W5 Cancer Chemotherapy (Gundrum).pdf

Cancer Chemotherapy Todd Gundrum, PharmD Ross University School of Medicine Learning Objectives 1. List the cancer chemotherapy drugs and assign them to the appropriate drug class. 2. Describe the mechanism of action of the cancer chemotherapy drugs. 3. Explain why some drugs are toxic in all phases...

Cancer Chemotherapy Todd Gundrum, PharmD Ross University School of Medicine Learning Objectives 1. List the cancer chemotherapy drugs and assign them to the appropriate drug class. 2. Describe the mechanism of action of the cancer chemotherapy drugs. 3. Explain why some drugs are toxic in all phases of the cell cycle and why other drugs have cell cycle specific toxicity. 4. Explain the reason for combination chemotherapy. 5. Explain the mechanism of drug resistance to the cancer chemotherapy drugs. 6. Describe the significant adverse effects of the cancer chemotherapy drugs. 7. List the drugs that are used to reverse or prevent toxicity to the cancer chemotherapy drugs: methotrexate, cyclophosphamide, doxorubicin, and cisplatin. 8. List the therapeutic uses of the cancer chemotherapy drugs with special attention to targeted therapies, drugs where the specific molecular target determines and limits the clinical use. Introduction Cancer cells are altered human cells, so it makes it difficult to specifically target them. Cancers most susceptible to chemotherapy are those having a high percentage of proliferating cells. Normal tissues that proliferate rapidly such as bone marrow, hair follicles, and intestinal epithelium are susceptible to damage from cytotoxic drugs. Most cancer drugs have a narrow therapeutic window and treatment is usually given to the point of toxicity. Combination chemotherapy is used to enhance efficacy while minimizing overlapping dose-limiting toxicity. Drugs used for cancer chemotherapy must have evidence of improved survival or time to further disease progression compared to the current “acceptable standard of care.” From 2016 to 2020, there were 207 FDA cancer drug approvals in oncology and malignant hematology. In 2021, 16 new drugs with oncology indications while in 2022, six new anti-cancer drugs were approved. Chemotherapy treatment approaches include: Primary (Induction) chemotherapy Chemotherapy drugs are used as first-line treatment. Adjuvant chemotherapy Chemotherapy drugs are used to eradicate any undetectable tumor in patients after primary chemotherapy or initial curative surgery or radiation. Neoadjuvant chemotherapy Drug therapy is used to treat localized tumors before primary treatment, usually surgery or radiation. The goal is to reduce the tumor mass and make surgery or radiation more effective.. Chemotherapy Drugs and the Cell Cycle Tumor cells are traversing the cell cycle more frequently and are more sensitive than normal cells to interference with DNA synthesis (toxicity will occur in S phase) and mitosis. (Toxicity will occur in M phase.) Slow growing tumors will be less susceptible to cell-cycle specific drugs. Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs, Tenth Edition. Alldredge et. al. PURINE AND PYRIMIDINE SYNTHESIS: DRUG TARGETS OF THE ANTIMETABOLITES Methotrexate Mechanism of action: Folic acid analog that binds with high affinity to the active site of dihydrofolate reductase (DHFR). This results in inhibition of synthesis of tetrahydrofolate (THF), which depletes cofactors that are required for the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. Methotrexate inhibition of these metabolic processes interferes with DNA, RNA, and proteins. Toxicity: black box warning = bone marrow suppression – neutropenia, thrombocytopenia. Other adverse effects can include GI – diarrhea and stomatitis, hepatotoxicity – fibrosis and cirrhosis, Infections due to immune suppression – potentially fatal bacterial, fungal or viral infections, tumor lysis syndrome – hyperuricemia that could result from widespread release and metabolism of purine from dying tumor cells. Methotrexate is Pregnancy Category X – Absolutely contraindicated in pregnancy. (Used off-label for medical abortion). Leucovorin (folinic acid) a fully reduced folate terminates the toxic effects of methotrexate and rescues rapidly dividing normal cells. Clinical use: Cancer: Acute lymphoblastic leukemia (ALL), breast cancer, head and neck cancer, osteogenic sarcoma, primary central system lymphoma, non-Hodgkin’s lymphoma, bladder cancer and choriocarcinoma, and lung cancer Psoriasis and rheumatoid arthritis (autoimmune disease) 5-Fluorouracil (5-FU) Mechanism of action: 5-FU is a pro-drug; it requires enzymatic conversion to the nucleotide form to be active. The active metabolite inhibits the enzyme thymidylate synthase. The triphosphorylated metabolite may also be incorporated into RNA where it interferes with RNA processing and mRNA synthesis. Leucovorin potentiates the activity of 5-FU by increasing the cofactor MTHF, which is a part of the inhibitory complex needed for inhibition of thymidylate synthase. Toxicity: The most concerning toxicity with 5-FU is bone marrow suppression. Other expected adverse events include mucositis - painful inflammation of the oral mucosa manifesting as erythema, ulcerations, and soft white patches, nausea, diarrhea, hand-foot syndrome - tingling sensation, pain, swelling, erythema with tenderness, and desquamation, Neurotoxicity - confusion, disorientation, ataxia, and visual disturbances. Patients with a deficiency in the enzyme dihydropyrimidine dehydrogenase (DPD) experience excessive toxicity to 5-FU. Clinical use: Colorectal cancer, anal cancer, breast cancer, and pancreatic cancer Topical: Actinic keratosis and superficial basal cell carcinoma 6-Mercaptopurine Mechanism of action: Mercaptopurine is metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to active metabolites that inhibit several steps of purine synthesis. Metabolism: xanthine oxidase. Avoid use or required dose reduction if administered with xanthine oxidase inhibitors (allopurinol and febuxostat.) Toxicity: bone marrow suppression, hepatotoxicity Clinical use: acute lymphoblastic leukemia (ALL) Hydroxyurea Mechanism of action: Inhibits ribonucleotide reductase which prevents the conversion of nucleotides to deoxynucleotides, and DNA synthesis is inhibited. Adverse effects: Bone marrow suppression Clinical use: Cancer: chronic myeloid leukemia (CML) and head and neck cancer Sickle cell anemia (Increases the expression of fetal hemoglobin [HbF].) Cytarabine Mechanism of action: Cytarabine is a cytidine analog that is metabolized to cytosine arabinoside, which competes with CTP for incorporation into DNA resulting in chain termination and cell death. Adverse effects: Bone marrow suppression, neurotoxicity, nausea and vomiting Clinical use: Acute myelogenous leukemia (AML) – most effective agent for remission of AML; ALL and CML in blast crisis Cladribine Mechanism of action: Cladribine is a nucleoside that gets incorporated into DNA after it is converted by phosphorylation to cladribine triphosphate. Incorporation into DNA results in breakage of the DNA strand and inhibition of DNA synthesis. Adverse effects: Bone marrow suppression, neurotoxicity, and nephrotoxicity Clinical use: Hairy cell leukemia Multiple sclerosis ALKYLATING AGENTS The alkylation of reactive amines, oxygens, or phosphates on DNA leading to cell death. The N7 position of guanine is particularly susceptible. The interactions can occur on a single strand or on both strands of DNA causing cross-linking. DNA can also be linked to a protein. Alkylation of guanine can also cause mispairing with thymine or excision of guanine. DNA cross linking appears to be the most important cytotoxic action. The alkylating agents are carcinogenic and mutagenic. (They are used to treat cancer, but they can also cause cancer.) Cyclophosphamide Mechanism of action: DNA cross-linking that inhibits function. Cyclophosphamide is a non-reactive prodrug that requires activation by hepatic CYP450 enzymes. Adverse effects: Bone marrow suppression, hemorrhagic cystitis (caused the metabolite acrolein which is concentrated in urine), and sterility in males and females (may be irreversible) The toxic effect of cyclophosphamide/acrolein can be detoxified by co-administration with mesna. Clinical use: Cancer: Broad spectrum, non-Hodgkin lymphomas (Burkitt lymphoma - report of cures with cyclophosphamide as the only drug treatment), Hodgkin lymphoma, breast and ovarian cancers, solid tumors in children (neuroblastoma) Autoimmune diseases (effective immunosuppressive drug) – Toxic to B and T cell but greater effect on B cells. Nephrotic syndrome, systemic lupus erythematosus, and rheumatoid arthritis (refractory) Busulfan Mechanism of action: Cross linking of DNA Adverse effects: Bone marrow suppression (prolonged and severe) Clinical use: Conditioning regimen (in combination with cyclophosphamide) prior to allogeneic hematopoietic progenitor cell transplantation for chronic myeloid leukemia (CML) Carmustine Mechanism of action: Cross linking of DNA leading to reduced function Adverse effects: Bone marrow suppression – may result in bleeding and overwhelming infections Pulmonary toxicity - Carmustine causes dose-related pulmonary toxicity. Patients receiving greater than 1,400 mg/m2 cumulative dose are at significantly higher risk than those receiving less. Delayed pulmonary toxicity can occur years after treatment, and can result in death, particularly in patients treated in childhood. Clinical use: Is highly lipophilic and crosses the blood brain barrier. Brain tumors, Hodgkin lymphoma, non-Hodgkin lymphomas, multiple myeloma (refractory) Cisplatin Mechanism of action: The cis conformation of cisplatin allows the drug to form intrastrand crosslinks between adjacent guanine residues, resulting in DNA damage. Like the other alkylating agents, cisplatin can also cause interstrand DNA crosslinking. Adverse effects: Nephrotoxicity – cumulative, dose related and severe. Pretreatment hydration and amifostine reduce renal toxicity. Ototoxicity – (manifestation of neurotoxicity) tinnitus and hearing loss Neurotoxicity – paresthesia of the hands and feet Hypersensitivity reaction - anaphylactic-like reactions (edema, bronchoconstriction and hypotension) Nausea and vomiting (one of the most emetic chemotherapy drugs) Clinical use: Testicular cancer (In combination with bleomycin, etoposide, and vinblastine, 90% of patients cured.) Ovarian, bladder, head and neck, cervix, endometrium, anal, and lung cancer Bone marrow suppression CYTOTOXIC ANTIBIOTICS Doxorubicin Mechanism of action: Anthracyclines intercalate with DNA directly affection transcription and replication. The main reason for cytotoxicity of doxorubicin is formation of a complex with DNA and topoisomerase II, resulting in a defect in DNA replication and repair. Liposomal doxorubicin improves drug penetration and tumor delivery. Adverse effects: Cardiotoxicity - myocardial damage (including congestive heart failure) as the total cumulative dose of doxorubicin approaches 550 mg/m2. Cardiotoxicity is an adverse effect of all anthracyclines; cumulative dose should include any prior anthracycline use. Cardiotoxicity can be reduced by co-administration with dexrazoxane. Bone marrow suppression Clinical uses: Breast cancer and ovarian cancer; metastatic or disseminated cancers Dactinomycin Mechanism of action: Dactinomycin binds double stranded DNA and intercalates between adjacent guanine-cytosine (G-C) base pairs of DNA. The complex that is formed blocked transcription DNA by RNA polymerase. Dactinomycin inhibits proliferation of rapidly proliferating normal and neoplastic cells. Adverse effects: Corrosive to soft tissues - If extravasation occurs during intravenous (IV) use, severe damage to soft tissues will occur. Bone marrow suppression, nausea, vomiting Clinical use: Wilms tumor (curative in combination with surgery, radiation and other drugs). Choriocarcinoma (curative in combination with methotrexate) Bleomycin Mechanism of action: Bleomycin is a mixture of glycopeptides that bind to DNA and chelates Fe2+, leading to the formation of free radicals that cause single and double-strand DNA breaks. Cells accumulate in the G2 phase of the cell cycle. Adverse effects: Pulmonary Fibrosis - The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving more than 400 units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses. (Damage is cumulative and irreversible.) Bleomycin caused very little bone marrow suppression compared to other DNA damaging drugs. Clinical use: Testicular cancer (curative when combined with cisplatin and vinblastine or etoposide) Hodgkin disease (curative as part of ABVD (doxorubicin/adriamycin, bleomycin, vinblastine and dacarbazine) regimen Head and neck cancers NATURAL PRODUCTS Topotecan Mechanism of action: Topotecan binds to DNA and stabilizes the DNA- topoisomerase I complex. This prevents topoisomerase I from relegating the broken strand. The collision of the single strand break and a replication fork causes an irreversible double-strand DNA break, ultimately leading to cell death. Adverse effects: Bone marrow suppression, GI toxicity (diarrhea) Clinical use: Ovarian cancer (resistant to cisplatin), cervical and small cell lung cancer Etoposide Mechanism of action: Binds to the DNA-topoisomerase II complex and prevents relegation of doublestranded breaks. Adverse effects: Bone marrow suppression; Increased risk of developing AML after treatment with etoposide Clinical use: Small cell lung cancer (first line), testicular cancer (refractory), Hodgkin lymphoma, non-Hodgkin lymphoma and Kaposi sarcoma Vinka Alkaloids (Vincristine and Vinblastine) Mechanism of action: Binds to β-tubulin and inhibits tubulin polymerization and microtubule extension. The mitotic spindle cannot form; cells are blocked in mitosis where they undergo apoptosis. Adverse effects: FATAL if given intrathecally Extravasation causes irritation and ulceration to the surrounding tissue Bone marrow suppression vinblastine > vincristine Nausea and vomiting Vinblastine has less neurotoxicity than vincristine Clinical use: Hodgkin and non-Hodgkin lymphoma, Kaposi sarcoma, testicular cancer Acute lymphocytic leukemia (ALL, neuroblastoma, rhabdomyosarcoma and Wilms tumor) Taxanes (Paclitaxel, Docetaxel) Mechanism of action: Bind to β-tubulin and promote microtubule polymerization. Stabilization of the microtubules in a polymerized state arrests cells in mitosis and eventually leads to apoptosis. Adverse effects: Peripheral neuropathy – manifests as “stocking and glove” sensory deficit in the extremities (limits cumulative dose) Bone marrow suppression, docetaxel less than paclitaxel Acute hypersensitivity reaction - Pretreat all patients with corticosteroids, diphenhydramine, and histamine H2 antagonists. Clinical use: Breast, ovarian and non-small cell lung cancer, AIDS-related Kaposi sarcoma TARGETED CANCER DRUGS Cancer cells have changes in their DNA that make them behave differently from normal cells. Cancer cells can grow faster than normal cells and they die less easily too. Targeted cancer drugs work by ‘targeting’ those differences that a cancer cell has. There are many different targets on cancer cells and different drugs that target them. However, not all patients are candidates for targeted therapy. A biopsy and genetic testing is usually required to determine eligibility. Targeted drugs might: Stop cancer cells from dividing and growing. Seek out cancer cells and kill them. Encourage the immune system to attack cancer cells. Stop cancers from growing blood vessels. Help carry other treatments such as chemotherapy, directly to the cancer cells. There are many different types of targeted drugs. These are grouped together depending on how they work. There isn't a simple way of grouping targeted drugs that is easy to follow. Some drugs belong to more than one group because they work in more than one way. For example, a drug that works by blocking cancer cell growth may also be a monoclonal antibody. Target drug therapies have advantages over traditional chemotherapy in a number of ways. Their toxicity is more selective to cancer cells and, therefore, are better tolerated and generally have fewer toxicities. A number of target drug therapies are able to be given orally so patients can take at home and do not have to travel to an infusion center or be admitted to the hospital to receive treatment. For many cancer types, survival rates are dramatically improved with the use of targeted drug therapy. Monoclonal Antibodies Monoclonal antibodies bind to the extracellular portion of transmembrane receptors or ligands and prevent binding of agonists ligands that cause receptor dimerization or tyrosine kinase receptor activity. Monoclonal antibodies can be recognized as their names all end with “mab.” Trastuzumab Mechanism of action: Trastuzumab is a humanized IgG1 monoclonal antibody that binds to the extracellular domain of HER2, inhibiting dimerization and signal transduction. HER2/Erb2/Neu is overexpressed in some breast cancers. Adverse effects: Cardiotoxicity - Incidence and severity was highest in patients who received trastuzumab concurrently with doxorubicin. Risk of cardiotoxicity reduced when combined with taxanes. Infusion reactions and pulmonary toxicity – fever, chills, dyspnea and rash Clinical use: HER2- overexpressing breast and gastric cancer as a single agent or in combination with (doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel) Bevacizumab Mechanism of action: Vascular endothelial growth factor (VEGF) initiates endothelial cell proliferation and vascular permeability when it binds to a member of VEGF receptor family (VEGFR). VEGF binding activates tyrosine kinase activity and activates antiapoptotic signaling pathways. Bevacizumab is a humanized monoclonal IgG1 antibody that binds to VEGF; preventing the interaction between VEGF and its receptors on the surface of endothelial cells and inhibits signaling that usually leads to vascular permeability and angiogenesis. Adverse effects: GI perforation, hemorrhage, surgery and wound healing complications, hypertension, and thromboembolism Clinical use: Ovarian, cervical, colorectal, and non-small cell cancer (non-squamous only); glioblastoma and renal cell carcinoma Rituximab Mechanism of action: CD20 is a surface antigen expressed on the surface of all B cells beginning with the pro-B cell through its terminal differentiation into plasma cells and is also expressed on malignant B cells. Rituximab is a chimeric mouse-human monoclonal IgG1 antibody that binds to CD20. Administration of rituximab results in depletion of circulating B cells due to complement mediated lysis. Adverse effects: Anemia and neutropenia (treat with filgrastim); infusion reaction (sometimes fatal) – (pretreat with antihistamine); hepatitis B reactivation Clinical use: Non-Hodgkin lymphomas – CD20 positive Chronic lymphocytic leukemia (CLL) – CD20 positive Granulomatosis with polyangiitis (Wegener’s granulomatosis) and rheumatoid arthritis (refractory) Tyrosine Kinase Inhibitors Small molecule kinase inhibitors directly inhibit intracellular tyrosine kinase activity. Tyrosine kinases help to send growth signals in cells, so blocking them stops the cell growing and dividing. Cancer growth blockers can block one type of tyrosine kinase or more than one type. TKIs that block more than one type of tyrosine kinase are called multi TKIs. Tyrosine kinase inhibitors can be recognized as their names all end with “nib”. Imatinib Mechanism of action: A single molecular event, the Philadelphia chromosome translocation t(9;22) leads to the expression of ABL and BCR. The fusion generates a constitutively active protein kinase BCR-Abl which results in continuous and uncontrolled cell division. BCR-ABL drives the malignant phenotype of chronic myeloid leukemia (CML). Orally bioavailable, small molecule inhibitor of BCR- ABL kinase. Imatinib also inhibits other receptor tyrosine kinases for platelet derived growth factor (PDGFR), and ckit. Adverse effects: Nausea and vomiting; fluid retention and edema Clinical use: Chronic myelogenous leukemia (CML) – Philadelphia positive in chronic phase or blast crisis Gastrointestinal stromal tumors expressing c-kit Erlotinib Mechanism of action: The epidermal growth factor receptor (EGFR) belongs to the ErbB family of transmembrane receptor tyrosine kinase receptors; it is also known as HER1 (human EGFR1). Ligands binding to the receptor causes dimerization and stimulates the protein kinase activity resulting in stimulation of signaling pathways such as MAPK, PI3/Akt and STAT. In epithelial cancer, overexpression of EGFR is a common finding. Erlotinib is a reversible inhibitor of the EGFR tyrosine kinase. Adverse effects: Diarrhea and skin rash Clinical use: Non-small cell lung cancer (NSCLC)– EGFR mutations only Pancreatic cancer (in combination with gemcitabine) Proteasome Inhibitors Proteasomes are barrel shaped structures found in all cells that help break down proteins the cell doesn't need into smaller parts. Drug treatments that block proteasomes from working are called proteasome inhibitors. They cause a buildup of unwanted proteins in the cell, which leads to cell death. Many forms of myeloma are susceptible to proteasome inhibitors. Proteasome inhibitor names all end with “mib.” Bortezomib Mechanism of action: Bortezomib reversibly inhibits chymotrypsin-like activity at the 26S proteasome, leading to activation of signaling cascades, cell-cycle arrest, and apoptosis. Adverse effects: Fatigue, neutropenia, peripheral neuropathy, thrombocytopenia, diarrhea, nausea, constipation, rash Clinical use: Lymphomas, myelomas Transplant rejection, amyloidosis mTOR inhibitors mTOR is a kinase protein that makes cells produce chemicals, such as cyclins, that trigger cell growth. It may also make cells produce proteins that trigger the development of new blood vessels. In some types of cancer mTOR is switched on, which makes the cancer cells grow and produce new blood vessels. mTOR inhibitors can therefore stop the growth of some types of cancer. Everolimus Mechanism of action: Reduces protein synthesis and cell proliferation by binding to the FK binding protein-12 (FKBP-12), an intracellular protein, to form a complex that inhibits activation of mTOR (mechanistic target of rapamycin) serine-threonine kinase activity. Also reduces angiogenesis by inhibiting vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF-1) expression. Adverse effects: Myelosuppression – black box warning With transplant use: renal graft thrombosis, nephrotoxicity, increased heart transplant mortality Clinical use: Breast cancer, carcinoid tumors, Hodgkin lymphoma, neuroendocrine tumor, renal cell carcinoma, thymoma and thymic cancers Transplantation – renal, lung, heart Phospho Inositide 3 Kinase (PI3K) Inhibitors PI3Ks do a number of different things in cells. For example, they act like switches in the cell turning on other proteins such as mTOR (see above). Switching on PI3Ks might make cells grow and multiply, or trigger the development of blood vessels, or help cells to move around. In some cancers, PI3K is permanently switched on leading to uncontrolled cell growth. Researchers have been developing new treatments that inhibit PI3K. Idelalisib Mechanism of action: Idelalisib is a potent small molecule inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ), which is highly expressed in malignant lymphoid B-cells. PI3Kδ inhibition results in apoptosis of malignant tumor cells. In addition, idelalisib inhibits several signaling pathways, including B-cell receptor, and CXCR4 and CXCR5 signaling, which may play important roles in CLL pathophysiology. In lymphoma cells, idelalisib treatment inhibited chemotaxis and adhesion, and reduced cell viability. Adverse effects: Black box warnings: hepatotoxicity, severe diarrhea/colitis, pneumonitis, infection, intestinal perforation Clinical use: Chronic lymphoblastic leukemia Histone Deacetylase Inhibitors Histone deacetylase inhibitors are also called HDAC inhibitors or HDIs. They block the action of a group of enzymes that remove acetyl groups from particular proteins. This can stop the cancer cell from using some genes that would help it to grow and divide. This might kill the cancer cell completely. Vorinostat Mechanism of action: Vorinostat inhibits histone deacetylase enzymes, HDAC1, HDAC2, HDAC3, and HDAC6, which catalyze acetyl group removal from protein lysine residues (including histones and transcription factors). Histone deacetylase inhibition results in accumulation of acetyl groups, which alters chromatin structure and transcription factor activation; cell growth is terminated and apoptosis occurs. Adverse effects: Myelosuppression, CNS – dizziness, fatigue; gastrointestinal – nausea, vomiting, diarrhea; Hyperglycemia, QT prolongation; hepatitis B reactivation; thromboembolic events Clinical use: Cutaneous T-cell lymphoma Hedgehog Pathway Blockers Hedgehog pathway blockers target a group of proteins known as the Hedgehog pathway. In the developing embryo, these proteins send signals that help cells to grow in the right place and in the right way. The Hedgehog pathway can also control the growth of blood vessels and nerves. In adults, Hedgehog pathway proteins are not usually active. But in some people, changes in a gene switch them on. Hedgehog pathway blockers are designed to switch off the proteins and stop the growth of cancer. Vismodegib Mechanism of action: Basal cell cancer is associated with mutations in Hedgehog pathway components. Hedgehog regulates cell growth and differentiation in embryogenesis; while generally not active in adult tissue, Hedgehog mutations associated with basal cell cancer can activate the pathway, resulting in unrestricted proliferation of skin basal cells. Vismodegib is a selective Hedgehog pathway inhibitor that binds to and inhibits Smoothened homologue (SMO), the transmembrane protein involved in Hedgehog signal transduction. Adverse effects: Pregnancy category X; severe dermatologic adverse reactions, musculoskeletal and connective tissue – muscle spasms, arthralgias, CPK elevations Clinical use: Basal cell carcinoma CHECKPOINT INHIBITORS Immune checkpoints are inhibitory signals that limit T cell activation. Antigen-presenting cells (APC) travel to the regional lymph nodes and present the antigen bound to MHC to stimulate the T cell receptors (TCR). Costimulatory signals leading to T cell activation are provided by the interaction between CD28 on T cells and B7 on APCs. Cytotoxic T lymphocyte–associated protein 4 (CTLA-4) is upregulated and limits T-cell activation by outcompeting CD28 for binding to B7. Activated T cells also upregulate programmed cell death 1 (PD-1) on their surface. Tumor cells upregulate the expression of PD-L1. PD-L1 binds to PD-1 on the surface of activated T cells, dampening the immune response in the tumor microenvironment. T-cell checkpoint inhibitors can enhance T-cell priming through blockade of CTLA-4 (ipilimumab) or by T-cell activation in the tumor via blocking the PD-1/PD-L1 interaction with antibody ligands to PD-1 (nivolumab). Ipilimumab Mechanism of action: Ipilimumab is a fully human IgG1 monoclonal antibody that binds to CTLA-4. Ipilimumab blocks the interaction of CTLA-4 with B7 ligands on APCs and thereby augments T-cell activation. Adverse effects: Compromised immune tolerance - Severe and fatal immune-mediated adverse effects may occur. Dermatitis (including toxic epidermal necrolysis), endocrinopathy, enterocolitis, hepatitis, and neuropathy. Clinical use: Metastatic melanoma Nivolumab Mechanism of action: Nivolumab is a fully human monoclonal IgG4 antibody that blocks the interaction between PD-1 and its ligands. This releases PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response Adverse effects: Rash – including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) Clinical use: Colorectal cancer, metastatic; head and neck cancer, squamous cell (recurrent or metastatic); hepatocellular carcinoma; Hodgkin lymphoma; melanoma (co-treatment with ipilimumab gives better response); non-small cell lung cancer, metastatic, progressive; Renal cell cancer, advanced Urothelial carcinoma, locally advanced or metastatic COMMON ADVERSE EFFECTS OF CHEMOTHERAPY DRUGS AND MANAGEMENT Nausea and Vomiting Development of nausea and vomiting is the most common adverse effect of chemotherapy. Chemotherapy-induced vomiting can be anticipatory, acute, or delayed. Anticipatory vomiting is a conditioned reflex and occurs prior to the administration of the chemotherapy drug. Acute vomiting occurs in the first 24 hours. Delayed vomiting usually starts 2-3 days after drug administration and can last up to 7 days. Drugs to prevent and treat nausea include: 5HT3 antagonists NK1 antagonist Glucocorticoids And will be covered in future module. Hyperuricemia & Tumor Lysis Syndrome Effective chemotherapeutic regimens lead to widespread release and metabolism of intracellular contents. Metabolism of purines from dying tumor cells results in hyperuricemia. Tumor lysis syndrome is most commonly seen following treatment of hematologic malignances due to large number of cancer cells, rapid cell turnover and high sensitivity to antineoplastic drugs. However, tumor lysis syndrome can develop from any tumor that is highly sensitive to chemotherapy. Laboratory abnormalities include: Hyperuricemia Hyperkalemia Hyperphosphatemia/hypocalcemia Allopurinol (xanthine oxidase inhibitor) or rasburicase (uric acid to soluble metabolite) may reduce the risk of tumor lysis syndrome. Complications of Bone Marrow Suppression Febrile neutropenia (infection) – Fever is the most common symptom in a neutropenic patient with a bacterial infection. Other signs of infection may be muted because the lack of neutrophils impairs the inflammatory response. Management of febrile neutropenia has conventionally included empirical coverage with antibiotics for the duration of neutropenia. Neutropenia– Filgrastim Anemia – Epoetin alpha, RBC transfusion Thrombocytopenia – Platelet transfusion Adverse Effects Related to Biologic Therapy Cytokine release syndrome – a systemic inflammatory reaction seen after the infusion of biologic drugs (recombinant cytokines and antibodies). Affected patients develop fever, chills, tachycardia, and hypotension shortly after the drug is administered, usually within 24 hours. Autoimmunity – Immune checkpoint inhibitors can lead to complications that are a result of tolerance attenuation and autoimmunity. This can result in overwhelming inflammation and tissue damage. Frequently affected areas are the endocrine system, skin, GI tract, pancreas ,and lungs. Chemotherapy Toxicities – Chemo Patient SUMMARY The goal of chemotherapy is to inhibit malignant cell proliferation and tumor multiplication, to avoid invasion and metastasis. Toxic effects of chemotherapy due to its effects on normal cells are commonplace and expected with traditional chemotherapeutic regimens. Traditional chemotherapy agents primarily affect either nucleic acid synthesis, function or repair of DNA, RNA, protein synthesis or affecting the appropriate functioning of the cell. Cell death may be delayed as a proportion of the cells die due to a given treatment. It is therefore common to repeat dosing as “cycles” until a response is achieved. To prevent resistance, reduce the risk of toxic side effects, and achieve the best possible response rates, combination chemotherapy is often utilized. Molecular targeted therapy focused on mechanisms of apoptosis, angiogenesis, metastasis, cell signal transduction, differentiation, and growth factor modulation have significantly increased in that past decade and continues to be a major point of ongoing research and development. Targeted chemotherapy, in most cases, is associated with fewer adverse effects and improved survival rates in many forms of cancer.