IHOP Objectives.docx

Course Intro: Explain cancer’s burden of disease in America 1.9 new cases in 2022 Rank cancer among other diseases in terms of death toll/year 2nd to CV disease: 609,360 annual deaths Describe the general trends in cancer over the last 100 years Survival rates have improved Outline advances...

Course Intro: Explain cancer’s burden of disease in America 1.9 new cases in 2022 Rank cancer among other diseases in terms of death toll/year 2nd to CV disease: 609,360 annual deaths Describe the general trends in cancer over the last 100 years Survival rates have improved Outline advances that have impacted cancer treatment and survival over the last 100 years Cytotoxic chemotherapy Targeted chemotherapy Clinical trials Explain the impact cancer screen can have on society Certain cancers have predictable pre-cancerous lesions that occur first (ie cervical, colon) – early detection However, this can lead to overdiagnosing in other types of cancers (prostate) Cancer pathophysiology Part 1: Describe normal cell cycle progression: G1: Preparation for DNA Replication (Cell grows and synthesizes proteins required for DNA replication). RB checkpoint: The presence of this checkpoint prevents cell cycle progression. A cell can proceed when Cyclin-CDK complexes phosphorylate bB and target for degradation.  QUESTION: What would happen if the Rb gene did not work properly? The cell will progress to the S-phase even if it should not. S: Synthesis and DNA Replication (DNA is replicated “make copy”) The more errors we make in copying the DNA, the more activation we get of protein called P53. G2: Preparations of mitotic spindles (Cell prepares to divide) M: Mitosis and Cell Division (One normal/Cancer cell becomes two) Differentiate characteristics of malignant cells from non- malignant cells: Malignant cells undergo uncontrolled and abnormal growth  Malignant cells may ignore signals that normally inhibit cell division  Malignant cells may evade apoptosis, whereas non-malignant cells undergo apoptosis when necessary for tissue homeostasis.  Cancer Pathophysiology Part 2: Describe the Hallmarks of Cancer: Sustained Proliferative signaling – too many pro-growth signals (aka too much gas pedal) Mutated growth factor receptors are always on (usually controlled by tyrosine kinases) Increased cell proliferation Upregulation/Stimulation of growth factors Autocrine (cell itself is stimulating growth factor) Paracrine (from nearby cells widespread inflammation) More cells proliferate more chance for mutation Ex. Constitutive activation of EGFR RAF mutation RAF loss of function cell would STOP proliferating; RAF is part of the signaling cascade, so if RAF stopped working, the signaling would also stop; cell would stop proliferating. Next, an alternative pathway bypasses RAF and activates MEK or ERK to maintain necessary signaling (detour – not the ideal or quickest, but sometimes necessary). “Bypassing” a pathway is a key mediator of resistance to drugs that block cell signaling. Evading growth suppressors – for every growth signal, there is a corresponding signal to prevent growth tumor suppressors PTEN inhibits PI3K/AKT/mTOR pathway If mutated, increased activation of pathway, because cell evaded growth suppressor Rb disruption – this is found at the interphase between G1 and S phases (checkpoint that stops from moving on to the next phase) increased chance of mutation during cell proliferation Tp53 inactivation – this is found at the S and G2 interphase; a tumor suppression gene 50% of human cancers have mutation/inactivation of tp53 Avoiding differentiation: There are certain mutations (ex. c-myc oncogene) that prevents cells from becoming the type of cell they are meant to be (hair, skin, etc.) Resisting cell death – more cancers in body more dysregulated growth more cancer cells start to become more and more different b/c of mutations more likely to be resistant to drug therapy because they are all different (can’t have one drug to kill them all if each cancer cell has a different genome) Recall: if during the G1 phase, cell is not ready to move on to S phase, Rb prevents it from moving into the next cycle. If you prevent cell cycle progression long enough, the cell should undergo programmed cell death (apoptosis). Tp53 does the same thing! Programmed cell death serves as protective function against potentially dangerous cellular abnormalities Ex. oncogene over-signaling Ex. DNA damage during proliferation – if you get so much DNA damage, the cell SHOULD die, but some DNA damage lead to mutations. If cell doesn’t die, it keeps growing with more mutations Cancerous cells develop ways of resisting apoptotic signals Ex. overexpression of Bcl-2 blood cancer/leukemia/lymphoma resisting cell death There are proteins in cell that serve as mediators of apoptosis mediators bind to proteins to then instigate apoptotic signaling/programmed cell death Bcl-2 binds to the messenger proteins that cause apoptosis and prevent them from carrying the message If you can’t cause apoptosis, cancer cell doesn’t die. We have drugs that can bind to Bcl-2 and prevent Bcl-2 from blocking those signals Inducing angiogenesis (angio = blood; genesis = production production of new blood vessels) – as cancer cells grow, it needs more blood to get nutrients in (oxygen, glucose, nucleotides, proteins) and also needs a way to get a waste out from the cell Vascular endothelial growth factor (VEGF) that is upregulated in many cancer cells and it causes growth of new blood vessels The larger the tumor, the more important angiogenesis becomes in the maintenance of the tumor Some tumors get so big and grow so fast that they can’t keep up with creating blood vessels and start to die from inside out (why you can find necrotic tissue inside large tumors) Enabling replicative immortality – normal cells possess a limited number of times you can go through the cell cycle (there is a cap called a telomere at the end of the DNA strand. Every time the cell replicates, the telomere gets shorter, like a MDI!) Telomerase adds back the telomere which gives cells a limitless number of copies made of themselves They become resistant to apoptosis Telomerase activity is common in cancer cells, but not in healthy cells It is advantageous that normal cells do not typically have telomerase activity because the lack of telomerase limits or caps the total number of times a cell can proliferate. If a cell proliferates or replicates enough times, it is likely a bad or oncogenic mutation will happen. This is a built-in safety feature of cells. The older a cell is and the more times it is replicated, the shorter its telomers. Once they are too short, the cell undergoes apoptosis. Cancer cells use telomerase to keep telomers long to allow for infinite replication and proliferation likely leading to even more genomic instability Activating invasion & metastasis – tumor genetic changes allow cancer cells to invade surrounding tissue Ex. ductal carcinoma in situ (DCIS) – cancer cells that have not yet had genetic change that allows them to invade tissue next door There has to be a certain set of genetic mutations that happen before it can invade local tissue Even more genetic changes later to invade far away tissue (metastasis) Local invasion: breast cancer that spreads from breast to axillary lymph node under the arm Metastatic invasion: breast cancer invades bone in hip, brain, liver etc. There are certain mutations in the breast cancer that allows it to go to bone vs brain (similar, yet different, genetic changes allow cancer cells to colonize distant tissues) Evading immune destruction – CANCER CAN AVOID IMMUNE DESTRUCTION We have drugs that target this avoidance of immune destruction T cells in body can see non-self cells – MHC1 holds peptide up (if not self, immune system will kill; such as protein/peptide fragments from viruses, gene products that are not supposed to be there because of mutations PD-L1 expression prevents T-cell activation upon a tumor cell. Immune system is not able to recognize that the non-self cell is non-self (think invisible cloak) Deregulating cellular energetics – cancer cells have their own diet and because they are constantly growing and dividing, they require more energy needs Identify hallmarks of cancer associated with physiologic conditions: Genomic instability – inability to repair DNA Cancer cells more likely to develop and keep genetic mutations Lots of overlap here in terms of mutations occurring in cancer cells Tumor-promoting inflammation – inflammation results in increased supply of bioactive factors Ex. chronic GERD and Barrett’s esophagus; HBV chronic inflammation have growth factors coming to locale; more growth factors, more gas pedal cell signaling, increasing chance for oncogenic mutation Unlocking phenotype plasticity – leopard can change its pattern Normal differentiation: precursor cell will differentiate to cell it is supposed to be Dedifferentiation go backwards, adult to teen (grow more, more likely to be oncogenic) Blocked Differentiation never grow up, stay as teenager more likely to become cancer Transdifferentiation changing of the spots ex. Barret’s esophagus (squamous columnar cells) Explains why breast cancer starts to grow in bone despite no disease in breast (phenotypic plasticity type of cell growing somewhere it shouldn’t be) Nonmutational epigenetic reprogramming – hallmark characteristics may develop without mutational changes Not actually changing the code, changing the C groups around the code which can turn genes on/off. Ex. hypoxic conditions result in impaired cellular function that may promote tumorigenesis Polymorphic microbiomes – Microbiome can be cancer protective or cancer promoting Bacteria in gut naturally prone to breaking down alcohol (irritating to GI) cancer protective Bacteria produce toxins which increase risk of cancer; ex. butyrate (oncogenic metabolite) Direct inflammation Senescent cells G0 phase (not growing) Senescence is thought to be a protective mechanism, but it appears some cells can be only temporarily senescent These cells go into G0 because telomeres are shortening/should not be replicating; but they can go back and forth into cell cycle and can be a key factor in drug resistance Identify drug targets for disrupting cancer growth: EGFR HER2 Kras VEGF Bcl2 TP53 PDL1 Define Oncogene and Tumor Suppressor Gene: Protooncogene – encodes for proteins that make cells grow & divide Oncogenes – mutation to protooncogene (always on or increased activity) make cell GO This makes the cell go through the cell cycle to synthesize, replicate, and divide EGFR (HER1), HER2 (ERBb2, Neu, EGFR2), CyclinD1, K-ras, N-ras, H-ras, Braf, Myc, Myb, Fos, FGF3, Ret, Src Tumor Suppressor Genes Brake Pedal TP53, Rb, APC, PTEN, BRCA1/BRCA2, NF1/NF2, VHL Alkylating Agents: Describe why “traditional” or cytotoxic chemotherapy agents work on rapidly dividing cells: Traditional or cytotoxic chemotherapy agents work on rapidly dividing cells because their mechanism of action targets processes that are crucial for cell division. These agents aim to disrupt the cell cycle and prevent the proliferation of rapidly dividing cells. Cells that are rapidly dividing are more susceptible to cytotoxic chemo Describe the mechanism of action of alkylating agents: Adds something to DNA molecule to cause a distortion in DNA strand to the point that RNA can no longer read the strand and use it for replication. Covalent bond forms on one side of DNA helix. Can’t unwind so stops DNA synthesis/replication. End result is cross-linking of DNA (create a bridge within strand or cross strands to impair DNA synthesis/kill a cell). Crosslinking of DNA Can lead to base excision Can lead to miscoding (possibility for mutations) Can lead to DNA strand breakage DNA adducts (addition to the DNA strand) This is NOT cell specific healthy cells will also be compromised in addition to tumor cells Alkylating Agents become highly electrophilic compounds which are attacked by nucleophilic groups on DNA to form COVALENT bonds Identify & list unique toxicities of alkylating agents: Traditional Toxicities: Myelosuppression – suppression of bone marrow (bone marrow makes RBC, WBC, and platelets) Nausea/ Vomiting – body knows it is getting toxins so tries to get rid of it Mucositis – inflammation of mucosal lining Alopecia (Hair blading) Unique Toxicities: Secondary Leukemias Gonadal toxicity (Infertility) Unique Toxicities of Cyclophosphamide & Ifosfamide HEMORRHAGIC CYSTITIS Myelosuppressive and immunosuppressive Ifosfamide produces Isophophoramide mustard: affects DNA adducts Chloro-acetaldehyde: neurotoxic metabolite Design a plan to prevent hemorrhagic cystitis in patients receiving cyclophosphamide or ifosfamide: Administer IV hydration before and after cyclophosphamide or ifosfamide administration. Adequate hydration helps flush the drugs and their metabolites from the urinary system, reducing their concentration in the bladder. Mesna chemoprotectant used to prevent ifosfamide-induced hemorrhagic cystitis Mitigates acrolein-induced toxicity by mimicking glutathione Cyclophosphamide (Cytoxan) – all patients encouraged to drink 2-3L of fluids the day of an infusion (similar for PO daily dosing) Mesna is reserved for higher doses: >750mg/m2/cycle Mesna considered for special conditions such a renal dysfunction Ifosfamide (Ifex) – IV hydration ALL patients receive Mesna Monitor for neurotoxicity (Risk factors: Renal dysfunction, Hypoalbuminemia, Aprepitant interaction) Describe the pathophysiology of cyclo-/ifosfamide- induced hemorrhagic cystitis and prevention strategies: Both cyclophosphamide and ifosfamide undergo hepatic metabolism. One of the main metabolites is acrolein. The active metabolites, including acrolein, are excreted through the urinary system. Acrolein, a toxic metabolite, causes direct damage to the urothelium lining of the bladder. This damage can lead to inflammation, ulceration, and bleeding within the bladder. The toxic effects of acrolein extend to the microvasculature of the bladder, causing damage to blood vessels. This microvascular injury contributes to the development of hemorrhagic cystitis. Define myelosuppression & Immunosuppression: Myelosuppression: suppression of bone marrow (bone marrow makes RBC, WBC, and platelets; so we are suppressing the production/function of bone marrow). No effects on mature WBC already in blood or RBC already in circulation; WBC have DNA (RBC do not b/c no nucleus). Immunosuppression: Suppression or weakening of the immune system’s activity; Impair T cell function Myelosuppressive agent is always immunosuppressive (b/c decreased production of WBC leads to immunosuppression) but immunosuppressive agent is not always myelosuppressive Cyclophosphamide (Cytoxan) and Ifosfamide (Ifex) are both myelosuppressive and immunosuppressive List the brand names of cyclophosphamide and ifosfamide: Cyclophosphamide Cytoxan Ifosfamide Ifex List unique toxicities of platinum (Cisplatin) agents: SEVERE Nausea and vomiting (highly emetogenic) Nephrotoxicity (acute and chronic/late effect): highly reactive intermediate binds to proteins and other cellular moieties including those in the kidney; Cisplatin is eliminated via the kidneys, so high concentrations accumulate Hypokalemia Hypomagnesemia Ototoxicity Neuropathy Gonadal toxicity (risk of infertility) Calculate the correct dose of carboplatin for a patient using the Cavlert equation: Dosing based on Calvert equation Dose (mg) = AUC * (GFR + 25) AUC = total drug exposure want 5-6mg/unit time Caveats: eGFR should be capped at 125mL/min Think of 125mL/min as the kidney’s physiology max rate Carefully weigh benefit of treatment with risk of toxicity Obese: using actual body weight for GFR estimate may overestimate GFR and result in excess toxicity Low baseline SCr (<0.8 mg/dL): using actual SCr for GFR estimate may overestimate GFR. May result in excess toxicity Design strategies to prevent cisplatin-induced nephrotoxicity: Since activity is dependent on the Cl- as leaving group, saturating the environment with Cls can offer protection Patients should receive IV fluids (1L) with normal saline (0.9% NaCl) pre- and post-cisplatin SLOW infusions (1mg/min) produce lower renal cisplatin concentrations Using D5W instead of normal saline would be most nephrotoxic Anti-Metabolites Describe the mechanism of action of methotrexate: MOA: Hijack utilization of folic acid in cell (inhibit a key enzyme in the folate pathway) Structurally designed to compete with 7,8-dihydrofolate for the dihydrofolate reductase (DHFR enzyme) – key enzyme in the folate pathway inhibiting this results in feedback inhibition for purine & pyrimidine biosynthesis Effects of inhibiting tetrahydrofolate production Impaired DNA & RNA synthesis Decreased production of cellular proteins (due to decreased production of methionine & serine) Identify toxicities associated with anti-folates: Myelosuppression MUCOSITIS Most often seen with weekly, low-dose MTX in autoimmune disorders (often in setting of too much drug such as in reduced renal clearance) LFT elevations (usually transient) Acute renal failure MTX can precipitate in the acidic environment of the kidneys causing damage Hydration & alkalization of urine can minimize/prevent this Pulmonary (chronic/cumulative in nature) Plan a supportive care regimen for a patient receiving high dose methotrexate: Leucovorin= reduced folic acid rescues healthy cells without rescuing cancer cells NECESSARY FOR HIGH DOSE MTX (Dose is adjusted by MTX levels) 10mg/m2 IV/PO Q6 hrs initially Maintain urine PH >7 and UOP > 100mL/hr IV fluid containing NaHCO3- Monitor renal function through serum creatinine Case Example IV fluid choice: ½ NS + NaHCO3- ½ NS = 77 mEq/L Na + 100 mEq/L of NaHCO3- ; Total 177 mEq/L Na (little hypertonic, but fine) Fluid rate: 100-150 mL/hr Depends on how fast you intend to start high dose MTX because urine pH would be at about 7 before you start Faster you give fluids, more bicarb in blood and more bicarb in urine, faster urine would be alkalinized, faster MTX can be given Pt could tolerate 200 mL/hr (older pt or HF pt, couldn’t give this rate) Leucovorin dose 10mg/m2 most people have bsa of 2 so about 20-25mg Monitoring parameter: MTX levels (serum conc) q24 hours urine pH, (UOP but not really) Plan a supportive care regimen for a patient receiving pemetrexed: Folic acid 400mcg to 1000mcg daily Vit B12 1000 mcg IM q 9 weeks Folic acid & B12 supplement reduce myelotoxicity Dexamethasone 4mg PO BID x3 days beginning the day before treatment Reduces cutaneous reactions (ex. desquamation); Prevent skin reaction/cutaneous reactions Describe the role of leucovorin as it pertains to high dose methotrexate: The folate transport mechanism is broken in a malignant cell. High dose MTX enters cell via passive diffusion so Leucovorin cannot enter (cancer cells develop a mutation that prevents the pump from working) The folate transport mechanism works fine in healthy cells so Leucovorin is able to enter the cell & rescue it from MTX Leucovorin uses cancer cell mutation against it Leucovorin serves as a source of reduced folates and can bypass the inhibited DHFR enzyme. By providing an alternative pathway for the synthesis of tetrahydrofolate, leucovorin helps counteract the inhibitory effects of methotrexate on the folate pathway. Leucovorin acts as a rescue agent for normal cells by providing the necessary folates to support DNA and RNA synthesis. This helps prevent or minimize the toxic effects of methotrexate on normal tissues, particularly the bone marrow and mucosal surfaces. List the brand name of pemetrexed Alimta Identify antidotes for methotrexate toxicity or overdose Glucarpidase (Voraxaze) Antidote for MTX toxicity/overdose Enzyme that hydrolyzes MTX Indication: delayed clearance of MTX following high-dose admin due to renal impairment Describe the mechanism of action of 5-fluorouracil (5-FU) & capecitabine: 5-FU: Inhibition of Thymidylate synthase Both lead to cell death RNA false base pair Capecitabine: Oral prodrug that is converted to 5-FU Thymidylate synthase is critical in DNA replication; 5FU creates a highly electrophilic false substrate for thymidylate synthase DNA synthesis is more upregulated in tumor cells so more affected by 5FU than healthy cells; Describe the role of leucovorin use with 5-FU When given with leucovorin, stronger inhibition of thymidiylate synthetase so INCREASES INHIBITION of thymidylate synthetase Leucovorin increases 5FU activity Describe the bio-activation of capecitabine: Capecitabine is the oral pro-drug of 5FU mimics infusional 5-FU There is a higher concentration of thymidine phosphorylase (capecitabine is activated by this) in tumor cells than in healthy cells when you give this drug, more 5FU is delivered to cancer cells than healthy cells Enzymatic steps helps to narrow effect to tumors The initial step involved the activation of capecitabine by Carboxylesterases, predominantly in the liver. 5' DFCR (intermediary #1) is then converted to 5'FDUR (Intermediary) by cytidine deaminase, an enzyme present in tissues and tumor. 5' FDUR is further converted to 5-FU by thymidine phosphorylase, an enzyme that is more often abundant in tumor tissues. Identify Pharmacogenetic determinants of 5-FU/capecitabine toxicity: Dihydropyrimidine dehydrogenase (DPD) is the rate limiting step in 5-FU metabolism Pt with DPD deficiency likely to experience life-threatening toxicity Neutropenia Mucositis Diarrhea Neurotoxicity List and differentiate side effects of 5-FU (Bolus vs. infusion) and Capecitabine: Bolus 5FU Myelosuppression (more DNA false base pair produced) Nausea/vomiting Capecitabine (PO BID x2 weeks/1 week off) & Continuous infusion 5FU (TS inhibition) Mucositis Diarrhea Hand-foot syndrome (esp Capecitabine) Design a supportive care plan for a patient receiving 5-FU or Capecitabine: Bolus 5FU Myelosuppression Supportive care: CBC, temperature monitoring Nausea/vomiting Supportive care: avoid sun exposure Capecitabine (PO BID x2 weeks/1 week off) & Continuous infusion 5FU (TS inhibition) Mucositis Supportive Care: Cryotherapy (ice chips) – vasoconstriction so less drug delivery Diarrhea Supportive Care: PRN anti-diarrheal Hand-foot syndrome (esp Capecitabine) Supportive Care: Emollients (10% urea) Avoid sun exposure List the brand name of Capecitabine: Xeloda Identify the antidote for fluoropyrimidine overdose: Uridine triacetate (Vistogard) – competes with FUTP for RNA incorporation Used to rescue patients with DPD deficiency or accidental overdose Describe the mechanism of action of Cytarabine and Gemcitabine: Cytarabine: Inhibits DNA polymerase S-phase specific Gemcitabine: Inhibits DNA polymerase S-phase specific Requires phosphorylation List toxicities of cytarabine and Gemcitabine: Cytarabine Hallmark: mucositis, myelosuppression, alopecia, n/v Rare: cytarabine syndrome (diffuse rash and nonspecific symptoms corticosteroids may be helpful) Gemcitabine: Hallmark toxicities: Especially thrombocytopenia Unique: Hemolytic uremic syndrome/ thrombotic thrombocytopenia purpura Identify safety measures necessary to prevent toxicity in patients receiving high dose cytarabine (HiDAC): Unique toxicities Cerebellar dysfunction requires monitoring during treatment Chemical conjunctivitis/keratitis Prophylaxis with corticosteroid eye drops: from start of tx to 48 hrs after end of tx List the brand name of Gemcitabine: Gemzar Describe the mechanism of action of purine analogs: MOA: Inhibit DNA synthesis & sometimes affect RNA synthesis Interfere with biosynthesis of purines May disrupt DNA synthesis by being incorporated into DNA structure Act as RNA & DNA false base pairs to inhibit purine synthesis Describe why purine analogs increase the risk of opportunistic infections: Lymphocytes do not have a salvage pathway; they are entirely dependent on the de novo pathway (which is what is being inhibited by purine analogs). Purine analogs are much more effective at killing lymphocytes than other types of cells this leads to low levels of B&T cells (lymphopenia) which increases the risk for opportunistic infections Identify purine analogs that require prophylactic antimicrobials: Fludarabine Cladribine Pentostatin Agents used for prophylaxis: Bactrim, pentamidine, dapsone, acyclovir, valacyclovir Identify drug interactions with purine analogs: Xanthine oxidase metabolizes 6-MP/6-TG Allopurinol, febuxostat drug interaction: increased 6MP/TG toxicity Allopurinol increases myelosuppression of 6MP by slowing metabolism (50% dose reduction needed) Some patients have altered metabolism of 6MP that creates more hepatoxic metabolites ADDING allopurinol decreases hepatotoxicity, but requires 6MP dose reduction to minimize severe myelosuppression Microtubule inhibitors: Differentiate the mechanisms of actions of taxanes and vinca alkaloids: Taxanes: Docetaxel (Taxotere), Paclitaxel (Taxol), Cabazitaxel, nab-paclitaxel (Abraxane) MOA: bind to tubulin, promote microtubule assembly Prevent disassembly (M-phase specific) Vinca alkaloids: Vincristine (Oncovin), Vinorelbine, Vinblastine MOA: Inhibits microtubule elongation by binding to alpha- and beta- tubulin Bind to tubulin, prevent microtubule assembly (M-phase specific) List unique toxicities of microtubules inhibitors presented: Taxanes: Docetaxel (Taxotere), Paclitaxel (Taxol), Cabazitaxel, nab-paclitaxel (Abraxane) Paclitaxel (Taxol) “paclitaxel paralyzes” Unique toxicities Hypersensitivity reactions (diluent) Cremophor diluent – a castor oil derivative Premedication required: dexamethasone, diphenhydramine, H2RA Peripheral neuropathy – any drug that inhibits microtubules will cause peripheral neuropathy Administration Special “Taxol” tubing required DHEP-free; in-line (0.22 micron) filter Infusion rate is dose-dependent (1 vs 3 vs 24 hours) Vesicant precautions (tissue necrosis if leaves blood) Nab-paclitaxel (Abraxane) Nab formulation has greater solubility No Cremophor vehicle required no hypersensitivity concern no premedication Faster infusion possible (30 minutes) Docetaxel (Taxotere) Unique toxicities Hypersensitivity reactions (less than paclitaxel) Edema Requires premedication: dexamethasone (edema is an odd manifestation of peripheral neuropathy) Peripheral neuropathy (less severe than pacli) Greater myelosuppression than pacli Vinca alkaloids: Vincristine (Oncovin), Vinorelbine, Vinblastine Unique Toxicities FATAL if given intrathecal Peripheral neuropathy (all agents) Constipation (a form of autonomic neuropathy) Vincristine dose capped at 2mg/dose Bone marrow suppression (myelosuppression) VinorelBine VinBlastine NOT Vincristine – makes it attractive for multi-agent chemo regimens Design a supportive care plan for patients receiving microtubule inhibitors Taxanes: Paclitaxel (Taxol) “paclitaxel paralyzes” Premedication required: dexamethasone, diphenhydramine, H2RA Administration Special “Taxol” tubing required DHEP-free; in-line (0.22 micron) filter Infusion rate is dose-dependent (1 vs 3 vs 24 hours) Vesicant precautions (tissue necrosis if leaves blood) Nab-paclitaxel (Abraxane) Nab formulation has greater solubility No Cremophor vehicle required no hypersensitivity concern no premedication Faster infusion possible (30 minutes) Docetaxel (Taxotere) Edema Requires premedication: dexamethasone (edema is an odd manifestation of peripheral neuropathy) Vinca alkaloids: Vincristine (Oncovin), Vinorelbine, Vinblastine Unique Toxicities FATAL if given intrathecal Mandatory aux label upon dispensing Best practice dispense in mini-bag vs syringe Peripheral neuropathy (all agents) Constipation (a form of autonomic neuropathy) Vincristine dose capped at 2mg/dose Bone marrow suppression (myelosuppression) VinorelBine VinBlastine NOT Vincristine – makes it attractive for multi-agent chemo regimens Describe the unique steps required to prepare & administer paclitaxel (Taxol) Special “taxol” tubing required DHEP free In-line (0.22 micron) filter Infusion rate is dose dependent List brand names of vincristine, paclitaxel, & docetaxel Paclitaxel: Taxol Docetaxel: Taxotere Vincristine: Oncovin Identify the conventional maximum dose of vincristine Vincristine dose often capped at 2mg/dose Topoisomerase I Inhibitors: Describe the mechanism of action of topoisomerase I inhibitors: MOA: cleaves one DNA strand and inhibits resealing List unique toxicities of topoisomerase I inhibitors: Early Diarrhea (during infusion) Cholinergic “storm” (SLUD – salivation, lacrimation, urination, defacation) Late Diarrhea (12-24 hours after infusion) Hallmark toxicities: Myelosuppression, n/v, alopecia, mucositis Design a plan to limit or treat toxicities from topoisomerase I inhibitors: Plan for diarrhea to occur Early diarrhea (during infusion) Atropine 0.25 to 1mg IV – an anticholinergic may also be used as prophy Late diarrhea (~12-24 hours after infusion) Loperamide 4mg initially, then 2mg Q2 until no loose stools x12 hours MAY exceed OTC max dose (16mg/day), but 48-hr limit Stay hydrated Identify pharmacokinetic & pharmacogenetic predictors of effect to topoisomerase I inhibitors: PK: Metabolized by CYP3A4 into two inactive metabolites Carboxylesterase turns it into SN38 (primary active agent) SN38 does most of the effect (good and bad) Inactivated by UGT1A1 a glucuronidase enzyme into SN38G Beta-glucoronidase (intestinal) produced by bacteria in gut and will de-glucoronidate SN38G back into SN38 in the lumen of the GI tract reactivated SN38 can cause diarrhea, & can be reabsorbed and cause more myelosuppression Both forms eliminated fecally (via bile into GI tract) Elevated tbili greater irinotecan toxicity (needs dose reduction) Ex. hepatic dysfunction, Gilbert’s syndrome UGT inducers decreased toxicity/effect Smoking (smokers breakdown SN38G very well, but will also decrease effect) Carbamazepine, phenobarbital, phenytoin (increase UGT activity) Normal dose: 125mg/m2 IV Q2weeks Inducer dose: 340mg/m2 IV Q2weeks Pharmacogenetic UGT1A1*28 deficiency Pre-testing not routine for conventional irinotecan Labeled doses different for liposomal irinotecan Usual 75mg/m2 50mg/m2 if homozygous for UGT1A1 allele List the brand name of Irinotecan: Camptosar Topoisomerase II inhibitors: Describe the mechanism of action of topoisomerase II inhibitors: MOA: Double DNA strand breaks, but religation is inhibited S/G2 phase arrest List unique toxicities of topoisomerase inhibitors: Secondary leukemia (MLL gene mutations) Happens 2-3 years later Significant myelosuppression, some n/v and mucositis Hypotension is rate limiting for Etoposide List the brand name of etoposide: Etoposide: Toposar Etoposide phosphate: Topophos Anthracyclines: Describe the mechanisms of action of anthracyclines: Cell Cycle specific Topoisomerase II inhibition (predominant MOA) The most important contributor to cytotoxicity Covalently binds to Topoisomerase II & DNA prevents religation Cell Cycle Non-specific DNA intercalation Insertion of a drug (or something else) in between DNA base pairs results in single & double strand DNA breaks Free radical production Mediated by enzymes and Fe-complexes Reactive intermediates are then capable of damaging intracellular proteins and metabolites that can covalently bind to DNA Historically believed to be a driving mechanism of the class’ cardiotoxicity VESICANT properties! Match anthracycline mechanisms with toxicities: Topoisomerase II inhibition Secondary leukemias DNA intercalation Free radical production Cardiotoxicity Vesicant properties List the unique side effects of anthracyclines: Cardiotoxicity Decreased left ventricular ejection fraction Vesicant Tissue necrosis with extravasation Red – colored urine/ tears following administration (Doxo and Dauno) Myelosuppression and cardiotoxicity more with bolus Secondary leukemias Plan a supportive care and monitoring plan for a patient receiving an anthracycline: LVEF assessment @ baseline ECHO (EF %) or MUGA (radioactive scan that will give exact number of ejection fraction) Signs/Sx of extravasation Tx with ice dexrazoxane CBC Typically antineoplastic nadir (lowest point): 10-14 days after dose LFTs Dose reductions for t. bili >1.2 (normal = 1) per package insert If bili is elevated, ability of body to eliminated drugs will be lower so more toxicity Counsel a patient on doxorubicin: Don’t be alarmed if you experience red-colored urine and tears. This is a common side effect of doxorubicin. Doxorubicin has an increased risk for cardiotoxicity, and this risk increases with more exposure to Doxorubicin, we will be closely tracking all of the Doxorubicin doses we administer to you and we will also administer tests to check your heart function. Alert someone right away if you experience pain or redness at the IV site. Drink plenty of fluids. Differentiate and explain the toxicity profile differences of liposomal doxorubicin and mitoxantrone from anthracyclines: Liposomal Doxorubicin (Doxil) Liposomal formulation leads to lower Cmax, but longer exposure Different toxicity profile from conventional doxorubicin Less n/v, myelosuppression, cardiotoxicity More dermatologic toxicity (mucositis) Hand-foot syndrome can be dose limiting Mitoxantrone (just 3 rings) Same MOAs, but less free radical production than anthracyclines Toxicity profile vs anthracyclines Less cardiotoxicity Less severe vesicant properties List the brand name of doxorubicin: Adriamycin Miscellaneous Agents: Describe the mechanisms of actions of drugs presented: Bleomycin: Inhibits DNA synthesis by creating single & double- strand breaks; antitumor antibiotic Procarbazine: Monoamine Oxidase Inhibitor; alkylating agent Dacarabazine: Involves its ability to damage DNA and interfere with DNA synthesis; alkylating agent Temozolomide: Serum hydrolysis to MTIC; alkylating agent Hydroxyurea: antimetabolite that inhibits ribonucleotide diphosphate reductase; causes G1/S phase arrest; antineoplastic Trabectedin: Alkylating agent that binds to DNA minor groove List unique toxicities of drugs presented: Bleomycin – cumulative lifetime exposure tracking (highest risk after 400 units lifetime exposure) Pulmonary Fibrosis, pneumonitis (PFT monitoring before tx, look for DLCO) Idiosyncratic reactions Change in skin tone Procarbazine: Serotonin Syndrome (consider drug interactions/tyramine-containing food and drink) Dacarabazine: Highly emetogenic Temozolomide: Lymphopenia Trabectedin: Hepatotoxicity Targeted Therapy Introduction: Describe the rationale for targeted agents in cancer treatment: The problem with chemo is that it kills ALL rapidly dividing cells (including the healthy ones!). This contributes to hallmark toxicities such as n/v, myelosuppression, etc. Targeted therapy has a focused effect on MALIGNANT cells. They can target unique extracellular expression (CD20, HER2) or upregulated/mutated pathways (EGFR) Compare and contrast the toxicity profile of targeted agents with traditional chemotherapy: Traditional chemotherapy: n/v, myelosuppression (anemia, infection, thrombocytopenia), alopecia, mucositis because it affects healthy rapidly dividing cells and is recognized by body as toxic (so tries to expel out through n/v). These toxicities are narrow but severe and can be organ specific based on drug MOA (ie. Anthracyclines causing cardiotoxicity, cyclophosphamide and ifosfamide causing hemorrhagic cystitis, and cisplatin causing nephrotoxicity) Targeted therapy toxicities have a wide breadth and greater variety. They are not as severe or life threatening and the side effects are dependent on the target. Compare and contrast the spectrum of activity of traditional chemotherapy and targeted agents: Traditional chemotherapy kills all rapidly dividing cells, including healthy cells Targeted agents aim to take advantage of unique biologic differences in cancer cells such as abnormal gene protein expression, upregulation of pathways, and are more targeted towards specific pathologic variants that make cancer cells more susceptible List brand name for Imatinib: Gleevec Explain why imatinib is so successful as a targeted agent: It takes just one switch to eradicate all CML cells. It targets a simple single mutation. Describe the ideal “target” for a malignancy: Intracellular inhibition through kinase inhibitors – a kinase adds a phosphate which acts as an on switch for signaling. Therefore, inhibiting kinase would inhibit signaling pathways and inhibit tumor cell growth Extracellular inhibition – monoclonal antibodies can bind on the outside of the cell (such as on cell receptors) or circulating ligand in the interstitial space of the blood. Blocking these receptors or ligands also inhibit the signaling pathway to inhibit further tumor cell growth. Describe what is meant by “on-target toxicity”: On target toxicities are toxicities associated with the pathways that are impacted by the drug (for example, EGFR is found all over the body in skin, GI tract, nails, etc., so on-target toxicities would be related to these pathways. Targeted Therapy 2: EGFR: Identify scenarios where an EGFR-targeting monoclonal antibody or tyrosine kinase Inhibitor may be effective: When EGFR becomes overexpressed, we can use mAbs that work OUTSIDE of the cell to inhibit sustained proliferative signaling EGFR are more numerous but still responds to on/off signals we would use mAbs to block this: Cetuximab, Panitumumab These agents prevent EGF ligand from binding to the receptor to block signal transduction. This would only work if you have WILD-TYPE OF RAS protein. Antibodies don’t work if you have a mutation inside the cell When EGFR becomes mutated These are always ON and are ONLY targeted intracellularly with TKIs We cannot block the pathway by blocking receptors outside of the cell. The mutation is in the cell and is causing the signal transduction to always be on. Predict toxicities in a patient receiving an EGFR-targeting agent: Infusion reactions, especially cetuximab Especially bad in people who have a history of tick bites Acne-like rash (on target toxicity) Diarrhea (on target toxicity) Hypomagnesemia only for mAbs that target EGFR HER2: Identify HER2- targeting agent: Trastuzumab Pertuzumab Ado-trastuzumab emtansine Fam-trastuzumab deruxtecan TKIs: lapatinib, neratinib, tucatinib Predict toxicity for HER2-targeting agents mAbs: LVEF and diarrhea Ado-trastuzumab emtansine: myelosuppression, LFTs, arthralgias, myalgias b/c of microtubule inhibitor Fam-trastuzumab deruxtecan: myelosuppression (neutropenia), interstitial lung disease Manage adverse drug reactions for HER2-targeting agents Prophylactic loperamide required with neratinib VEGF: Predict toxicities of patients receiving VEGF- targeting agents On target toxicities: Hypertension: decreased NO (block intracellular production of nitrous oxide; vasodilation vasoconstriction) a marker of success (sign of pharmacologic activity) Proteinuria (mAbs > TKIs) Impaired wound healing (mTOR-associated effect) leads to surgery concerns (hold drug for certain period of time before and after surgical procedures Bleeding often at site of cancer; if you are trying to make a blood vessel/in the middle of making a blood vessel, and suddenly stop producing VEGF, will bleed because not finished (like stop plumbing your house halfway through) Thromboembolic events (body has a way of fixing holes in coagulation system; coagulation pathway will be upregulated and you end up with thromboembolic events Common toxicities hypertension, hand-foot-skin reaction, hypothyroidism, diarrhea, increased LFTs, skin/hair color changes or discoloration Rare Toxicities: Hemorrhage Impaired wound healing VTE/ATE Because kinase inhibition is promiscuous, will get other unique toxicities For example, if targets include EGFR, can have acne/rash, diarrhea, etc. Identify VEGF- targeting agents Bevacizumab (Avastin) Ziv-aflibercept Sunitnib BRAF: Identify scenarios where an BRAF- targeting agents may be effective: BRAF is an important oncogene/player in MAPK signaling pathway BRAF targeting agents are most effective when used with MEK. Doing so blocks the primary pathway and the pathway of acquired resistance. This results in longer disease control Predict toxicities in a patient receiving an BRAF- targeting agent: Common toxicities: Rash/HFSR/hyperkeratosis, alopecia, photosensitivity Mostly dermatologic Cyclin Dependent Kinase Inhibitors: Describe the mechanism of action of CDK 4/6 inhibitors: G1 phase is the preparation for DNA replication. Rb is the checkpoint between G1 and S phases. To proceed in the cycle, CDK phosphorylates Rb to turn it off and allow the cell to progress. If you block CDK 4/6, this will cause G1/S phase arrest List toxicities of CKD 4/6 inhibitors: Shared toxicities: hallmark side effects such as myelosuppression, nausea, alopecia, diarrhea Rare: QT prolongation Identify CDK 4/6 inhibitors: -CICLIB: palboCICLIB, riboCICLIB, ademaCICLIB CD-20 Targeting Agents: Identify CD-20 targeting agents: Rituximab List toxicities of CD-20 targeting agents: HBV reactivation Infusion Reactions Mild; fever, urticaria Moderate: hypotension, chills Severe: acute respiratory distress Potential immunosuppressive side effects if continuous dosing (rheumatologic conditions) Identify required pre-dose safety measures to ensure safe delivery of CD-20 targeting agents: Screen for HBV prior to treatment (HBsAg & anti-HBc screening) If positive, START entecavir, lamivudine (HBV antivirals) Monitor HBV during and for 6-12 months post-rituximab completion Infusion reactions are common, especially with the first dose Premedicate with acetaminophen and diphenhydramine Immune Checkpoint inhibitors: Describe how cancer cells evade immune system surveillance T-lymphocytes survey cells to look for non-self antigens (viruses, malignancies) This process (initiation of T-cell activation) requires: Initial stimulus (TCR) Co-stimulus (CD28) ABSENCE of negative stimulus (CTLA4)—CTLA-4 is a brake pedal; checkpoint system (a way of preventing immune system from overreacting and attacking own body) If PDL1 binds to PD1, it will NOT kill tumor cells PDL1 on tumor cells bind with Pd1 on T cell to EVADE tumor cell death Describe how immune checkpoint inhibitors work Immune checkpoint inhibitors have revolutionized cancer treatments; bc cancer cell is growing rapidly, going through much more cell division and accumulates lots more mutations; some mutations lead to upregulation of PDL1 which is like an invisibility cloak (helps hide from immune system) PD1/PDL1 (programmed death-1/ “ “ ligand-1) invisibility cloak As long as PD-1 is NOT engaged, tumor cell can be killed Checkpoint inhibitors Allow immune system to “find” cancer cells Similar to viral infection process: virus infects cells virus inserts its genome into human genome to try to trick cells into making more virus particles in the process, will make viral DNA and viral protein will express on MHC-1 CD8+ T cells will look at that and say not normal peptide, I’m going to kill the cell! this is also how body fights cancer List common toxicities of immune checkpoint inhibitors (ICIs) LEGS (liver, endocrinopathies, diarrhea, skin), pneumonitis, nephritis, encephalitis, and more Compare & contrast the expected effects of CTLA-4 blocking agents vs PD-1/PD-L1 blocking agents Design a treatment plan to treat ICI-related toxicity High-dose corticosteroids Hormonal Agents: Tamoxifen & AIs (commonly used to treat breast cancer) Describe the differences in ER activity of tamoxifen by tissue Bone: estrogenic helps stabilize BMD Endometrium/uterus: estrogenic: causes endometrium to grow Blood/Liver: estrogenic clot risk Breast: ANTIestrogenic has inhibitory effect; code-switching Compare & contrast the different mechanisms of action and biologic effects of tamoxifen and aromatase inhibitors (AIs), include adverse events Two ways estrogen is produced: Pre-menopause: Hypothalamus GnRH/LHRH Pituitary gland FSH/LH Ovaries estrogen Peripheral tissues: androstenedione estradiol via aromatase Post-menopause: No FSH/LH hormones to ovaries so not making estrogen in ovaries Peripheral tissues are producing estrogen via aromatase Tamoxifen – can be used as preventive therapy MOA: has different effects on different tissues; namely antiestrogenic in breast Biologic Effects: estrogenic in endometrium so risk of endometrial cancer, estrogenic in bone so less risk of fracture Adverse Events: more hot flashes, endometrial cancer Aromatase Inhibitors (Letrozole, Anastrozole, Exemestane) DO NOT use in premenopausal women MOA: block aromatase and decrease peripheral production of estrogen; ONLY use in POSTmenopausal women Biologic Effects: accelerate BMD loss even greater, so risk of fractures Adverse Events: arthralgia/myalgia, fractures Describe how GnRH (LHRH) analogues work GnRH Analogues: Goserelin, Leuprolide increase the signals between Hypothalamus and Pituitary gland which will initially cause an increase in FSH and LH production by the pituitary gland. Overtime, due to negative feedback, FSH and LH will decrease and cause the ovaries to STOP functioning chemical menopause Identify appropriate uses of hormonal agents in women with breast cancer based on menopausal status Both agents are used to treat breast cancer AI monotherapy CANNOT be used in premenopausal women postmenopausal patient only Tamoxifen is approved to reduce risk of breast cancer if high risk Hormonal Agents: Antiandrogens Describe the differences between GnRH agonists and GnRH antagonists Two ways testosterone is produced: Hypothalamus GnRH/LHRH Pituitary gland FSH/LH Testes testosterone Adrenal glands: testosterone via aromatase IN THE PROSTATE Testosterone is converted to dihydrotestosterone via 5-alpha reductase BOTH result in chemical castration GnRH Agonists (Goserelin, Leuprolide) Initially works like an agonist, in the long run, works like an antagonist More convenient Can put on antiandrogen for 2 weeks to block effects of testosterone spike Would be better to use 1st generation here because you wouldn’t use it for a long enough period that you have to worry about anti-agonist phenomenon GnRH Antagonists (Degarelix) Decreases androgen levels much faster (advantageous in: spinal cord compression and urethral obstruction) Describe how antiandrogens work Androgens (testosterone) bind to androgen receptor (AR). 1st generation antiandrogens (Bicalutamide, Nilutamide, Flutamide) Over time, AR mutates in cancer cells exposed to 1st generation antiandrogens they become partial agonists prostate cancer cells can begin growing again. 2nd generation antiandrogens (Enzalutamide, Apalutamide, Darolutamide) do NOT become partial agonists with prolonged exposure NOT the preferred antiandrogen when required for long treatment periods Commonly used to treat prostate cancer IN COMBO with GnRH analogue never used as monotherapy List and identify consequences of androgen deprivation in men Hot flashes Decreased libido Metabolic syndrome Depression Mood changes Coronary artery disease Decreased bone mineral density Gynecomastia Diabetes mellitus Coronary artery disease Key Points Inactivation of Rb’s function potentially leads to cancer because there would be an increased chance of mutations during cell proliferation. TP53 Evading growth suppressors Tumor suppressor gene commonly mutated or inactive Constitutive activation of EGFR Sustained proliferative signaling PD-L1 expression Avoid immune system destruction Bcl-2 over expression Resisting programmed cell death VEGF upregulation inducing angiogenesis HPV affects cell cycle progression of infected cells DNA replication occurs in the S phase; Separation of copied chromosomes occur in the M phase HBV can cause cancer because it causes chronic inflammation HIV is implicated in causing cancer due to immunosuppression Telomerase promotes cancer development because it allows cells to divide an unlimited number of times, increasing the odds of the cell acquiring an oncogenic mutation. Oxaliplatin: causes peripheral neuropathy that is exacerbated by cold temperatures, including cold beverages Mesna chemoprotectant used to prevent ifosfamide-induced hemorrhagic cystitis Alkylating agents form covalent bonds with DNA base pairs leading to DNA cross-links, which impairs DNA synthesis Ifosfamide-induced hemorrhagic cystitis caused by toxic metabolite (acrolein) which damages the urothelial lining of the bladder Cisplatin AE: hypomagnesemia, hypokalemia, severe nausea Cyclophosphamide (Cytoxan) Hemorrhagic cystitis cyclophosphamide Ifosfamide (Ifex) Shared toxicity of all alkylating agents: secondary leukemias Nephrotoxic Cisplatin MTX MOA inhibits a key enzyme in the folate pathway MTX AE mucositis Supportive care for high dose MTX (>1gm/m2) Urinary alkalization Leucovorin rescue Sustained UOP >100mL/hr High dose MTX w/o proper supportive care death, kidney failure Pt with delayed clearance following high-dose MTX treatment Voraxaze Pharmacogenetic test to predict toxicity to 5FU Dihydropyrimidine dehydrogenase 6-mercaptopurine thiopurine methyltransferase (TPMT) Leucovorin with 5FU increase 5FU activity MTX rescue healthy cells from MTX toxicity Gemcitabine Gemzar Pemetrexed Alimta Supportive care meds required to be given: vit b12, folic acid, dexamethasone Capecitabine Xeloda Cytarabine cell-cycle specific: S phase AE of high-dose cytarabine (>1000 mg/m2) Chemical conjunctivitis/keratitis Cerebellar dysfunction AE of hand-foot syndrome capecitabine More pronounced AE with purine analogs low levels of B & T cells MOA of 5FU Incorporation into RNA as a false base pair, inhibition of thymidine monophosphate production Accidental 5-FU overdose Uridine Triacetate (Vistogard) Greater myelosuppression: 5-FU 500mg/m2 IV bolus weekly x6 weeks of an 8 week cycle Agent to tx diarrhea following irinotecan that occurs immediately after completion of infusion atropine Days after completion of infusion loperamide Irinotecan topoisomerase I Most to least cardio toxicity: Daunorubicin Mitoxantrone Etoposide Daunorubicin’s vesicant properties free radical production Etoposide inhibition of topoisomerase II Unique toxicity secondary leukemia Test before Epirubicin ECHO Doxorubicin Adriamycin Red-colored urine doxorubicin Predict toxicity from irinotecan UGT1A1 Decrease the risk of cardiomyopathy with doxorubicin Zinecard Agent approved to treat doxorubicin extravasation injury Totect Irinotecan Camptosar Vincristine and Bleomycin are NOT myelosuppressive Imatinib Gleevec Example of a good target for treating cancer with a signal transduction inhibitor a mutated kinase with continuous activity that is usually inactive in healthy cells VEGF on target toxicity hypertension Targeted mechanism of action for a targeted agent binding to a cell surface agent to attract immune system destruction Renal cell carcinoma – kidney cancer drive by up-regulation of VEGF Targeted Agent Acute leukemia – fast growing malignancy Cytotoxic chemotherapy Gastrointestinal stromal tumor (GIST) -- a sarcoma that is driven by activity of the KIT kinase Targeted agent Non-small cell lung cancer (NSCLC) with a tumor population with a high percentage of an activating EGFR mutation Targeted agent AE of tamoxifen but not exemestane thrombotic events Agents that interact with tamoxifen: fluoxetine, bupropion (b/c of CYP2D6 interaction) Prolonged anastrozole use: bone mineral density loss Common AE of anastrozole and tamoxifen: hot flashes Common AE of tamoxifen and letrozole: arthralgia