Prostate Cancer

Prostate Cancer Gauri Sabnis, PhD Recommended Reading: Katzung et al, Basic and Clinical Pharmacology, Chapter 54 Dipiro et al, Pharmacotherapy: A pathophysiologic Approach, Chapter 108 2ndleadingcause ofdeath Risk Factors ✥ Age ✥ Race (AA > Caucasians) ✥ Genetic I ❊ Prior history of prostate cancer (self or family – first degree paternal) ❊ Familial risk – autosomal dominant Mutations in p53, CDH1, AR, MSI, gBRCA1 and gBRCA2 mutations ✥ Environmental – regional incidence rates rather than racial differences ❊ Cd exposure ✥ Diet – high fat, high meat, Vit E, dairy products and reduced intake of Vit. D, βcarotene/Vit. A ❊ ❊ Folate – U-shaped response ✥ Hormonal testicedremoved we ❊ Does not occur in castrated males ❊ Up to 80% dependent on androgens ⇥ AA – 15% higher level of testosterone ⇥ Japanese – Decreased 5α- reductase activity 7 Androgens ✥Testosterone gets activated to DHT ❊ 5α-reductase enzyme ⇥ Males (XY) lacking the enzyme are phenotypically female – unable to activate the program of male differentiation ⇥ Responsible for development of external genitalia ❊ DHT binds to the androgen receptor (AR) I 5α-reductase Finasteride Testosterone Inhibitsa reductase(DHT) dihydrotestosterone 8 Choestre p so Bs Inhibit Testosten soreductase Testostronform edit tematsteroids beEstriol Terminalsteroids Males – All ages (After puberty) Hormone Release ✥Androgen release is regulated by hypothalamuspituitary gonadal axis ❊HPG axis ✥Hypothalamus secrets ✥LH increases release of so testosterone from the testes GnRH (pulsatile) not Low blood levels of testosterone (M) stimulates release of 2 GnRH stimulates the release of LH by AP gonadotrophs 5 Elevated testosterone inhibits Anterior release of LH pituitary LH 3 LH released into blood stimulates Leydig cells 4 (negative feedback) GnRH ✥Pituitary secrets FSH and LH (gonadotropin) Hypothalamus 1 Testosterone released into blood by Leydig cells Testes (M) 9 Neuroendocrine Control of Gonadotropin Release Is per ✥Neuronal oscillator “clock” releases GnRH at intervals ❊ Pulsatile release ✥The frequency of pulses varies at different stages in the menstrual cycle ✥Pulsatile release is essential ✥Continuous administration of GnRH results my of gonadotropin (FSH & LH) in cessation release ➜ cessation of ovarian/testicular steroid production ❊ Leuprolide (Lupron, Eligard) ❊ Goserlin (Zoladex) on only ❊ Degarelix (Firmagon) LHRH Agonists ❊ Triptorelin (Trelstar) oath ✥ e LHRH Antagonist AE: Tumor flare, loss of BMD, hot flashes, impotence, gynecomastia, bone pain, µ injection site pain, QT prolongation, enloyment ofbookin dyslipidemia, hyperglycemia mates ❊ ℞ w/ antiandrogens for 7 days Px - symptoms of flare ❊ Degarelix doesn’t produce flare PHAR-616 ⇥ ↓ in T on day 1 10 Androgen Receptor Signaling ✥Normal growth and differentiation of prostate cells depends on androgens – DHT e SHBG ARE ✥Examples of AR responsive genes ❊ Erythropoietin ❊ SREBP ❊ TGF-β ❊ Cyclins (such as D1) ❊ PSA SHBG – sex hormone binding globulin Hsp – heat shock proteins ARE – androgen response element 11 goodindicatorfor prostateaderbal we Prostate Specific Antigen (PSA) itingt specific ✥ PSA is a biomarker can be measured in the blood ❊ Elevated in prostate cancer to ❊ Also elevated in ⇥ Acute urinary retention, acute prostatitis, prostatic ischemia or infarction as well as BPH ✥ Normal level ~ 4 ng/mL; levels between 4.1 and 10 can’t distinguish between BPH and Prostate cancer ✥ Risk vs. benefit of PSA testing ✥ Controversies galore!! ❊ Threshold for PSA ❊ False positives ❊ False negatives ❊ When to screen and who to screen? ⇥ https://www.cancer.gov/types/prostate/psa-fact-sheet ✥ Monitoring treatment and progression of established disease 12 Screening and Diagnosis ✥Digital rectal exam (DRE) ✥PSA test ✥Trans-rectal ultrasonography (TRUS) – if either DRE/PSA is positive ✥Biopsy ❊ Diagnosis ❊ Gleason score ✥Imaging ❊ Bone scans 13 no Gleason Score Higherthescorethe reoatsome worstt ✥Prostate cancer grading – Gleason score or Gleason sum ✥Gland architecture is rated on calllooks Nirmal go 3 2 5,5609 Ex foresomor a scale of 1 (well WIT differentiated) – 5 (poorly differentiated) ✥2 different areas of the specimen are scored and added ❊ Scores of 2 – 4: well differentiated ❊ Scores of 5 – 6: moderate ❊ Scores of 7- 10: poorly 14 Symptoms infant ✥ In situ or localized PCa - asymptomatic ✥ Symptoms of localized advanced– similar to BPH ❊ Urethral dysfunction As ❊ Frequency, urgency, hesitancy and dribbling ❊ Impotence ✥ Metastatic disease ❊ Back pain ❊ Cord compression ❊ Lower extremities edema ❊ Pathologic fractures ❊ Anemia and weight loss 15 Treatment ✥Observation vs. Active surveillance Butsnou ❊ PSA (or PSADT) ✥Surgery out ❊ Radical prostatectomy (RP) – removal of prostate gland, seminal vesicles and distal vas deference Testostron Brachytherapy ⇥With or without orchiectomy ✥Radiation coal p coals goes doin ❊ External beam radiation ❊ Brachytherapy preferred m as prostate ✥Adjuvant treatment ❊ Cytotoxic chemotherapy ⇥Docetaxel (Taxotere) Firstlinetreatratt ❊ Hormonal therapy as ⇥ADT (androgen deprivation therapy) ⇥CAB (combined androgen blockade) gig g 17 Androgen Deprivation Therapy I ADRs for ADT ✥↑ Cardiovascular disease risk ❊ Ischemic heart disease (MI, stroke, sudden e cardiac death), e 2❊ QT prolongation ❊ Hypertension, ↑ thromboembolism risk (E2 effect) Why Surgery ✥Androgen source ablation s ❊ Orchiectomy ✥↓ BMD and muscle mass, ❊ Adrenalectomy ❊ Hypophysectomya Removepituitary giant ❊ Gonadotropin suppression ⇥ LHRH agonists • Leuprolide (Lupron) • Goserlin (Zoladex) • Triptorelin (Trelstar) ⇥ LHRH antagonist ❊ Risk of fractures and falls ✥Anemia 7 Loss of glycemic control/hyperglycemia ✥ ✥8CNS effects g ❊ Irritability, anger (GnRH) g ❊ Anxiety, depression, insomnia 9 ❊ Seizures __ ✥Hormonal or sexual effects • Degarelix (Firmagon) ❊ Gynecomastia, mastalgia, hot flashes • Relugolix (Orgovyx) ❊ Sexual dysfunction (ED, loss of libido, ↓ sperm to counts) ✥Hepatotoxicity ❊ Elevations in liver enzymes ❊ Liver failure 18 GnRH Analogs ✥LHRH agonists ❊ Leuprolide (Lupron, Eligard) ❊ Goserlin (Zoladex) ❊ Triptorelin (Trelstar) ✥LHRH antagonist ⇥ No tumor flare ❊ Degarelix (Firmagon) sa Need to know various dosage forms/routes of administration ❊ Relugolix (Orgovyx) ⇥ PO medication (Approved December 2020) Firmagon SQ injection Eligard SQ injection Orgovyx PO tablets Zoladex SQ implant Lupron IM Depot 19 Treatment Options for CRPC ✥Castrate resistant prostate cancer (CRPC) ⇥Prostate cancer that has relapsed while being treated with ADT ⇥CRPC still remains responsive to ADT ❊Abiraterone + prednisone ❊Docetaxel + prednisone ❊Cabazitaxel + prednisone ⇥Docetaxel resistant cancer ✥Immunotherapy ❊Sipuleucel – T (Provenge) ❊Pembrolizumab (for MSI-H or dMMR) ⇥Hormone refractory cancer 20 AntiandrogensMtINSIA 1st generation NSAA Apalutamide Bicalutamide Flutamide R=H Hydroxyflutamide R =OH 2nd generation NSAA Darolutamide Nilutamide R=H Hydroxynilutamide R =OH Enzalutamide 21 AR Targeted Therapy ✥Antiandrogens (non-steroidal or NSAA) ✥Indicated for prostate cancer, BPH Halo High ÉOTE g g ga ⇥ Off label use and being studied for gender transition, precocious puberty, female hypergonadism, hirsutism etc.) ❊ Antiandrogens are contraindicated in women - reproductive risk ⇥ Tablets are coated - females should not touch a broken tablet ✥First generation NSAAs ❊ Flutamide (Eulexin) ❊ Nilutamide (Nilandron) ❊ Bicalutamide (Casodex) ✥Second generation NSAAs ❊ Enzalutamide (Xtandi) ❊ Apalutamide (Ereada) ❊ Darolutamide (Nubeqa) Approved July 30th, 2019 22 ✥First generation NSAA, based on trifluoromethylaniline moiety Antiandrogens ✥Flutamide (1989 mostly replaced by newer agents) and Nilutamide (1996) ❊ AE: sexual/hormonal, BMD, anemia ⇥ Rare but severe hepatotoxicity (same metabolism as APAP - DDI), (flutamide > nilutamide) Lung as ⇥ Interstitial pneumonitis progressing to pul. fibrosis disease ⇥ Delayed ocular adaptation to darkness, impaired color vision, disulfiram-like reaction (alcohol intolerance) 1st generation NSAA ❊ Weak inhibitor of CYP17A1 - effect only noticeable if Rx w/ GnRH (does not inhibit 5α reductase) ⇥ ↑DHT levels (flutamide > nilutamide) ❊ Flutamide metabolized to hydroxyflutamide - 10-20X affinity for AR and more potent but ⇥ Very short t½ - TID dosing ❊ Nilutamide metabolized to hydroxynilutamide but both equally active as hydroxyflutamide Flutamide Hydroxyflutamide R=H R =OH Nilutamide Hydroxynilutamide R=H R =OH ⇥ Longer t½ QD dosing 23 Newer Antiandrogens (NSAA) ✥Bicalutamide (Casodex) – 1st generation ❊All same ADRs as ADT ⇥ ↑ E2 levels – ↑ gynecomastia, mastalgia feminization and ↑ thromboembolism risk • Does not bind to any other steroidal 3 receptor • Occupied AR  T converted to E ❊Highly protein bound – DDI w/ se 1st generation NSAA 2nd generation NSAA other protein bound drugs – warfarin ❊No CYP17A1 or 5α-reductase inhibition ❊Long t½ - 1 wk – 4 - 12 months to reach ss ⇥ Saturable absorption/metabolism (racemic mixture with R isoform being active) Je⇥ Potency enough to inhibit AR at same level Bicalutamide as flutamide on day 1 24 seeasphenytoinI Newer Antiandrogens (NSAA) go ✥2nd generation – thiohydantoin antiandrogen ❊ Pure antiestrogens, more potent than Casodex ❊ Prevent translocation of AR to nucleus ✥Enzalutamide (Xtandi) É ❊ Much higher affinity for AR – 2-3X Casodex only 2-3X lower than DHT ⇥ ⇥ Active against 1 type of mutant AR (Casodex is not) Complete blockade of AR signaling • No translocation to the nucleus and binding to DNA ❊ Same AEs as 1st generation but more CNS effects – including seizures, PRES 2nd ⇥ Off-target binding to GABA-A receptor ⇥ ↓ seizure threshold, overdose can induce seizures (caution in pts. w/ seizure dis/brain injury) generation NSAA • Permanently discontinue if seizure ⇥ Two two ❊ No Liver failure/ ↑LFTs – still monitor O ✥Apalutamide (Ereada) ❊ Same ADRs – ↑ E2, ADT ❊ ↓ CNS effects and GABA-A binding ❊ Inducer of CYP3A4, CYP2C19 – DDI ❊ Inducer of PgP, ABCG2 efflux pumps, UDP- Apalutamide Enzalutamide Posterior Reversible Encephalopathy Syndrome – altered mental status, headaches, hypervigilance, anxiety, seizures (status epilepticus) glucuronsyltransferse (UGT) - DDI ❊ Can cause hypothyroidism - ↑ TSH 25 lessseizurecompeoret 3 Newer Antiandrogens (NSAA) ✥Darolutamide pm (Nubeqa®) theother dress ❊ Newest – approved July 30th, 2019 ❊ Active against various forms of mutated AR ❊ No CYP induction/inhibition but induces PgP efflux pumps ✥ADRs: Apalutamide 2nd generation NSAA ❊ Same as ADT ❊ Hepatotoxicity, CV ❊ Neutropenia observed ✥Absence of thiohydantoin and CF3 group ❊ No penetration through BBB ❊ No GABA-A binding ⇥ ↓ CNS toxicity Daralutamide ✥CYP induction/inhibition is significantly reduced Enzalutamide 26 Androgen Synthesis Inhibitors Finasteride ✥5α-reductase inhibitors ❊Finasteride (Proscar) Dutasteride 2 ❊Dutasteride (Avodart) PrCa Prevention? ✥Lyase (CYP17) inhibitors ❊Abiraterone acetate (Zytiga, Abiraterone Yonsa) ✥Other 3❊Progesterones castration chemical go agents ⇥ Cyproterone acetate Y❊Ketoconazole It'sNgtosedonymore ⇥ Antifungal w/ weak anti-AR activity and CYP17 inhibition 5❊ Cimetidine Cyproterone acetate ⇥ H2RA w/ weak anti-AR activity also ↓ hepatic E2 metabolism 27 Zytiga no Yoga Abiraterone ✥CYP17A1 (17, 20 – Lyase) Inhibitor ⇥ 17α-hydroxypregnenolone to DHEA ⇥ 17α-hydroxyprogesterone to androstenedione ❊ Synthesis of all androgenic steroids ❊ Can also antagonize AR own as ADT ✥ADRs – same C-21 Progestins ❊ Significant hepatotoxicity - ↑LFTs 3β-HSD ❊ Mineralocorticoid excess 17α-hydroxy Pregnenolone 17α-hydroxy Progesterone CYP17A1 CYP17A1 e 17β HSD 3β-HSD 4-Androstenediol to prefsoneislucocortigd • Adrenal insufficiency (masked by MR excess) – stress, infections, interruption of daily GCs!! Androstenedione 17β HSD • Caution in pt w/ HF (EF < 50%), CVD ⇥ Must be given with GC 3β-HSD DHEA ⇥ HTN, hypokalemia, fluid retention • Monitoring for the combination ✥2 formulations — NOT interchangeable ✥Zytiga ❊ 1000 mg QD w/ 5mg prednisone Testosterone 5α-reductase ❊ Empty stomach — AUC↑ 10X if given w/ food ✥Yonsa ❊ Micronized formulation C-19 Androgens ❊ 500 mg QD w/ 4mg methylprednisolone DHT ❊ w/o regard to food 28 ✥Isolated from the bark of pacific yew tree (Taxus Taxanes brevifolia); now semi-synthetically from European yew (renewable resource) ✥Taxanes bind to polymerized β tubulin at a specific hydrophobic receptor site located deep within the tubular lumen ✥Promotes a stable tubulin conformation similar to that of GTP-bound β-tubulin ❊ Renders microtubules resistant to depolymerization and prone to excessive polymerization ⇥ Inhibits disassembly of microtubules in the mitotic spindle ⇥ Polymerization occurs in absence of microtubule associated proteins and GTP ❊ Promotes elongation phase of dynamic instability at the expense of shortening phase ❊ Extensive polymerization leads to formation of large dense aberrant structures ⇥ Asters - contain stabilized microtubule bundles ✥Taxanes are substrates for P-gp - cellular efflux pump - expression associated with resistance to taxanes Taxol-induced microtubule aster ✥Low aqueous solubility (solubalizers) ❊ Paclitaxel more lipophilic than docetaxel 32 Docetaxel (Taxotere) ✥More potent and more soluble than paclitaxel ❊ Does not need Kolliphor - uses Polysorbate 80 - preRx still required (and Taxol tubing) ❊ Hypersensitivity despite pre-treatment may require discontinuation (BBW) ✥Adverse effects: ❊ Neutropenia (more than paclitaxel) - DLT ⇥ Do not administer if ANC <1,500cells/mm3 (BBW) ❊ Fluid retention with repeated doses ⇥ Begins as peripheral edema → generalized edema w/ 2 kg weight gain ⇥ Pleural effusion requiring immediate drainage, dyspnea at rest, cardiac tamponade, ascites with abdominal distention ❊ Skin – alopecia (can be permanent), rash, stomatitis, edema etc. ❊ Arrhythmia, fall in BP; neuropathy (less frequent) ✥Metabolized in the liver ❊ By CYP3A4 - DDI ❊ Treatment associated mortality in patients with impaired liver function - BBW 33 Cabazitaxel ✥Lowest affinity for P-gp compared to other taxanes as ❊ Sustained retention in tumors ⇥ Effective in docetaxel resistant P-gp expressing tumors ❊ Higher BBB penetration ✥Adverse effects: ❊ Neutropenic deaths reported ⇥ Do not administer if ANC <1,500cells/mm3 (BBW) ❊ Peripheral motor and/or central neuropathy ❊ High incidence of diarrhea ⇥ Accumulation of drug in the enterocytes, which constitutively express P-gp bloodinovine ❊ Genitourinary - hematuria, UTIs, cystitis, radiation cystitis (radiation recall cystitis) in patients who have received pelvic radiation ❊ Similar H2O solubility as docetaxel - same vehicle - same hypersensitivity - pre- treatment required (GC+H1RA+H2RA) ✥CYP2C8 and CYP3A4 (major) metabolism 34 comped ✥Cell-based immunotherapy – Sipuleucel-T potisteroids immunostimulant (Provenge) g Collect Blood ❊ Antigen-presenting dendritic cells (CD54+) are extracted by leukapheresis ❊ Cells incubated with PA2024 fusion protein ⇥ Prostatic acid phosphatase (antigen) Separate PBMC (leukapheresis) ⇥ GM—CSF ❊ Activated blood product is infused into the patient ❊ Approved for mCRPC, hormone Send to lab (Cells activated) refractory (N1+M+) ✥ADRs – ❊ Infusion related, hypersensitivity, Infuse activated cells chills, fever, pain, myalgias  premedication with acetaminophen, diphenhydramine, H2RA, a meperidine 35 spreadofcancerfrom yo locationtoother original partsofthebody Pathogenesis of Bone Metastasis GI ✥Certain cancers have a high propensity to metastasize to the bone – breast and prostate a as Osteolytic – excessive breakdown of bone (resorption) – pathologic destruction of bone ❊ Osteoblastic – excessive bone remodeling – excessive bone formation – disorganized and compromised structural integrity ❊ Mixed ❊ resorption Bone 36 Osteolytic vs osteoblastic metastasis Osteoblastic metastasis 37 Bisphosphonates and Denosumab ✥Bone loss induced by hormonal therapy (Tertiary OP) ❊ Osteoporosis doses and osteoporosis brands ⇥ Zoledronate - Reclast ⇥ Denosumab - Prolia ✥Skeletal events ❊ Bone metastasis ❊ Hypercalcemia of malignancy ⇥ Higher dose and/or intensity ⇥ Different brand • Zoledronate - Zometa • Denosumab - Xgeva to song 38 5mi58 Dosing in osteoporosis vs. Skeletal events usedfor Canbe Ma Osteoporosis prostate and breast ✥Reclast (zoledronate) - IV Skeletal event ✥Zometa (zoledronate) - IV ❊ Not the DOC for ❊4 mg Q 3-4 weeks - Bone ⇥ Drug-induced OP ❊ 5 mg Q 2 years - OP prevention Off label ❊ 5 mg Q 1 year - GC-induced OP ❊ 4 mg Q 6 months - AI-induced OP ❊ 4 mg Q 1 year - ADT-induced OP ❊ CrCL <35 ml/min - use is contraindicated ✥Denosumab (Prolia) - SQ ❊ 60 mg Q 6 months Off label postmenopausal OP mets of solid tumors, MM ⇥ 4 mg Q 12 weeks - bone mets of breast and prostate cancer ⇥ 4 mg in single dose, wait 7 days and reassess - Ca2+ >12 mg/dL ⇥ CrCL 30-39 - reduce dose to 3 mg; <30 use not recommended ✥Denosumab (Xgeva) - SQ ❊ 120 mg Q 4 weeks no 39 39 AMP + PPi ⇒ ATP Bisphosphonates ✥Analogs of pyrophosphate (PPi) ❊P-O-P bond replaced by P-C-P ⇥ binds to hydroxyapatite ⇥ resistant to chemical + enzymatic hydrolysis (PPi) ✥Two P- required for binding and for antiresorptive activity ❊-R1-varies adsorption to mineral ⇥ Presence of -NH2, -OH - ⇧ binding ❊-R2-varies anti-resorptive activity (potency) ⇥ Presence of N and N in ring ⇧anti-resorptive potency PHAR-616 40 Mechanism of action - BPs Non-nitrogenous Both ✥BPs bind to the hydroxyapatite of the bone. ✥Acid from the OCs causes dissociation of BPs from the hydroxyapatite. ✥BPs are then taken up by the OCs. toblastlooklikea Ose ✥Non-nitrogenous (alkyl) BPs are metabolized in the OCs to non-dry hydrolyzable analogs of ATP (non-functional). ❊ Interfere with OC metabolism leading to OC apoptosis Nitrogenous ✥Nitrogenous BPs inhibit cholesterol biosynthesis pathway. lessostopf lessbone A resorption ❊ Inhibition of farnesyl pyrophosphate synthase (FPP), a key enzyme responsible for the synthesis of isoprenoids ❊ Isoprenoids (fernasyl diphosphate and geranylgeranyl diphosphate) are required for prenylation of small GTPase proteins ❊ Prenylated proteins are required for osteoclast function and survival PHAR-616 41 OC Take Up BP HMG CoA Inhibition of FPP: OC fcn BP vary on Ability to Inhibit FPP R1= Cl, OH Binding R2=N or N in ring anti-resorptive potency [Russell 2008 Ost Int 19(6):1433] 43 pidntgoft Most potentogentiboofnitggenring Bisphosphonates NonNitrogenous (Alkyl) Nitrogenous (Amino) 44 ✥Osteoblast precursors express Mechanism of action rosis ligand for RANK (Receptor - Denosumab so prola tostop ca fgoner skeletal event activator of NF-κB) ✥Osteoclast precursors express RANK ✥Binding of RANK to RANKL activates osteoclast precursors ✥Monocyte colony stimulating factor (M-CSF) then forms mature osteoclasts. ✥Upon binding to RANK, RANKL induces osteoclast formation and maturation ✥Denosumab inhibits binding of RANK to RANK-L and thereby inhibits maturation of osteoclasts PHAR-616 Bone 45 resorption RANKL Inhibitor- Denosumab ✥Denosumab inhibits binding of RANK to RANK-L and thereby inhibits maturation of osteoclasts ❊ Inhibits osteoclastic bone resorption ✥Degree of anti-resorptive activity is far greater than bisphosphonates 46 ✥Denosumab preferred over zoledronic acid for skeletal complications of prostate cancer 47 AEs ✥Dermatologic –rash and eczema ✥Increased risk of serious infections a Yes ✥Hypocalcemia, hypophosphatemia with Xgeva ✥Over-suppression of bone turnover ❊Atypical sub-trochanteric fracture BEE no loss ✥Osteonecrosis of the jaw ies blood e supply ❊Rare at doses given for ℞ of osteoporosis 48 Adverse Effects Bisphosphonates PO BPs peg ✥GI – dyspepsia, esophagitis ❊Esophageal irritation - full glass of water and remain upright Both ✥Musculoskeletal - Bone pain, joint pain, muscle OP & cancer doses cramps, muscle pain ✥Hypocalcemia, hypophosphatemia ❊More potent agents, high doses ✥Atypical sub-trochanteric fracture Cancer doses Denosumab ❊Over-suppression of bone turnover ✥Osteonecrosis of the jaw ✥Increased risk of serious infections ✥Dermatologic –rash and eczema OP & cancer doses 49 Atypical subtrochanteric femur fractures Classic “hip fractures” Atypical PHAR-616 50 no Osteonecrosis of jaw Notreversible ✥1-3% of those with M. myeloma or other cancers treated with monthly IV zoledronic acid, following tooth/jaw surgery ⇥ Rare with oral BP, <5% of total cases ⇥ RISK: 1/10,000 to 1/100,000 person yrs PHAR-616 51 sheskipped Pack Year Calculation this ✥Divide the number of cigarettes smoked per day by 20 (Each pack has 20 cigarettes) ✥Then multiply by number of years a person has smoked ✥Example: ❊ John Doe smoked 12 cigarettes everyday for 15 years "# $%&'()**)+/-'. #/ $%&'()**)+ %0 ' 1'$2 × 10 $%&'( = 0.6×10 = 6 ,&-. $%&'( ❊ Mrs. Janie is 68 years old, and she has been smoking 25 cigarettes everyday since she was 18 years old ⇥ 68 years old and has been smoking since she was 18 – that is 40 years of smoking 25 $%&'()**)+/-'. × 40 .)'(+ = 1.25×40 = 50 1'$2 .)'(+ 20 $%&'()**)+ %0 ' 1'$2 52