276. Chemotherapy Basics Flashcards
What are the 4 goals of chemotherapy?
What are the 3 big categories of chemo-toxicity?
How has cancer therapy affected cancer over time?
Goals
- Reduce tumor size (promote resection)
- Treat micro-metastatic disease (decrease relapse)
- Prolong survival
- Can be CURATIVE
SE: cytotoxicity, teratogenic, carcinogenic
Cancer death rates are DECLINING due to tx improvements
What are the differences between Phase I, II, III, and IV trials?
Phase I
- Goal: define toxicity, develop max tolerated dose (MTD)
- Subjects: relapsed refractory pts with various tumor types (low # pts)
- Study: Dose escalation 3+3 study
- Endpoint: toxicity
Phase II
- Goal: provide general response rates (RR) at predetermined MTD, with addt’l safety data
- Subj: small group pts with specific tumor type
- Endpoint: Response: Complete (CR), Partial (PR), Rate (RR), Stable Disease (SD), Progressive Disease (PD)
Phase III
- Goal: Efficacy of drug in specific line of therapy (multi-agent or single agent)
- Study: RCT, double blind
- Subj: large cohort with specific type of cancer at SAME level of tx
- Endpoints: overall free survival and progression free survival
Phase IV
- Post-market safety monitoring
- studies completed after drug is FDA approved
- long term effect studies
Combination Chemotherapy
- two reasons why it is used
- what are the features of the two agents that will be used in combo?
Difference in goals b/w neoadjuvant and adjuvant chemotherapy
define concurrent, maintenance, remission induction, and consolidation therapy
Combo: overcome inherent drug resistance to single agents; delay/prevent acquired resistance
- agents must have different MoA’s with non-overlapping toxicities (prevent SE buildup)
Neoadjuvant: BEFORE surgery; goal to decrease tumor size to increase likelihood of complete remission
Adjuvant: AFTER surgery; goal to eliminate micro-metastatic tumor cells and decrease risk of tumor recurrence
Concurrent Tx: two tx modalities at same time (Chemo + RT) - synergistic effect but increased risk of toxicities
Maintenance Therapy: After initial chemo treatment, delays tumor return, less toxic risks
Remission Induction: FIRST course of chemo in heme cancers (ex. ALL), Very POTENT dose, goal to eradicate 99% initial tumor burden and restore hematopoiesis
Consolidation Tx: when in remission, high intensity doses with goal of reducing leukemic burden and decreasing likelihood of relapse
What are two ways to increase “dosing?”
Define: Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, Drug Resistance
- Increase dose intensity (more each time)
- Increase dose density (less intervals b/w doses)
PK: What body does to drug (ADME - absorption, distribution, metabolism, excretion)
PD: what drug does to body
PG: how genome affects drug
Drug Resistance: cancer develops mechanisms of proliferation around drug’s mechanism of action
What classes of drugs are cell cycle specific? What are not?
Nonspecific: Alkylating Agents (Methylating agents, Nitrogen mustards, Platinums); Anthracyclines
S Phase: Antimetabolites (Folate Antagonists), Topoisomerase I inhibitors (-tecans)
G2 Phase: Topoisomerase II inhibitors
M Phase: Antimicrotubules (Taxanes, Vinca Alkaloids)
Alkylating Agents
- MoA
- Toxicity (esp. Busulfan, Cyclophosphamide/Ifosfamide, Nitrosureas)
MoA: reactive carbonium ion covalently binds phosphates, amines, sulfhydryl, hydroxyl groups
Toxicities: myelosuppression, CINV, mucositis
Busulfan: PULM Toxicity and vaso-occlusive disease
N mustards: cyclophosphamide, ifosfamide
- Pro drugs
- Toxicity: Hemorrhagic cystitis (Acrolein metabolite), interacts with CYP
Nitrosureas: Carmustine and Lomustine
- Delayed myelosuppression
- PULM FIBROSIS
Non-Classical Alkylating Agents (Platinums)
- MoA
- Toxicities of Carboplatin, Oxaliplatin, Cisplatin
Metal adducts cross link DNA
Carboplatin: Myelosuppression (thrombocytopenia)
Oxaliplatin: Myelosuppression, NEUROTOXICITY (cold sensitivity, peripheral neuropathy)
Cisplatin: NEPHROTOXICITY, Ototoxicity, DELAYED CINV
Antimetabolites
- MoA
- General toxicity
- purine antagonists: types
- purine analogs: types
- difference b/w purine analog and antagonist
- pyrimidine analog: types, specific SE
- MoA and SE of Azacitidine, Decitabine
- MoA and SE of Gemcitabine
- MoA and SE of Cytarabine
- MTX SE
MoA: analogs in DNA/RNA pathways to inhibit synthesis of nucleic acids or incorporate into DNA or RNA to cause defective product
SE: myelosuppression
Purine Antagonists: 6-MP - inhibit de novo purine synthesis (metabolized by thiopurine methyltransferase)
Purine Analogs: Cladribine (-bines) - mimic deoxyadenosine, get incorporated, then cause problems
Pyrimidine Analogs: 5-FU, capecitabine, gemcitabine, cytarabine
- SE: Hand foot syndrome, mucositis, diarrhea (5-FU and Capecitabine)
Azacitidine, Decitabine: hypomethylation of DNA by inhibition of methyltransferase (SE: myelosuppression)
Gemcitabine: cytadine analog converts to triphosphate to inhibit DNA polymerase (SE: thrombocytopenia, flu-like sx)
Cytarabine: inhibits DNA polymerase by converting to ara-cytosine triphosphate (SE: CEREBELLAR NEUROTOXICITY, OTOTOXICITY)
MTX: NEPHROTOXICITY - needs basic urine, good GFR, good urine output, TDM of [MTX] in plasma
Topotecan, Irinotecan
- mechanism
- SE (mechanism of one)
- metabolism
MoA: inhibits Topoisomerase I (reversible ssDNA breaks)
SE: myelosuppression, diarrhea
Metabolism: inactivated by UGT1A1 (GLUCURONIDATION)
- diarrhea due to gut flora de-glucuronidating = activity/toxicity in gut = DIARRHEA
Anthracyclines
- names
- MoA (2)
- SE (2)
“rubicins”
MoA: intercalate DNA b/w bases to induce topo II strand breaks; free radicals cause oxidative stress damage
SE: VESICANTS, CARDIOTOXICITY
Cardiotoxicity: Acute (1st dose), Delayed (within 1 year, dose-dependent), Late (5-20years, more common in adolescents)
- Dexrazoxane reduces cardiotoxicity
Topoisomerase II Inhibitors
- types (2)
- MoA and SE for each
Bleomycin (Anthracenediones)
- MoA: chelates Fe, free radical formation
- SE: PULM FIBROSIS, interstitial pneumonitis
Etoposide (epipodophyllotoxins)
- MoA: inhibits Topo II - ss and dsDNA breaks
- SE: myelosuppression, SECONDARY LEUKEMIA (rearrangement at 11q23)
Antimicrotubule agents
- types (2)
- MoA and SE for each
Taxanes (paclitaxel, docetaxel)
- MoA: stabilize polymerized microtubules against depolymerization
- SE: neurotoxicity (axons use microtubules), myelosuppression
Vinca Alkaloids (Vincristine, Vinblastine, Vinorelbine)
- MoA: inhibit microtubule polymerization by inhibiting spindle formation
- SE: neurotoxicity (DO NOT GIVE INTRATHECALLY - will liquefy brain), vesicant
What are four mechanisms of tumor cell chemotx resistance?
tx for chemotx toxicity: myelosuppression, N/V, alopecia, mucositis
- Drug inactivation
- Drug efflux
- Repair of damage
- Survival signal
Tx Myelosuppression: platelets when <10k, G-CSF to raise WBC count, RBC transfusion/EPO if sx anemia
Tx N/V: triple or quad treatment if high risk (NK-1 antagonist, 5HT3 antagonist, steroid, Olanzapine)
Tx Alopecia: no proven tx
Tx mucositis: prevent with good oral hygiene and cryotherapy (ice chips), tx with mouthwash, opioids, bioadherent gel
What are 3 long term effects of chemo-tx? NEED TO KNOW
What is a major drug interaction?
- Infertility (Alkylating Agents)
- Organ Dysfx
- Cardiomyopathy: Anthracyclines
- Pulmonary Fibrosis: Topoisomerase II inhibitors (Bleomycin)
- Nephrotoxicity: Platinums
- Neuropathy: Antimicrotubule agents - Secondary Malignancy: Alkylating Agents (MDS, AML), Topoisomerase II inhibitors (AML)
MTX and PPIs
Capecitabine and PPIs
Capecitabine and Folic Acid
