Study Guide for Exam 5 Lung Cancer

Study Guide for Exam 5 – Dr. Leiva (31 Questions) Lung Cancer (16) • LCA screening – who is appropriate to receive screening, what is it? o Smoking history of 20 pack-year or more o AND smoke now or have quit within past 15 years o AND b/w 50-80 years old  Pack year: smoking an average of one-pack of cigarettes/day x 1 year • Ex: 20-pack year history by smoking 1 pack/day x 20 years or 2 packs/day x 10 years o When should we stop screening?  Yearly lung cancer screening stop when: • 81 y/o • Not smoked in 15 years or more • Develops health problem and unable to have surgery if lung cancer found • SCLC vs. NSCLC in terms of disease activity, response to chemo, treatment approaches and histology differences. o SCLC  Highly sensitive to radiation therapy and chemotherapy = chemoradiation Limited Disease Extensive Disease • one hemithorax and regional lymph nodes can be contained in a tolerable radiation port • NCCN Category 1: • Cisplatin- or carboplatinCisplatin-etoposide w/ based combination concurrent radiation chemotherapy for q21 days 4-6 cycles • Cisplatin D1, etoposide o can be combined D1-3 q21 days x 4-6 with either cycles etoposide or o 60/120 irinotecan mg/m2 or 75/100 (“platinum mg/m2 doublets”) • Cisplatin D1-3, etoposide D1-3 q21 days x 4-6 cycles o 25/100 mg/m2 • If intolerable → Carboplatin o NSCLC non-squamous vs. squamous and treatments that are/not appropriate given the histology  Adenocarcinoma (37 – 47%) : Most common type in non-smokers Early Stage (Stage I) Locally Advanced (Stage II-III) Stage IIIB (unresectable) • Tx of choice: Surgical • Non-squamous: • Platinum resection (pneumonectomy or Pemetrexed/Cisplatin q 21 based lobectomy) → best chance for days x 4 cycles chemothe cure o Pemetrexed rapy + o Lobectomy: removal of 500mg/m2 IV on radiation x 1 lobe of lung Day 1 <8 o Pneumonectomy: removal of whole lung o Cisplatin 75 mg/m2 cycles IV Day 1 • Squamous: Cisplatin/Docetaxel q 21 days x 4 cycles o Cisplatin 75 mg/m2 IV Days 1 o Docetaxel 75 mg/m2 IV Day 1 o (Pemetrexed not active in squamous) • Etoposide administration issues as well as side effect profile o Etoposide (VP-16)  Epipodophyllotoxin: Derived from mayapple or mandrake plant  Forms complexes with topoisomerase II and DNA to inhibit strand rejoining after breakage  Hypotension occurs with rapid infusion (need to give over at least 60 minutes)  Secondary malignancies may develop 5-8 years later  concentration dependent stability • Solutions prepared at < 0.4mg/mL are stable for 24 hours • Solutions > 0.4mg/mL are very unstable and may precipitate within a few minutes  Solubilized in Polysorbate 80 → leach plastic→ use low sorbing tubing • Increases infusion-related reactions • Cisplatin vs. carboplatin – toxicity considerations, administration differences (electrolytes, mannitol, hydration for cisplatin, etc. Cisplatin Carboplatin • • • • • DLT 35-40% of pts: Nephrotoxicity • Electrolyte abnormalities are common: Hypomagnesemia, Hypokalemia • Optimal administration requires concurrent saline hydration and mannitol (this is still controversial) diuresis to minimize the likelihood of potentially lethal damage to the kidneys Electrolyte wasting Nausea & vomiting (delayed) DLT behind N/V without prophylaxis: Ototoxicity • Recommended: Baseline audiology exam and periodic evaluations during therapy • C/I: patients with pre-existing hearing deficit Neurotoxicity → form of Peripheral Sensory Neuropathy • Paresthesias and numbness • • • • • • • Thrombocytopenia Neutropenia Nausea & vomiting Hypersensitivity (HSR)-delayed (7-8 doses) • Mild: Flushing, rash, itching, diaphoresis, facial edema, fever, chills • Serious/life threatening: hypertension/hypotension, tachycardia, breathlessness, chest pain, palpitation, altered sensorium, wheezing, stridor, laryngeal edema, shock • Example Desensitization Premedication o Dexamethasone: 8–12 mg (i.v.) single dose immediately before the infusion of carboplatin o Ondansetron hydrochloride: 24 mg (i.v.) single dose immediately before the infusion of carboplatin Nephrotoxicity Dose based on Calvert Equation: Dose = (CrCl + 25) x target AUC A single dose should generally not exceed 900mg • Dose higher in pediatric patients • • • • occur in a classic stocking• Rarely some adult protocols call for AUC 7 glove pattern or 8 • Tends to occur after several cycles of therapy and risk increases with cumulative doses • May be irreversible • Poor penetration through the blood-brain barrie Myelosuppression Dosed based on BSA Dose should generally never exceed 50mg/m2/week (low dose vs. high dose) Recognize driver mutations and that patients should be treated for those first because they respond better than to chemo. o K-RAS + EGFR → EGFR TKIs single agent  Erlotinib (Tarceva), Gefitinib (Iressa) o EML4-ALK Mutation → ALK TKI  Alectinib (Alecensa®)*  Brigatinib (Alunbrig®)*  Lorlatinib (Lorbrena®)*  Indication: • patients with advanced NSCLC whose tumors contain the anaplastic lymphoma kinase (ALK) fusion oncogene • patients with PS 0-4 o ROS1-Rearranged NSCLC → Dual ALK + ROS1 inhibition  Crizotinib(Xalkori®) • Moderate emetogenic • Administration: With or without food • Drug Interactions: CYP3A4 substrate and inhibitor • Monitoring: CBC w/diff, EKG, HR and BP, ocular toxicity • ADRS: EDEMA, bradycardia, neutropenia, diarrhea, constipation, hypophosphatemia, blurred vision, cardiac arrhythmia, PE, fever, and hepatotoxicity  Ceritinib (Zykadia®)  Entrectinib (Rozlytrek®)  Treat regardless of PS • Know the oral EGFR TKI medication chart but not the dosing • Bevacizumab limitations of use in NSCLC depending on histology o NCCN guidelines  bevacizumab in combination w/ platinum-based doublet as 1st-line therapy for advanced non-squamous cell NSCLC, in patients with ECOG PS 0-1 o May be used as single agent maintenance therapy after completion of chemotherapy o FDA indicated as 1st-line therapy for unresectable, locally advanced, recurrent or metastatic non-squamous cell NSCLC in combination with carboplatin and paclitaxel o NOT indicated in the adjuvant setting Pemetrexed toxicities and drug interactions o SE: Rash, myelosuppression, stomatitis, N/V, fatigue o Patients must receive at least 350 mcg p.o. daily of folic acid, and 1mg IM vitamin B12 q 9 weeks while on pemetrexed to reduce hematologic toxicity o Dexamethasone 4mg p.o. bid x 3 days starting day before chemo Day 1 to minimize skin toxicity. o Avoid aspirin and NSAIDS: Inhibit renal excretion of pemetrexed, resulting in ↑ toxicity Supportive care considerations for the regimens/drugs we covered related to emetogenicity o High  5HT3 antagonist + Dexamethasone + NK1 antagonist ± Olanzapine o Moderate  5HT3 antagonist + Dexamethasone ± NK1 antagonist o Low  5HT3 antagonist + Dexamethasone + NK1 antagonist ± Olanzapine Erlotinib dosing differences in a smoker vs. non-smoker o Erlotinib (Tarceva)  NCCN recommendation for continuation of therapy in asymptomatic disease progression  Dose adjustment for concomitant smoking: • • • If smoking is unavoidable, increase dose at 2 week intervals in 50mg increments to max dose of 300mg. • Reduce dose to recommended starting dose upon smoking cessation Class effects for EML4-ALK TKIs o ALK TKI Class SE  Edema, diarrhea, nausea, vision disorders, QTc prolongation Crizotinib – emetogenicity profile o Moderate emetogenic Side effect profile of the PD-1 and PDL-1 inhibitors o immune-related adverse events (irAEs):  Cause “Anything-itis”  Diarrhea/Colitis  Pneumonitis  Endocrinopathies • Hyper, hypothyroidism (no steroids for this) • Type I Diabetes • Adrenal insufficiency • Treatment is with high dose steroids tapered over 4-6 weeks • • • • Colon Cancer (15) • Screening guidelines for average and high-risk persons – discussed pros and cons of colonoscopy as a screening and diagnostic and prevention tool o Colon Cancer Screening Recommendations o Colonoscopy Advantages • • • • • Views entire colon Provides information on the mucosa of the entire colon Can be used for biopsy or excision of polyps Highly sensitive diagnostic tool Disadvantages • • • • Full bowel preparation Expensive Sedation needed Risk of bowel tears or infection CEA tumor marker – knowing how we use in the context of treatment response and disease progression • • • o CEA (Carcinoembryonic Antigen) - Tumor Marker  CEA is a glycoprotein normally found in embryonic entodermal epithelium  Increased levels of CEA may be found in colorectal cancer  Smokers = higher levels of CEA  May be useful in monitoring colorectal cancer response to treatment Monitoring CEA is not recommended for colorectal cancer screening  Most healthy subjects (97%) have values ≤ 3 ng/mL – smokers can have higher CEA levels  Serial monitoring of CEA should begin prior to therapy to verify post therapy decrease in concentration and to establish a baseline for evaluating possible recurrence  Grossly elevated CEA concentrations (>20 ng/mL) in a patient with compatible symptoms are strongly suggestive of the presence of cancer and also suggest metastasis Capecitabine toxicities and monitoring o Brand: Xeloda o Monitoring: CBC w/diff, LFTs, SrCr, BUN o ADRs: paresthesias, HA, peripheral neuropathy, Hand-foot syndrome (~60%), cardiac events, BMS, diarrhea – median time to first occurrence was 34 days o Adverse effects  Similar to continuous-infusion regimens of 5-FU  Constant blood level is maintained through oral administration  Diarrhea  Mucositis  Hand-foot syndrome (Palmer-Plantar Erythrodysesthesia)  Minimal myelosuppression Infusional 5-FU and related toxicities – we discussed pump errors and the risk of fatal overdose. Discussed an oral antidote that can be used. o Antidotes to 5-FU: Uridine Triacetate (Vistoguard)  10 grams orally every 6 hours for 20 doses o Drug Interactions: Allopurinol interferes w/ activation of 5-FU o ADRs: Stomatitis, diarrhea, hand-foot syndrome, photosensitivity, alopecia, cardiac events – vasospasm/angina/cardiac failure, neutropenia, neurotoxicity – acute cerebellar syndrome (confusion, ataxia, visual disturbances) o Patients with dihydropyrimidine dehydrogenase deficiency (DPD) should not receive 5FU.  Creates an inability or impaired ability in some patients to detoxify fluorouracil in the liver  Increases risk for acute early-onset toxicity  Severe, life-threatening and fatal adverse reactions  Routine screening is not universally performed Special considerations for EGFR inhibitors - rash prevention and allergic reactions related to Cetuximab, Magnesium wasting o Cetuximab (Erbitux)  ADRs: 88% of patients get acneiform rash w/in first 2 weeks of therapy, diarrhea, bone pain, and fatigue; Severe ALL reactions in the Southeast due to alpha-galactose cross-reactivity from tick bites (Alpha-gal syndrome) and other potential antigen exposures  Administration: • Premed w/ Diphenhydramine First dose higher (LD); if concurrent w/radiation, loading dose must be given 7 days prior to XRT. • Use in-line filter to administer • NTE 10 mg/min infusion rate o Loading Dose given over 2 hours o Subsequent doses given over 1 hour • Considerations for combining nivolumab and ipilimumab – particularly related to dosing and administration, monitoring parameters for immunotherapy Nivolumab • MOA: PD-1 receptor inhibitor, • Monitoring: (Opdivo) immune checkpoint inhibitor o CBC w/diff and CMP prior to every dose • Dosing: o Full thyroid panel (every 6 weeks or o 240 mg with ipilimumab 1 every cycle if given with ipilimumab), mg/kg on the same day Free random cortisol every 8 weeks every 3 weeks for a o No dose reduction for OPDIVO is maximum of 4 doses, recommended. In general, withhold then 240 mg every 2 OPDIVO for severe (Grade 3) weeks or 480 mg every 4 immune-mediated adverse weeks OR reactions. Permanently discontinue o 240 mg every 2 weeks or OPDIVO for life-threatening (Grade 480 mg every 4 weeks 4) immune-mediated adverse • Administration: reactions, recurrent severe (Grade o In-line filter for 3) immune mediated reactions that administration require systemic o Run over 30 minutes; immunosuppressive treatment, or an always give first when inability to reduce corticosteroid giving in combo dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids • ADRs: o As a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection o In combination with ipilimumab: fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness • Ipilimumab (Yervoy) • • MOA: CTLA4 inhibitor Dosing: o 1 mg/kg on the same day • Monitoring: o CBC w/diff, CMP prior to every dose, full thyroid panel every 3 weeks for a maximum of 4 doses ONLY in combo with Nivolumab. o Not used as a single agent in CRC Administration: o In-line filter for administration o Run over 30 minutes • • o Free random cortisol every 6-9 weeks • ADRs: o Most common adverse reactions (≥20%) with YERVOY as a single agent are fatigue, diarrhea, pruritus, rash, nausea, and headache. • o Most common adverse reactions (≥20%) with YERVOY in combination with nivolumab are fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness Testing considerations for early vs. advanced/metastatic disease – genetic testing for mutations, response to immunotherapy for those who are dMMR/MSI-H o Test ALL colon cancer patients regardless of stage o Predictive Response to Checkpoint Inhibitors and no benefit to 5FU in early stage disease (Stage II)  Mismatch Repair Deficient (dMMR)  Microsatellite Instability High (MSI-H)  Lynch Syndrome – Autosomal dominant Germline mutation that increases risk of colorectal cancer related to dMMR • Checkpoint inhibitors often effective for metastatic disease if not appropriate for aggressive therapy o Treatment  CAN tolerate aggressive therapy • Nivolumab + Ipilimumab OR pembrolizumab (dMMR, MSI-H only)  CAN’T tolerate aggressive therapy • Nivolumab or Pembrolizumab (dMMR, MSIH only) Toxicity profiles for FOLFOX, FOLFIRINOX, and FOLFIRI regimens, individual drugs within the regimen, and monitoring parameters FOLFOX (Given every 2 weeks x 6 months) Oxaliplatin Leucovorin Fluorouracil (Continuous IV infusion + bolus) FOLFIRINOX o Folinic acid (Leucovorin) o Fluorouracil (5-FU) o Irinotecan o Oxaliplatin o Folinic acid (Leucovorin) FOLFIRI o Fluorouracil (5-FU) o Irinotecan 5-FU/Fluorouracil • Drug Interactions: Allopurinol interferes w/ activation of 5-FU • Monitoring: • CBC w/ diff, LFTs, neuro checks • Nadir Day 9-14, recovery Day 30 o o o • • ADRs: Stomatitis, diarrhea, hand-foot syndrome, photosensitivity, alopecia, cardiac events – vasospasm/angina/cardiac failure, neutropenia, neurotoxicity – acute cerebellar syndrome (confusion, ataxia, visual disturbances) Patients with dihydropyrimidine dehydrogenase deficiency (DPD) should not receive 5-FU. • Creates an inability or impaired ability in some patients to detoxify fluorouracil in the liver • Increases risk for acute early-onset toxicity • Severe, life-threatening and fatal adverse reactions • Routine screening is not universally performed Leucovorin • • Drug Interactions: Potentiates 5-FU activity ADRs: Related to concurrent chemotherapy; N/V, diarrhea, and dehydration Oxaliplatin (Eloxatin) • • Monitoring: CBC w/ diff, LFTs, SrCr ADRs: Alopecia, moderately emetogenic, acute and persistent neuropathy, BM suppression, HSR Irinotecan (Camptosar) • Caution: UGT1A1*28 polymorphism • 10% of North Americans are homozygous for UGT1A1*28 allele • Decreased glucuronidation of SN38, thus increased toxicity of irinotecan Moderately emetogenic Monitoring: CBC w/ diff, LFTs ADRs: Severe diarrhea!!! ("I ran to the can"), Alopecia, BM suppression, other cholinergic ADRs • Two phases of irinotecan-induced diarrhea: • Early-onset diarrhea (≤ 24 hrs): Atropine 0.25 – 0.4 mg IV is given prophylactically • Cholinergic surge from inhibition of acetylcholinesterase • Late-onset diarrhea (> 24 hrs): Treated with intensive loperamide • 4 mg po at 1st onset, then 2 mg p.o. q2h until diarrhea-free for 12 hours; max dose of 16 mg/day doesn’t apply • Incidence • Chemotherapy-induced diarrhea (CID) ~ 50-80% • Regimens containing 5-FU and irinotecan ~80% • • • • • Understanding toxicity and place in therapy for regorafenib o Regorafenib as single agent is the last-ditch effort. Final drug in the arsenal.  Must have failed: 5FU/Capecitabine, Oxaliplatin, Irinotecan, anti-VEGF, and antiEGFR (if appropriate) o ADRs: Muscle stiffness, GI perforation, hypertension, delayed wound healing, hepatoxicity, bleeding, hand-foot syndrome, diarrhea, the “penias” When and what patients to use EGFR inhibitors – left sided vs. right side tumors o EGFR inhibitors → left-sided tumors  Indication: KRAS/NRAS/BRAF WT Left sided Tumors or In combination with encorafenib for patients with BRAF V600E mutations. • Cetuximab (Erbitux) o Only efficacious in KRAS/NRAS WT/BRAF WT patients with Leftsided tumors UNLESS it’s given with encorafenib if they have a BRAF V600E Mutation • Panitumumab (Vectibix) o Only efficacious in KRAS/NRAS WT/BRAF WT patients with Leftsided tumors UNLESS it’s given with either Dabrafenib + Trametinib OR Vemurafenib because they have a BRAF V600E mutation  CAN tolerate aggressive therapy • FOLFOX - o Addition of Bevacizumab o EFGR inhibitor ONLY FOR KRAS/NRAS/BRAF WT LEFT SIDED TUMORS • FOLFIRI o Addition of VEGF Inhibitor OR EGFR inhibitor o EFGR inhibitor ONLY FOR KRAS/NRAS/BRAF WT LEFT SIDED TUMOR  CANNOT tolerate aggressive therapy • EFGR inhibitor ONLY KRAS/NRAS/BRAF WT LEFT SIDED TUMORS o KRAS, NRAS, BRAF inhibitor → right-sided tumors