroids (e.g. 5-FU, methotrexate) Enzymes (e.g. asparaginase) 8  Classification of Chemotherapy Agents How can we use this classification information? – Slow-growing vs. fast-growing tumour Slow-growing: Choose a phase non-specific drug Fast-growing: Less difference in effectiveness between phase-specific and phase non-specific drugs – Repeated/prolonged exposure to the same phase- specific drug (original concentration) is more effective than using a single-dose, higher concentration exposure of the drug 9  Alkylating Agents Cell-cycle specific, phase-nonspecific E.g. cyclophosphamide, cisplatin Mechanism of action: – Alkyl group is attached to a guanine base in DNA resulting in cross-linked DNA strands – Leads to DNA strand breakage and prevents DNA replication 10  Anti-Tumour Antibiotics Most are cell-cycle specific, phase-nonspecific Anthracyclines (e.g. doxorubicin, daunorubicin) Mechanism of action: Insertion between DNA base pairs (intercalation) Inhibition of topoisomerase II enzyme (involved in unwinding DNA) Generation of free radicals that damages cell membranes 11  Topoisomerase Inhibitors E.g. Etoposide (G2), Mitoxantrone (phase non-specific) Mechanism of action: – Interferes with topoisomerase I and II enzymes, which are involved in unwinding DNA strands during replication 12  Antimetabolites (S phase) E.g. 5-FU, methotrexate Structural analogues of substances needed for normal metabolic reactions Mechanism of action: – Substitutes in for normal components of DNA, RNA or protein synthesis – Inhibits critical enzymes needed for DNA or RNA synthesis Folic Acid - helps prevent anemia Methotrexate 13  Mitotic Inhibitors (M phase) Includes vinca alkaloids (e.g. vincristine, vinblastine) and taxanes (e.g. paclitaxel) Mechanism of action: – Interferes with microtubule activity during mitosis – Prevents proper mitotic spindle formation → cells cannot divide 14  Goals of Chemotherapy Cure (“curative intent”) – Total eradication of cancer cells and cancer does not come back – QUESTION: Can you name a cancer that can be cured with chemotherapy? Control – Control the disease when cure is not possible (e.g. shrink tumour, help slow cancer growth and spread) – Treat cancer like a chronic disease – Can improve quality of life and survival Palliation (“palliative intent”) – Relieve symptom burden (e.g. pain, pressure, SOB) – Improve quality of life (not necessarily survival) 15  Roles of Chemotherapy Induction: first-line treatment given to attain remission Consolidation (intensification therapy): subsequent therapy given to sustain remission (kill any residual cancer cells) Maintenance: ongoing, less intensive therapy aimed to prevent disease recurrence Salvage: 2nd line chemotherapy given after initial induction chemo has failed (either no response or recurrence of disease) 16  One Drug or Multiple Drugs? Treatment often includes a combination of drugs Strategies WHY? – Choose drugs with: – Increased cell killing – Different mechanisms of efficacy (additive or action synergistic effect) – Different mechanisms of – Minimize resistance resistance to one chemo drug – Non-overlapping toxicities – Tolerable toxicity – Consider patient co-morbidities Examples: ABVD (Hodgkin’s lymphoma), AC (breast cancer) 17  Single vs. Multimodality Treatment Chemotherapy can be combined with other treatment modalities (e.g. surgery, radiation therapy) Adjuvant chemotherapy: chemotherapy is given AFTER surgery or radiation to remove any residual microscopic disease – Reduces risk of recurrence – Improves chance of cure – E.g. Adjuvant AC chemo after breast lumpectomy 18  Single vs. Multimodality Treatment Neoadjuvant chemotherapy: chemotherapy is given BEFORE surgery or radiation to help shrink the cancer – May allow surgery to be used in previous non-surgical candidates – Can help to minimize the extent of surgery → better cosmesis (e.g. locally advanced breast cancer) – Can potentially reduce radiation treatment volume → fewer side effects – Kill micrometastatic disease 19  Single vs. Multimodality Treatment Concurrent (concomitant) chemotherapy: chemotherapy given at the SAME time as other treatment modalities – E.g. concurrent chemoradiation for glioblastoma (temozolomide), head and neck cancers (cisplatin) – Synergistic effect – chemotherapy acts as a radiosensitizer – Increased treatment toxicity 20  Routes of Administration Most common routes: Intravenous (IV), Oral (PO) Intrathecal: injected into the cerebrospinal fluid (CSF) surrounding the brain and spinal cord 21  Chemotherapy Scheduling Most effective scheduling = high-dose therapy with intermittent administration (i.e. cycles) Scheduling is usually based on both tumour and patient factors: – (1) The potential doubling time of the tumour – (2) The time that normal tissues take to recover from toxicity Benefit vs. Toxicity 22  Determining the Right Dose Dose is usually based on a person’s body surface area (mg/m2) Other factors to consider: – Age (adult vs. child) – Kidney and liver function – Co-morbidities – Blood counts 23  Evaluating Treatment Response Complete response (CR): Disappearance of all tumoural lesions (remember: it does not mean cancer is cured!) Partial response (PR): A significant decrease in tumour size, but disease is still detectable Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD Progressive disease (PD): A significant increase in tumour size or the appearance of new lesions For more info, check out: RECIST guideline version 1.1 24  Other Measures of Response Duration of response (DOR): Length of time from documentation of CR/PR to disease progression Disease-free survival (DFS): Length of time from treatment initiation to disease recurrence/death after curative-intent treatment Progression-free survival (PFS): Length of time from treatment initiation to disease progression/death after treatment to control/palliate cancer DOR Diagnosis CR/PR Time Treatment Disease recurrence/progression DFS/PFS 25  How can chemotherapy fail? Chemoresistance – Cancer cells are resistant or become resistant to certain chemotherapy agents Treatment is too toxic – Some patients may need to stop chemotherapy altogether and do not receive the full benefit of treatment 26  Chemoresistance Mechanisms Drug is pumped out of the cell (efflux pumps) Decreased cell membrane permeability to the drug Increased drug degradation Decreased drug activation Enzymatic deactivation of drug through conjugation with glutathione Altered drug target 27  Chemoresistance Mechanisms Increased DNA repair Increased anti-apoptotic potential due to mutated proteins (e.g. p53) or expression of alternative proteins Sanctuary sites: areas of the body that are somewhat protected from the effects of chemotherapy (e.g. CNS, testes) QUESTION: How do you minimize chemoresistance? 28  Chemotherapy Side Effects Recall: Chemotherapy is most effective against cells that grow and divide rapidly Most side effects resolve shortly after treatment, but some persist long-term and can be permanent QUESTION: What are the most common acute side effects of chemotherapy? 29  Chemotherapy Side Effects More long-term side effects – Cardiac toxicity (adriamycin/doxorubicin) – Pulmonary fibrosis (bleomycin) – Ototoxicity (cisplatin) – Hepatotoxicity (cisplatin, asparaginase, methotrexate) – Nephrotoxicity (cisplatin, ifosfamide) – Peripheral neuropathy (vinca alkaloids, taxanes, platinum-based drugs) – Cognitive changes – Infertility – Secondary cancers 30  Supporting Patients Through Chemo GOAL: Prevent and/or reduce the severity of chemotherapy-related side effects to help patients complete chemotherapy treatment Anti-emetics (e.g. ondansetron) Close monitoring of blood counts with regular blood tests Blood transfusions, platelet infusions Filgrastim (Neupogen) injection to increase WBC Fertility preservation, sexual health and intimacy counselling 31 HORMONAL THERAPY 32  What are Hormones? Hormone: a chemical released by a cell or a gland in one part of the body that controls and regulates the activity of other cells and organs (i.e. chemical messenger) Regulates physiology and influences behaviour (e.g. metabolism, growth, mood, aggression) Cells respond to a hormone when they express the receptor to that hormone Hormone binds to receptor protein → activation of a signal transduction pathway 33  What is Hormonal Therapy? Some cancers depend on hormones to grow – Breast → estrogen – Prostate → androgens (e.g. testosterone, DHT) Hormonal Therapy: Treatment that provides, blocks, or removes hormones to slow or stop the growth of hormone-sensitive cancer cells – It is a type of targeted therapy 34  Hormonal Therapy Types Surgery – Remove the gland that produces the hormone Radiation – Damage the gland to stop hormone production Hormonal Drug Therapy – Inhibit hormone production – Block action of hormone in the body – Routes of administration: oral, IV, IM 35  Treatment Planning Considerations Hormonal therapy is often used in combination with other treatment modalities – Neo-adjuvant (to shrink tumour before surgery/radiation) – Adjuvant (after surgery/radiation to reduce risk of recurrence) – Concurrent (with radiation) Can also be primary treatment (e.g. metastatic prostate cancer) 36  Treatment Planning Considerations Likelihood of treatment response – Hormone receptor status tests (e.g. for breast cancer) Length of treatment – Can be a specific length of time – Can be used as long as the cancer responds to treatment – Can depend on patient’s side effects to treatment Treatment dose scheduling – Can be given continuously (e.g. pill taken once daily) – Can occur at regular intervals (e.g. monthly injections) 37 Estrogen and Breast Cancer Estrogen – Produced in the ovaries (mainly) and in the adrenal glands (small amount, in post- menopausal women) – Stimulates breast and uterine cell proliferation 38  Estrogen and Oncogenesis NOTE: Estrogen does NOT directly cause cancer 39  Hormonal Therapy for Breast Cancer Indications: Cancer cells are estrogen receptor- positive (ER+) and/or progesterone receptor- positive (PR+) Treatment Options – Selective Estrogen Receptor Modulators (SERM) – Aromatase Inhibitors – Steroidal Anti-estrogens: Bind to ER and block the effect of estrogen on cancer cells – LHRH Agonists Ovarian ablation – Gland Ablation 40 Selective Estrogen Receptor Modulators Non-steroidal (unlike estrogen) Bind to ER Selective stimulation or inhibition of estrogen effects in different tissues SERMs do NOT change estrogen levels in the body Effects of SERMs are reversible 41  Tamoxifen First SERM that showed anti-cancer effects (1970’s) Blocks cells in G1 phase of cell cycle Cytostatic drug Usually taken daily as a pill Used by pre- and post-menopausal women Uses Treatment Duration Neoadjuvant Therapy 3-6 months Adjuvant Therapy 5-10 years Recurrent/Metastatic Cancer Continue treatment as long as effective 42  Tamoxifen Benefits – risk of recurrence – risk of new cancer in contralateral breast – survival – Protects bone density Risks – Increased risk of uterine cancer – Increased risk of blood clots 43  Tamoxifen Side Effects Side Effects can include: – Hot flashes – Night sweats – Vaginal dryness/discharge – Irregular menstrual cycles – Weight gain – Mood swings – Nausea 44  Aromatase Inhibitors Prevents peripheral conversion of androgens to estrogen by aromatase, reducing estrogen levels Used by post-menopausal women E.g. Anastrozole (Arimidex) 45  Aromatase Inhibitors Uses Treatment Duration Neoadjuvant Therapy 3-6 months Adjuvant Therapy Usually up to 5 years Recurrent/Metastatic Cancer Continue treatment as long as effective Daily pill taken orally Can be taken alone or sequentially after tamoxifen Benefits – Further reduction in risk of recurrence than tamoxifen Risks – Increased risk of osteoporosis and bone fractures – Side Effects: menopause symptoms, muscle and joint pain 46  Resistance to Hormonal Therapy – Breast Cancer Examples – ER activation in the absence of estrogen – Hypersensitivity of ER to low estrogen levels Mechanisms – ER mutation – Increased expression of co- activator proteins 47  Androgens and Prostate Cancer Prostate cells and prostate cancer cells are dependent upon androgens (male sex hormones) for survival and growth Testosterone (T): Produced in the testes (~95%) and the adrenal gland (~5%) Dihydrotestosterone (DHT): Has greater affinity for androgen receptor than testosterone 5-α reductase Testosterone DHT 48  Hormonal Therapy for Prostate Cancer Called androgen deprivation therapy (ADT) Indications: intermediate-risk and high-risk patients, patients with metastatic disease – Radiation + ADT (if non-metastatic) → improved local control and survival Risk is based on: – Extent of cancer spread – Aggressiveness of cancer cells (Gleason score) – Prostate-specific antigen (PSA) level 49  Androgen Deprivation Therapy Treatment Options – LHRH agonists – LHRH antagonists – Anti-androgens: Bind to androgen receptors and block the effect of androgens on cancer cells – 5-α reductase inhibitors: Block conversion of T to DHT – Estrogen therapy (rarely used) – Orchiectomy (rarely used) – Combination Therapy Evaluating treatment response: – Monitor PSA and T levels regularly during and after ADT – Imaging tests (e.g. CT, MRI, bone scans) 50 51  LHRH Agonist vs. Antagonist LHRH Agonist LHRH Antagonist Binds to receptors on the pituitary gland Reduces testicular production of T (effect similar to orchiectomy, but is reversible) Also called chemical/medical castration Given as injections at regular intervals Associated with initial T flare → Lowers T more quickly than Give anti-androgen to minimize T LHRH agonists with no T flare flare symptoms (e.g. bone pain) E.g. Leuprolide (Lupron), E.g. Degarelix (Firmagon) Goserelin (Zoladex) 52  Limitations of ADT Castrate-resistant cancer – Cancer is still growing after ADT when T levels are low – Seen in almost all patients after 18-36 months – Solution: Try other forms of ADT (e.g. newer drugs) Hormone-refractory cancer – No hormone therapy works anymore – Solution: Try chemotherapy (e.g. docetaxel), bisphosphonates to strengthen bones 53  Side Effects of ADT Erectile dysfunction Loss of sexual desire (libido) Shrinkage of testicles and penis Loss of muscle mass and bone density Hot flashes Weight gain Fatigue 54 MOLECULAR TARGETED THERAPY  Targeted Therapy Definition: Treatment that uses drugs to target specific molecules involved in the growth and spread of cancer cells Goal: Exploit characteristics that make cancer cells behave differently than normal cells Ideal Target: – Specific to cancer cells, but absent in normal cells – Target major “driver” mutations (altered genes +/- their protein gene products) 56  Targeted Therapy Eligibility: Test whether the patient’s tumour has the gene/protein mutation that a drug is designed to target Treatment can include a combination of multiple targeted therapies Usually used in combination with surgery, radiation, and/or chemotherapy Can be given intravenously or orally (pill) 57  Targeted Therapy Types Two main types: – Monoclonal antibodies (mAb) target specific antigens found on the cell surface (e.g. transmembrane receptors) or outside the cell Produced in the lab Drug names end in “–mab” (i.e. monoclonal antibody) 58  Targeted Therapy Types Small molecules can penetrate the cell membrane to interact with targets inside the cell Most are tyrosine kinase inhibitors (TKIs) Tyrosine kinases are enzymes important for cell signalling, growth, and division Drug names end in “-ib” (i.e. inhibitors) 59 Examples of Targeted Therapy 60  The Hallmarks of Cancer How do cancer cells enable their growth and spread? 61 The Hallmarks of Cancer 62 Targeting the Hallmarks of Cancer 63  Mechanisms of Action Signal-transduction inhibitors – Block chemical signals that tell cancer cells to grow and divide – E.g. TKIs Angiogenesis inhibitors – Prevent the formation of new blood vessels in cancer cells – Remove oxygen and nutrients required for continued cancer cell growth – E.g. Bevacizumab (Avastin) Apoptosis inducers – Restore signals that tell cancer cells to die – E.g. DNA repair enzyme inhibitor 64  Mechanisms of Action Trigger the immune system – Binding a mAb to a specific target on cancer cells can trigger the immune system to kill the cancer cells – E.g. Rituximab Deliver cell-killing substance directly to cancer cells – Bind mAb with attached toxin to target cancer cell – Normal cells are not affected 65  HER2 and Breast Cancer HER2 overexpression occurs in 20-30% of breast cancers (i.e. HER2+ receptor status) Adverse prognostic factor Associated with: – aggressive disease – risk of recurrence – disease-free and overall survival 66  Trastuzumab (Herceptin) Herceptin is a humanized monoclonal antibody that binds to the HER2 receptor Can be used as a single agent or with chemotherapy Given as regular IV injections (e.g. weekly) Typical treatment duration: 1 year risk of cancer recurrence survival 67  Trastuzumab (Herceptin) Mechanisms of action: – Inhibits HER2 activation – Induces receptor endocytosis and degradation – Induces immune- mediated cytotoxicity Risks: – Cardiomyopathy – Pulmonary toxicity – Infusion reactions 68  Side Effects of Targeted Therapy Diarrhea Hepatitis Elevated liver enzymes Skin rash, dry and itchy skin Swelling and redness around nails Impaired wound healing Gastrointestinal bleeding Usually from Increased risk of blood clots angiogenesis inhibitors Increased blood pressure 69  Limitations of Targeted Therapy Cancer cell resistance – Mutation of target – Cancer cell growth that does not depend on target – Solution: Try combination therapy (e.g. multiple targeted agents; targeted therapy + other treatment modalities) Lack of available drugs for certain known targets 70 Chemotherapy vs. Targeted Therapy Chemotherapy Targeted Therapy Targets all rapidly dividing Targets specific molecules cells (normal cells and associated with cancer cancer cells) cells Lower specificity Higher specificity Significant side effects Usually better tolerated than chemotherapy Cytotoxic Mostly cytostatic 71