Cancer Treatment Methods PDF

Lab tests (blood tests) Complete blood count Count the number of different types of cells in the blood Abnormality in number and morphology: possibility of blood cancer (leukemia, lymphoma and myeloma) Bone marrow biopsy: confirm blood cancer Blood protein staining Test...

Lab tests (blood tests) Complete blood count Count the number of different types of cells in the blood Abnormality in number and morphology: possibility of blood cancer (leukemia, lymphoma and myeloma) Bone marrow biopsy: confirm blood cancer Blood protein staining Test of abnormal immunoglobulins (antibodies) Tumor marker tests Example: CA-125 for ovarian cancer Circulating tumor cell (CTC) tests (uncommon) Test of cancer cells floating in the bloodstream 5 Complete blood count (CBC) Red blood cell (RBC) test RBC count, hemoglobin (carrying protein for O2 and CO2), hematocrit (volume proportion of blood that consists of RBC) and reticulocyte count (count of immature RBCs) White blood cell (WBC) test WBC count and WBC differential (count for each type of WBCs) WBC cell types: monocytes, lymphocytes, neutrophils, basophils and eosinophils Platelets (PLTs) test Platelet count, mean platelet volume (average size of platelets) and platelet distribution width (uniformity of platelets) 6 Blood protein staining Serum electrophoresis Test protein abnormality and loss of proteins Aid in the diagnosis of lymphoma, chronic lymphocytic leukemia and multiple myeloma Electrophoretic zones: albumin, alpha-1 antitrypsin, alpha-2 macroglobulin, beta-1 & beta-2 transferrin (some cases of myeloma and leukemia), and gamma globulin (some cases of myeloma and lymphoma) 7 Tumor marker tests Commonly used tumor makers are listed at: https://www.cancer.gov/about-cancer/diagnosis- staging/diagnosis/tumor-markers-list Examples of tumor markers: Marker Sample Cancer type Purpose CA-125 Blood Ovarian cancer Diagnosis & treatment CD25 Blood Non-Hodgkin Targeted therapy lymphoma EGFR gene Tumor Non-small cell lung Treatment & mutation cancer prognosis Estrogen receptor Tumor Breast cancer Hormone therapy & targeted therapy 8 CA-125 & ovarian cancer Cancer antigen 125: glycoprotein with molecular weight > 200 kD Tested by immunoassay Normal range in blood: less than 46 U/mL Higher than normal range: Ovarian cancer (diagnosis and treatment) Endometriosis Liver diseases Menstruation Pregnancy Uterine fibroids 9 70-Gene signature (70-GS,  MammaPrint ) Predict metastasis and recurrence of breast cancer Test the activity of 70 different genes in the breast cancer tissue (< 3 infected lymph nodes) Aid to early-stage breast cancer treatment 10 Circulating tumor cell (CTC) tests CTC test for breast cancer CTC test for colorectal cancer CTC test for prostate cancer All three are liquid biopsy tests developed by CellSearch and approved by FDA Ferrofluid nanoparticle-based technology CellSearch CTC test video (suggested) https://www.youtube.com/watch?v=8vx9ABD3_g4 (Menarini Silicon Biosystems) 11 Cancer diagnostic imaging Breast mammogram CT scan PET scan MRI imaging 12 Breast mammogram Low-dose X-ray imaging Two images of each breast at ~ 0.4 millisilverts Show abnormal areas in the breast Used for screening of breast cancer 13 CT, PET and MRI Computerized Tomography (CT): X- Ray scan from different angles and computer-processed cross-sectional images Positron Emission Tomography (PET): Use a radioactive drug as a tracer, such as fluorodeoxyglucose (18F-FDG) Magnetic Resonance Imaging (MRI): uses magnetism, radio waves, and a computer to produce images 14 Cancer biopsy Main way to diagnose most types of cancer Remove a piece of tissue from a patient’s body and analyze it in a laboratory Bone marrow biopsy Endoscopic biopsy Needle biopsy Skin biopsy Surgical biopsy Biopsy analysis Confirmation of cancer Cancer grade Targets for targeted therapy 15 Surgery Remove the entire tumor Debulk a tumor: remove some but not all of a tumor because entire tumor removal might damage the organ Ease cancer symptoms: remove tumors causing pain and pressure Smaller residual tumor volume may be associated with longer survival for cancer patients 19 Types of surgery Open surgery Minimally invasive surgery: through tiny incisions, non-robotic and robotic surgery Cryosurgery: use liquid nitrogen to treat skin cancers and retinoblastoma Laser surgery: tumors on the surface of the body Hyperthermia: radiofrequency ablation 20 Radiation therapy Apply high doses of radiation to kill cancer cells and reduce tumor size Purpose: treatment and palliative care External beam radiation therapy and internal radiation therapy External beam radiation therapy Photons, protons and electrons 3D conformal radiation therapy (3D-CRT) Intensity-modulated radiotherapy (IMRT) 22 3D conformal radiation therapy (3D-CRT) Allow doctors to direct radiation beams (photons) to conform the shape of a tumor CT scan is used to provide the 3D dimension of the tumor and nearby organs Beams are arranged to avoid normal organs and target the tumor 23 Intensity-modulated radiotherapy (IMRT) CT scan is used to provide the 3D dimension of the tumor and nearby organs Multiple beams are positioned for the therapy Each big beam is divided into many small beams (beamlets) Special software is used to identify beamlet patterns (> 50) for precise radiation IMRT can be used for hard-to-treat areas 24 Internal radiation therapy Brachytherapy: a sealed container of radioactive material into tumors Radioisotope therapy: such as I-131 for thyroid cancer Radioimmunotherapy: combination of radioisotopes and monoclonal antibodies Radioembolization: radioactive beads along with embolization (reduced blood supply to an organ) 26 Chemotherapy Widely used in cancer treatment Use alone or in combination with other therapies Adjuvant chemotherapy Often used after primary treatments, such as surgery or radiotherapy Destroy micro-metastasis Prevent or reduce cancer recurring Neoadjuvant chemotherapy Given before the main treatment such as surgery or radiotherapy Reduce tumor size to make primary treatment easier or more effective 28 Chemotherapy types DNA-damaging agents Alkylating agents Antimetabolites Purine antagonists Pyrimidine antagonists Antimitotics Taxanes and vinca alkaloids Antitumor antibiotics Intercalating agents (anthracyclines) – doxorubicin and daunorubicin DNA-repair enzyme inhibitors PARP inhibitors 29 Alkylating agents Nitrogen mustards Melphalan, Cyclophosphamide, Ifosfamide, Chlorambucil and Estramustine Nitrosoureas Carmustine, Lomustine, Nimustine and Streptozocin (Streptozotocin) Platinum drugs Carboplatin, Cisplatin, and Oxaliplatin Miscellaneous alkylating drugs Busulfan, Procarbazine, etc. 30 Platinum alkylating agents Alkylate and crosslink DNA (intra- and inter-) Cell-cycle non-specific DNA-protein crosslinks → rare 36 Busulfan Remove mesylate (CH3SO3-) to form R–CH2+ Nonspecific alkylating agent (N7-guanine) Cause intra- and inter-crosslink of DNA molecules Used to treat chronic myelogenous leukemia 37 Procarbazine Form methyldiazonium ion (CH3-N+≡N) and methyl cation (CH3+) Nonspecific alkylating agent which methylates guanine at O6 May inhibit protein, RNA and DNA synthesis Used to treat Hodgkin’s lymphoma (stages III and IV), non-Hodgkin’s lymphoma and gliomas 38 Antimetabolites Prevent the biosynthesis of normal cellular metabolites Pyrimidine antimetabolites, purine antimetabolites, folic acid analogues, and others 5-Fluorouracil (5-FU), capecitabine, gemcitabine, cytarabine and azacitidine NH2 O O NH2 O CH3 N HN HN N N N HN O N O N O N N NH H2N N NH H H H cytosine thymine uracil adenine guanine 39 Antimetabolites: MOA Cytarabine Inhibit the conversion of cytidylic acid to 2’-deoxycytidylic acid DNA-dependent DNA polymerase Miscoding due to incorporation into DNA/RNA Effective during S-phase NH2 NH2 N N O N O O O O N HO O O P P P O O HO O O O HO OH OH 41 Antimitotics – taxanes First isolated from the Pacific yew tree Paclitaxel → breast, lung, and ovarian cancers Docetaxel → breast, lung, stomach, prostate, and head and neck cancers Bind to free tubulin Produce stable microtubules Inhibit microtubule disassembly Microtubules arrange in a parallel fashion rather than a spindle 42 Vinca alkaloids First isolated from the Madagascar periwinkle plant Vinblastine, vincristine, vindesine and vinorelbine Prevent microtube polymerization Function is opposite of that for taxanes Used to treat cancers like Hodgkin’s lymphoma, non-small cell lung cancer, bladder cancer and melanoma Intravenous injection 43 Antitumor antibiotics Anthracyclines → DNA intercalating agents Daunorubicin, doxorubicin, epirubicin, idarubicin and mitoxantrone O O O O OH O OH O OH CH3 CH2 OH CH2 OH OH OH OH OCH3 O OH OCH3 O OH OCH3 O OH O O O H H OH O O O CH3 CH3 CH3 OH OH H NH2 NH2 NH2 Daunorubicin Doxorubicin Epirubicin O O OH CH3 H NH OH OH O N OH O OH O OH O N OH H H NH O CH3 Mitoxantrone OH NH2 Idarubicin 44 Mechanism of action (MOA) for anthracyclines Intercalate with DNA perpendicular to its longitudinal axis Cause single and double stranded DNA cleavage A T H N N H CH3 O B N N H N N N O B O OH O HO H N N H CH3 O B N N H N N N O B A T 45 PARP inhibitors: DNA-repairing enzyme inhibitors PARP: Poly (ADP-ribose) polymerase Involved in DNA repair Overexpressed in many types of cancer 46 PARP inhibitors PARP inhibitors Olaparib, rucaparib, niraparib, iniparib and talazoparib (BMN 673) Block DNA repair in cancer cells and cause cancer cell death 47 Targeted therapy Slow down cancer growth Kill cancer cells Relieve symptoms caused by cancer Small molecule agents and monoclonal antibodies 49 Targeted therapy agents Tyrosine kinase inhibitors (TKIs) Imatinib, Gefitinib, Ibrutinib, etc. Monoclonal antibodies Trastuzumab, Pertuzumab, T-DM1, Zenocutuzumab Bevacizumab, Rituximab, etc. Apoptosis-inducing agents Bortezomib, Oblimersen, etc. Angiogenesis inhibitors Bevacizumab, Sunitinib, etc. 50 Tyrosine kinase inhibitors – TK domain Tyrosine kinase (TK) domain is present in growth factor receptors, such as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR), and signaling protein kinases such as Ras and Raf 51 Imatinib Treat chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) Inhibit BCR-ABL tyrosine kinase Inhibit proliferation and induce apoptosis in BCR-ABL positive cells Tablets: 100 mg and 400 mg CML: 400 mg daily; ALL: 600 mg daily 52 Gefitinib Inhibitor of epidermal growth factor receptor (EGFR) Signaling via EGF-EGFR promotes DNA synthesis, proliferation, migration and survival Prescribed for non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R mutation 53 Monoclonal antibodies Trastuzumab – targeting Her2 Approved for Her2-subtype breast cancer Monoclonal antibody targeting Her2/neu/Erbb2 protein Bind to subdomain IV of Her2 protein IV infusion (1st: 90 min; if well- tolerated: 30 min) ADRs: chills, fever, body pain, weakness, nausea 54 Pertuzumab Monoclonal antibody binds to subdomain II of Her2 protein Block homodimerization of Her2 and heterodimerization of Her2-Her3 Inhibit Her2-signaling pathway and decrease cell growth Trastuzumab + pertuzumab + docetaxel for metastatic and recurrent Her2+ breast cancer 55 T-DM1 (ado-trastuzumab emtansine) Conjugate of trastuzumab (T) and emtansine (DM1) Emtansine, which is a potent cytotoxic agent, is cleaved from T-DM1 and released inside breast cancer cells Treat Her2+ metastatic breast cancer and early-stage Her2+ breast cancer after surgery Intravenous injection every three weeks 14 cycles in total for early-stage Her2+ breast cancer Video on trastuzumab, pertuzumab and T-DM1 (suggested) https://www.youtube.com/watch?v=jq5cqBeL73M 56 Apoptosis-inducing agents Bortezomib Proteasome inhibitor and apoptosis-inducing agent Bind to 26S proteasome, prevent proteosome-mediated degradation of pro-apoptotic factors and induce apoptosis Treat multiple myeloma and Mantle cell lymphoma (B-cell non- Hodgkin lymphoma) Hodgkin vs. non-Hodgkin: presence of Reed-Sternberg cells Video on proteasome inhibitors (suggested) https://www.youtube.com/watch?v=eNewTSGAnAM (Myeloma UK) 57 Angiogenesis inhibitors Bevacizumab Anti-angiogenesis monoclonal antibody blocking vascular endothelial growth factor (VEGF) VEGF and its receptors (VEGFR) can induce and promote angiogenesis Starve cancer cells Treat various types of cancer such as colon cancer and lung cancer Intravenous injection: 5-15 mg/kg every 2-3 weeks depending on cancer type Video of bevacizumab (suggested) https://www.youtube.com/watch?v=IqdVnCiy-sw (Bowel Cancer Australia) 58 Sunitinib Multiple-targeted tyrosine kinase inhibitor Inhibit VEGFR, platelet-derived growth factor receptor (PDGFR), colony stimulating factor receptor (CSFR) and tyrosine-protein kinase KIT (CD117) Angiogenesis inhibitor Prescribed for renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumor and metastatic pancreatic cancer 59 Immunotherapy Stimulate immune system to fight cancer Immune checkpoint inhibitors T-cell transfer therapy Monoclonal antibodies Treatment vaccines Immune system modulators 60 Innate immune response vs. adaptive immune response Innate immune response Nonspecific immune response Response is immediate Recruit immune cells to infection site to release chemical factors such as cytokines Adaptive immune response Create immunological memory Recognize specific antigen Take 4-7 days to respond 62 PD-1 and PD-L1 PD-1: programmed cell death protein 1 (CD279) Surface protein on T-cells Prevent T-cells from attacking other cells upon binding PD-L1 Check immune responses PD-L1: programmed cell death ligand 1 (CD274 or B7-H1) Transmembrane protein Prevent T-cells from killing PD-L1-containging cells Suppress adaptive immune responses during events such as pregnancy Upregulated in cancer cells 64 Immune checkpoint inhibitors PD-1 inhibitors Pembrolizumab Nivolumab Cemiplimab PD-L1 inhibitors Atezolizumab Avelumab Durvalumab Video on immunotherapy (suggested) https://www.youtube.com/watch?v=UbFjiWOBErA (Society for Immunotherapy of Cancer) 66 Hormonal therapies Hormones can bind estrogen receptor (ER) and progesterone receptor (PR) to promote cancer cell growth Hormonal therapies are used for breast cancer cells with the expression of ER and PR Tamoxifen Block ER and inhibit breast cancer cell growth May slightly increase the chance of getting uterine cancer Oral: 20-40 mg per day 67