SM_276b: Chemotherapy Basics Flashcards
Describe systemic therapy for cancer
Systemic therapy is one of the major cancer treatment modalities
- Reduce tumor size: can promote resection
- Treat micro-metastatic disease: decreasing relapse
- Prolong survival
- Can be a curative treatment modality
- Chemotherapy: cytotoxic, teratogenic, carcinogenic
- Cancer treatment is fluid
Describe the drug development process
Drug development process
- Drug discovery
- Preclinical research
- Phase 1
- Phase 1
- Phase 3
- FDA approval (may be done earlier with accelerated FDA approval or adaptive trial design)
- Phase 4
Describe Phase I studies
Phase I studies
- Goal: define toxicity (dose limiting doxicity, maximum tolerated dose)
- Patient population: typically refractory patients, various tumor types
- Dose escalation studies: often use a 3+3 design
- Key characteristics: low number of patients, multiple doses used, toxicity endpoints
Describe Phase II studies
Phase II studies
- Goals: provide general response rates at maximal tolerated dose, provide additional safety data
- Patient population: small group of patients with specific tumor type
- Key characteristics: more but not a ton of patients, may not provie clinical benefit
Describe Phase III studies
Phase III studies
- Goal: efficacy in a specific line of therapy
- Patient population: large cohort with specific type of cancer at same level of treatment
- Key characteristics: large number of patients, usually a RCT with set control, gold standard points for assessment (overall survival, progression free survival)
Describe Phase IV studies
Phase IV studies
- Post-market safety monitoring
- Studies completed after drug has been FDA approved
- Long term effect
- Key characteristics: enormous number of patients, retrospective or FDA dictated RCT, gold standard points for assessment
Describe types of cancer treatment
Cancer treatment: CREST
- Chemo
- Radiation
- Endocrine therapy
- Surgical intervention
- Targeted therapy
- Immune therapy
Describe chemotherapy basics
Chemo basics
- Goal: cure vs palliation
- Requirements: killing most cancer cells, control most cancer cells, differentiation of cancer cells
- Mechanism: exploit differences between cancer cells and normal host cells to develop anti-cancer agents
Describe combination chemo
Combination chemo
- Used to overcome inherent drug resistance to single agents, delay / prevent acquired resistance
- Which agonists?: single agent activity against tumor, differing mechanisms of action, non-overlapping toxicities
Describe neoadjuvant and adjuvant treatment
- Neoadjuvant: given prior to removal of the tumor, to decrease tumor size in order to increase likelihood of complete resection
- Adjuvant: given after removal of tumor, to eliminate micro-metastatic tumor deposits and decrease risk of tumor recurrence
Describe concurrent therapy
Concurrent therapy
- Two treatment modalities at same time: chemo + radiation
- Chemo radio sensitizes tumor to increase tumor killed
- Increased risk of toxicities
Describe maintenance therapy
Maintenance therapy
- After initial chemo treatment
- Delays return of tumor
- Less return of toxicities
Describe remission induction
Remission induction
- First course of chemo in hematologic cancers
- To eradicate 99% of initial tumor burden and restore normal hematopoiesis and performance status
Describe consolidation therapy
Consolidation therapy
- During remission
- Administered at high level of intensity
- To reduce leukemic burden and decrease likelihood of relapse
____ and ____ are important dosing considerations
Dose intensity and density are important dosing considerations
Describe doxorubicin + cyclophosphamide dosing
Doxorubicin + cyclophosphamide dosing
- Traditional dosing: doxorubicin 60 mg/m2 IVP on day 1 + cyclophosphamide 600 mg/m2 IV on Day 1 of every 21 day cycle
- Dose dense: doxorubicin 60 mg/m2 IVP on day 1 + cyclophosphamide 600 mg/m2 IV on Day 1 of every 14 day cycle
Pharmacokinetics is ___
Pharmacokinetics is what body does to drug
- ADME: absorption, distribution, metabolism, and excretion
Pharmacodynamics is ___
Pharmacodynamics is what drug does to the body
Describe cell cycle
Cell cycle
- G0: cell cycle arrest
- G1: cellular contents, excluding chromosomes, are duplicated
- S: each of 46 chromosomes is duplicated by the cell
- G2: cell double checks the duplicated chromosomes for error and makes repairs
- Mitosis
- Cytokinesis
___ is a chemotherapeutic agent that targets G1
Asparaginase is a chemotherapeutic agent that targets G1
___ and ___ are chemotherapeutic agent that target S
Antimetabolites and topoisomerase-I inhibitors are chemotherapeutic agents that target S
___ and ___ are chemotherapeutic agents that target G2
Epipodophyllotoxins and anthracenediones are chemotherapeutic agents that target G2
____ are chemotherapeutic agents that target M
Antimicrotubule agents are chemotherapeutic agents that target M
Describe chemotherapy classes
Chemotherapy classes
___ and ___ are cell cycle nonspecific chemotherapeutic agents
Alkylating agents and anthracyclines are cell cycle nonspecific chemotherapeutic agents
Describe types of alkylating agents
Alkylating agents
Describe alkylating agents
Alkylating agents
- Reactive carbonium ion covalently binds to phosphates, amines, sulfhydryl, and hydroxyl groups
- N7 guanine is the main alkylation site: inhibit DNA transcription and replication -> mispair DNA, strand breakage -> apoptosis
- Toxicities: myelosuppression, CINV, mucositis
Describe alkylating agent toxicities
Alkylating agent toxicities
- Alkyl sulfonates (busulfan): pulmonary toxicity
- Nitrogen mustards (cyclophosphamide, ifosfamide): pro-drugs, hemorrhagic cystitis
- Nitrosureas (carmustine, lomustine): pulmonary fibrosis
Platinum alkylating agents are ___, ___, and ___
Platinum alkylating agents are cisplatin, carboplatin, and oxaliplatin
Metal adducts that cross-link DNA
Carboplatin has toxicity of ____
Carboplatin has toxicity of thrombocytopenia (myelosuppression)
Oxaliplatin toxicity is ___
Oxaliplatin toxicity is neurotoxicity (cold sensitivity, peripheral neuropathy)
Cisplatin toxicities are ____ and ____
Cisplatin toxicities are nephrotoxicity and delayed CINV
Alkyl sulfonates (busulfan) have toxicity of ___
Alkyl sulfonates (busulfan) have toxicity of pulmonary toxicity
Nitrogen mustards (cyclophosphamide, ifosfamide) are ___ and have toxicity of ___
Nitrogen mustards (cyclophosphamide, ifosfamide) are pro-drugs and have toxicity of hemorrhagic cystitis
Nitrosureas (carmustine, lomustine) have toxicity of ___
Nitrosureas (carmustine, lomustine) have toxicity of pulmonary fibrosis
Describe types of antimetabolites
Antimetabolites
Describe antimetabolites
Antimetabolites
- Analogs in DNA and RNA pathways to inhibit synthesis of nucleic acids or incorporate into DNA or RNA which result in defective product
- Myelosuppression
Purine antagonists (mercaptopurine and thioguianine) ___ and are ___
Purine antagonists (mercaptopurine and thioguianine) inhibit de novo purine synthesis and are metabolized by thiopurine methyltransferase
- Thiopurine methyltransferase has polymorphisms
Purine analogs (cladribine, fludarabine, clofarabine, and pentostatin) ____
Purine analogs (cladribine, fludarabine, clofarabine, and pentostatin) mimic deoxyadenosine
- Myelosuppression
Pyrimidine analogs (capecitabine, fluorouracil, gemcitabine, cyarabine, azacytidine, and decitabine) mimic ___
Pyrimidine analogs (capecitabine, fluorouracil, gemcitabine, cyarabine, azacytidine, and decitabine) mimic pyrimidines
- Capacitabine and fluorouracil lead to hand foot syndrome, mucositis, and diarrhea
Describe azacitidine and decitabine
Azacitidine and decitabine
- Hypomethylation of DNA by inhibition of methyltransferase
- Myelosuppression
Describe gemcitabine
Gemcitabine
- Deoxycytidine analog converts to a triphosphate to inhibit DNA polymerase
- Thrombocytopenia and flu-like symptoms
Describe cytarabine
Cytarabine
- Inhibits DNA polymerase by convertinto ara-cytosine triphosphate
- High dose causes neurotoxicity and otoxicity
Methotrexate can cause ___
Methotrexate can cause nephrotoxicity
- Nephrotic damage may be irreversible
- Requires basic urine to prevent crystallization: give bicarb
- Requirements to receive high dose methotraxe: urine pH ≥ 7 until cleared from body
___ and ___ are topoisomerase I inhibitors
Topotecan and irinotecan are topoisomerase I inhibitors
- Camptothecins
- Semi-synthetic compounds from plants
- Inhibit topoisomerase I: reversible single strand breaks
- Myelosuppression and diarrhea
Describe diarrhea in irinotecan
Diarrhea in irinotecan
- Active metabolite SN-38 is inactivated by UGT1A1 (glucuronidation): polymorphism UGT1A1*2B (reduced enzyme activity)
- Gut flora deglucuronidates SN38 -> diarrhea
Doxorubicin, daunorubicin, epirubicin, idarubicin, and valrubicin are ___
Doxorubicin, daunorubicin, epirubicin, idarubicin, and valrubicin are anthracyclines
- Intercalate DNA between bases to induce topoisomerase II strand breaks -> free radicals cause oxidative stress damage
- Vesicants
- Cardiotoxicity
Anthracycline is associated with ___ toxicity
Anthracycline is associated with cardiac toxicity
- Acute: within first dose or course of treatment
- Delayed: within 1 year of treatment, dose dependent
- Late onset: 5-20 yaers, more common in adolescents
Topoisomerase II inhibitors consist of ___ and ___
Topoisomerase II inhibitors consist of anthracenediones and epipodophyllotoxins
___ is the most common anthracenedione
Bleomycin is the most common anthracenedione
- Chelates iron -> free radical formation
- Toxicities: pulmonary fibrosis and interstitial pneumonitis
___ is a epipodophyllotoxin
Etoposide is a epipodophyllotoxin
- Inhibits topoisomerase II: causes primarily single strand and some double strand breaks
- Myelosuppression
- Secondary leukemia: rearrangement of mixed lineage leukemia at 11q23
____ and ____ are antimicrotubule agents
Taxanes and vinca alkaloids are antimicrotubule agents
___ and ___ are taxanes
Paclitaxel and docetaxel are taxanes
- M phase, inhibit mitotic spindle used in cell division
- Stabilize polymerized microtubules against depolymerization
- Neurotoxicity and myelosuppression
___, ___, and ___ are vinca alkaloids
Vincristine, vinblastine, and vinorelbine are vinca alkaloids
- M phase, inhibit mitotic spindle used in cell division
- Inhibiti microtubule polymerization by inhibiting mitotic spindle formation
- Neurotoxicity
- Do NOT give intrathecally
- Vesicants
Describe chemotherapy classes
Chemotherapy classes
Chemotherapy resistance can be ___, ___, or ___
Chemotherapy resistance can be pharmacokinetic, tumor microenvironment, or tumor-cell specific
Common chemo toxicities are ____, ____, ____, ____, and ____
Common chemo toxicities are myelosuppression, nausea and vomiting, alopecia, fatigue, and mucositis
Describe myelosuppression in chemo toxicity
Myelosuppression in chemo toxicity
- Decreased platelets -> bruising and bleeding
- Decreased WBCs -> risk of infection
- Decreased RBCs -> anemia and fatigue
Describe other chemo toxicities
Chemo toxicities
Describe long terms effects of chemo
Long-term effects of chemo
- Infertility: alkylating agents
- Organ dysfunction
- Anthracyclines: cardiomyopathy
- Topoisomerase II inhibitors: pulmonary fibrosis
- Platinums: nephrotixicity
- Antimicrotubule agents: neuropathy
Describe monoclonal antibodies
Monoclonal antibodies
- Targeted antibody: rituximab, nivolumab
- Drug conjugates: gemutuzumab
- BITE therapy: blinatumomab (fragment antigen binding)
Targeted therapies target the ____ pathway and ____ pathway
Targeted therapies target the tyrosine kinase pathway and JAK/STAT pathway
Summarize targeted and monoclonal therapy
