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Bone Marrow Depression - leukopenia, neutropenia(ANC<500x10^9/L), lymphopenia, anemia(hypox, fatigue, CHF exacerb), thrombocytopenia (<100worry, <10 or active bleeding-transfuse) Nadir - lowest point of WBC/platelet after chemo, usu 10-14days after tx *Risk factors for neutropenia: A. Degree=ANC B. Immune system function – 1. Cellular (HIV, transplant, CS, lymphoma) 2. Humoral (dec. gG, Bcell malig) C. defects in host defense – 1. Nutrition (ca pts don’t eat well) 2. Physical barriers (mouth/skin ulcers, altered gut flora, invasive procedures) D. Patient Specific risk factors – Two Models to predict risk Type I – predict severe or febrile neutropenia or reduced dose intensity. Risk Factors: age, performance status, dose intensity, serum LDH Type II – predict bacteremiaor consequences of febrile neutropenia. Risk Factors: age, leukemia/lymphoma, high temp, low blood pressure Other predictors: advanced age, myelosuppress chemo, perform status, depth of ANC nadir, precipitous drop in all hematopoietic CBC I. Granulocyte colony stimulating factor (G-CSF,) filgrastim(Neupogen)-made w E. coli bacteria (recover neutrophils 4-5days sooner) Pharmacol- lineage spec grow fact, glycoprotein for production, maturatation, function of cells of neutrophil lineage, focus on commit progenitors, produced by many cell types. Pk/Pd- rapid absorption with SC admin (preferred), T1/2=3.5hrs, metabolic/elimination dose dependent elevation in neutrophil count. Indications/dosing: 1. following myelosuppress chemo – 5mcg/kg/day SC 2.follow BMT- 510mcg/kg/day 3. peripheral blood progenitor cell mobilization and collection- 5-10mcg/kg/day SC; cont. through leukapheresis 4. Cyclic/idiopathic neutropenia- 5mcg/kg/day SC Contraindications: simultaneous admin or admin within 24hr of chemo may potentiate hematologic toxicity, hypersensitivity to hematologic growth factors or Ecoli, caution in pts w/ hairy cell leukemia, gout, psoriasis, preexist cardiac conditions ADR: Common -Bone pain, fever, generalized rash, injection site redness, bruising. Less common – flare of bone scans, transient neutropenia following IV infusions, dyspnea w/ infiltrates on chest x-ray in pts with underlying pulmonary disease Pegfilgrastim (Neulasta)- Pharmacol- same differs in 20kD pegylated molecule attached to N-terminus, stimulates neutrophil lineage Pk/Pd- non-linear kinetics (clearance decreased with increased dose), neutrophil receptor binding correlates with clearance of PEG-filgrastim, serum clearance direct related to # of neutrophils, T1/2 15-80hrs following SC admin, time to Cmax 72hrs Indications/dosing: decrease infection incidence(due to neutropenia), dose: 6mg admin once per chemo cycle. CIs: hypersensitivy to formulation ADR: Bone pain, fever, splenic rupture(due to high WBC in spleen) II. Gran.macrophage-CSF Sargramostim – Pharmacology: glycoprotein w/ multilineage effects, induces partially committed progenitor cells to divide/differentiate into gran-macropage pathways, stimulate neutrophils, monocytes, dendritic cells, eosinophils Pk/Pd: rapid absorpt after SC admin, T1/2=2hrs, decrease in WBC/neutrophil count following discontinuation Indications/dosing: 1. following autologous/allogenic BMT, BMT failure/engraftment delay, mobilization and follow transplantation of autologous peripheral blood progenitor cells - 250mcg/m2/day SC CIs: hypersensitivity to formulation or yeast, caution in pts w/ preexist fluid retention, liver, lung, heart disease, pleural/pericardial effusion simult admin or w/in 24hrs of chemo may potentiate hematologic toxicity. ADE: common-fever(low grade), bone pain, myalgias, rash, inj site redness, bruising. Less common- dyspnea esp in preexisting lung disease, peripheral edema, capillary leak syndrome, pleural/pericardial effusions III. Application of G-CSF and GM-CSF A. neutropenia assoc. w/ std dose chemo – more data w/ GCSF, prophylaxis after chemo shows signif reduction in incidence of febrile neutropenia, length of hospitalization, confirmed infections, duration of abx. No effect on moratlity or tumor response rate or survival. Primary px- if chemo expected to cause >20% incidence of febrile neutropenia. Secondary –pts who had neutropenic complication (infection/sepsis) with prior chemo cycle. B. Autologous BMT – growth fact. reduce period of neutropenia, dec. hospitalization, abx use, infections; no effect on mortality or response rate. ii. Allogenic BMT – reduce period of neutropenia, but no reduction in hospital stay or infection C. AML – i. initial caution b/c it is thought to stim leukemic cell growth (do not give in active leukemia) ii. Priming during AML induction-not recommended outside clinical trial iii. After induction chemo-may consid if benefit (reduce hosp) >cost iv. recommend. after consolidation chemo (in remiss/ no leukemia) IV. Admin. a. SC route preferred. b. Timing-at least 24hrs after chemo finished (within 24-72hrs) c. endpoint GCSF,GMCSF- ANC at 2000-3000x10^9/L unless being used for mobilization V. Oprelvekin (interleukin-11) –px severe thrombocytopenia in pts on chemo for non-myeloid malignancies Pharmacol- i. growth fact. produced by stromal cell w/ activity on progenitor, Bcells, intestinal crypt cells, osteoclasts ii. Acts synergist w/ oth growth fact to support prolifer of hemato progenitor cells iii. used clinically as platelet growth fact to stim magacaryocytopoiesis and thrombopoiesis. Pk/Pdterminal T1/2=6.9hrs, eliminated via kidneys, peak incidence in platelet count observed after 14-19days of therapy if admin alone with chemo, cont’d increase in platelet count up to 7days after stopping treatmentDose: 50mcg/kg SC daily (do not round up) initiated 6-24hrs after chemo complete & cont. for 14-21days or until post-nadir platelet count of >/=50,000 cells/mm3 is reached. Dosing beyond 21 days not ecommended. must stop drug at least 48hrs prior to chemo. ContraInd.-hypersensitiv.Caution: left vent. dysfunc, arrhythmias, resp dx, thromboembolic disorders, renal dysfunct, HTN. ADE: edema, SOB, tachy, eye redness, atrial arrythmias, peripheral edema, HA, dizzy, arthral/myalgia, thrombosis in catheter. Drug must be admin w/in 3hrs of reconstitute. Monitor plts, heart rate, neuro status, s/sx of swelling, urine input/output, eye exam Neutropenia= ANC < 500 **Neutropenic Fever; Fever= >/= 101F(38.3C) or temp >/=100.4F(38C) for at least 1hr. Initial Eval: a. Assessment (mouth, skin, lung, UT, neuro) b. Culture (blood-2sets, urine, stool, CSF, ulcers/lesion) c. Labs (CBC w/ diff, LFT, SCr), d. Chest X-Ray Organism: Gram (+) bacteria 60-70%(staph, strep, entero), Gram (-)(Ecoli, kleb, pseudo, enterobact, citrobact, proteus), fungal,viral Empiric Abx choice- potential infecting org, potential infect site, antimicrob susceptibilities, import of broad spectrum, allergy, pt infect risk Gen Principles- tx immediately! bactericidal agents, use agents effective against organisms in hosp, minimize toxicity Low risk (outpt): ANC>100, normal CXR, normal kidney/liver, neutropenia<7days, expect resolution in 10days, no IV catheter infect, bone marrow recovery, malignancy in remission, peak temp <39C, no mental status change, no ab pain, no comorbid complications Outpt-PO abx: i. cipro and amox/clav (if PCN allergy, use cipro and clindamycin) ii. IVabx same as for high risk Inpatient(highrisk)- monother(3rd/4th gen) cefepime 2grams IV Q8H duel ther.- aminoglyc(gent or tobra) Plus cefepime, piper/tazo, meropenem Vanco- 10-15mg.kg/dose IV Q12h(dose adjust renal) for infect tunnel catheter, gram(+) blood culture, HoTN/sepsis, MRSA ceph resist severe mucositis/viridians strep Antifungal-voricon, fluconazole, caspo, lip AmphoB Antiviral-acyclovir Re-eval/modification: if afeb after 3-5days and eti known, adjust approp. If still febrile for 3-5dys consider: cont abx, switch abx, antifungal therapy. If afeb, (-) culture, no infect site, ANC>500 for 2consec days then d/c abx. Infection Px: handwash, minimize invasive procedures, avoid crowds, fresh fruit/veget/flowers. Decrease endogen orgs. antimicrob prophylax NCCN pts w/ ANC<100 for >7dys. Cont. until fever absent or ANC>100. Antifungal/viral prophylax NCCN guidelines: BMTand acute leukemia receiving non-transplant regimen Acute emesis- 1st 24hrs. of chemo. 24 hrs. after chemo-may occur up to 5-7 days after, Anticipatory emesis specific stimuli (sights, smells, sounds), Breakthrough emesis- on the day of chemo, Refractory emesis- nausea on previous cycles of chemo Reasons-gi- gastric outlet obstruction, gastroparesis, bowel obstruction, constipation, hepatic metastases :neurologicsevere chronic pain, anticipatory, metastases, vestibular dysfunction, incr. intracranial press:metabolic-hyperca, hypergly, hypoadrenalism, hypona, uremia:drugs-opiods, digoxin, chemo., anesthetics, ethanol:psychophysiologic-anxiety, anticipatory n/v. vomiting center-located in lateral reticular formation of medulla, activation leads to efferent transmission to salivary, vasomotor, respiratory centers, and to cranial nerves VIII and X. Indirect activation of vomiting center: cerebral cortex, hypothalamus, thalamus, vestibular apparatus, peripheral visceral vagal afferents:Chemo trigger zone-most drugs act here, located in the area postrema of the brain, located outside the blood brain barrier, accessible to either blood or CSF borne toxic stimulus, transmits signals to vomiting center using serotonin or dopamine, may be stimulated by chemo agents, dig, opiods, anesthetics: CTZ and vomiting center send efferent transmissions to effector organs (abdominal muscles, diaphragm, stomach, and esophagus) to coordinate expulsion of stomach contents, stimulation of neurokinin 1, 5HT3, D2, H1, norepinephrine, apomorphine, neurotensin, angiotensin2, vasopressin, opiate and or substance P receptors start emetic process: Complications-dehydration, electrolyte imbalance (Na, K, Cl), acid/base disturbance (pH and CO2), malnutrition, aspiration, pneumonia, mallory-weiss syndrome, prolonged hospitalizations, diminished QOL: Risk-female, motion sickness, pregnancy, prior chemo experience, age <30 or >60 incr. risk of extrapyramidal side effects, anxiety, alcohol intake (>100 gm/d), type of chemo, Emeto-identify one or more level 2 agents incr. the emetogenicity by one level greater than the most emetogenic agent in the combination, adding level 3 or 4 agents incr. the emetogenicity of the combination by one level per agent: so 2+2=3, 2+2+2=3, 3+2=4, 3+2+2=4, 3+3+3=5: Goals -achieve complete control in all settings, provide maximum convenience for patients and staff, eliminate potential side effects, minimize $ and drug admin, Serotonin recep antag: dolasetron 100mg po/iv 7.5hrs half life, ondansetron 8-16mg po/iv 4 hrs (these given 1 dose prior to chemo to prevent n/v), palonosetron 0.25mg iv only 128 hl (given 1 dose Q5days): MOA-direct selective antagonism of serotonin receptor sites, blocked in two ways, peripheral-enterochromaffin cells in gi tract, central-medulla (vomiting center), ADR-HA, constipation/diarrhea, somnolence, dizziness, serotonin syndrome, asymptomatic and transient EKG abnormalities, elevated transaminases: Cortico-decadron 8-20mg po/iv pre chemo, delayed n/v-4mg po/iv Q68H, mechanism- inhibition of prostaglandin synthesis in cortex, decr. Serotonin turnover in CNS, modulation of higher cortical pathways that head to the vomiting center, ADR-hypergly, fluid retention, HTN, electrolyte imbalance, euphoria, insomnia, anxiety, incr. appetite, immunosupp: Neurokinin1 antagonists-aprepitant, MOA-blocks substance p in brainstem vomiting center and gi tract, drug interactions (CYP3A4, CYP2C9), given 3 days per cycle, when administered >14 days=inducer, select agents metabolized by CYP3A4-docetaxel, etoposide, ifosfamide, irinotecan, imatinib, paclitaxel, vinblastine, vincristine, vinorelbine, oral contraceptives, warfarin, dexamethasone, midazolam:CYP3A4 inhibitors like macrolides, azoles, may increase aprepitant AUC, CYP3A4 inducers may decr. AUC, ADR-astehnia/ fatigue, dizziness, hiccups, gastritis, heartburn, diarrhea, incr. LFTs (mild/transient): Phenothiazines- compazine 5-10mg po/iv Q46HPRN, phenergan 12.5-25mg po/iv Q6HPRN, MOA-dopamine receptor antagonists (CTZ is target), ADR-EPS (anxiety, tremors, restlessness), excessive sedation, hypotension, liver dysfunction, bone marrow aplasia: Butyrophenones- haldol 0.5mg po/iv Q46HPRN mechanism-DA receptor antagonist (CTZ is target), ADR-EPS, sedation, anticholinergic, torsades:Benzamide analogs-reglan 10mg po/iv Q6HPRN, tigan 300mg po Q6HPRN, mechanism-DA and 5HT receptor antagonists, enhances response to Ach of tissue in upper gi tract causing enhanced motility and accelerated gastric emptying, ADR-sedation, confusion, EPS, diarrhea, edema:Cannabinoids-dronabinol 2.5 mg po BID (titrate up to maximum 20 mg/day), mechanism-may inhibit endorphins in the vomiting center, suppress pg synthesis, or inhibit medullary activity through an unspecified cortical action, ADR -drowsiness, dizziness, euphoria, dysphoria, mood changes, orthostatic hypotension, ataxia, hallucinations, time disorientation, incr. appetite:Benzo- ativan .5-2mg iv/po Q46H, causes antegrade amnesia, decr. no activity as antiemetic, ADR -sedation, hypotension, hallucinations, urinary incontinence, motor incoordination:Antihistamine- meclizine 12.5-50mg po Q12H, mechanism-cental anticholinergic action by blocking CTZ, ADR -slight to mod drowsiness, HA, thickening of bronchial secretions: Belladona Alkaloid-scopolamine (apply 1 patch behind ear every 3 days, mechanism-blocking Ach receptors in the vestibular apparatus, ADR -dry mouth, sedation, impaired eye accommodation, Non-drug therapy-relaxation, guided imagery, desensitization, hypnosis, acupuncture: prevention of CINV-evaluate pt individually, evaluate chemo regimen, most effective when give px, flexibility-you may need to change therapy daily or with each cycle, PO and iv have equal efficacy, Guidelines for Px:levels 4 and 5 start 30 min prior to chemo on day 1. give aprepitant, serotonin receptor antagonist, decadron: aprepitant-acute 125mg po on day 1 pre-chemo, then 80 mg po on days 2,3 and serotonin receptor antagonist acute 100mg po or iv on day 1 and decadron 12mg po or iv on day 1, then 8 mg po or iv on days 2, 4. for delayed compazine 10mg po Q4HPRN. For level 3 regimens use the exact same treatment as level 4,5 except only use aprepitant in a select group of patients! Level 2-decadron 8mg po/iv x1 and compazine 10mg po/iv Q46HPRN, level 1 regimen-none unless they have a history of n/v. delayed n/v use compazine 10mg Q4HPRN, anticipatory-benzodiazepines and non-drug therapy, motion=antihistamine or belladonna Drug Morphine Codeine Oxycodone Dilaudid Hydromorph Meperidine Methadone Route IM PO IM PO PO IM PO IM PO IM PO Equiv. Dose 10 30 130 300 30 1.5 7.5 75 300 10 20 Duration 4 4 4 4 3-5 4 4 4 (2?) 4 (2?) 6-8 6-8 Plasma T½ 2-3.5 Duration Acute Hours/Days Chronic Malig Months/Years Chronic Non Unpredictable 3 Pathology Present Usually Not common ? 2-3 Bio Value Psych Effects High,until none Uncommon Low Yes Low/None Yes 3-4* *normerperidine 12-24 Social Effects Minimal Varies, marked Profound Treatment Analgesics Pharm, other modal Multimodal, phys /behav., Pharm Ovarian: 63 (post-menopausal), lifetime risk 1.7%, white ETIO: “Incessant Ovulation” y—# of ovulation cycles disruption and repair of lining of ovary; Tumor supp genes BRCA1(25-45%risk), 2(27%),&p53 5-10% cases; Hereditary non-polyposis colorectal cancer (HNPCC) (Lynch II) role in 5-10%RISK: Inc: early menarch(<12) late menopause (>55), (0 pregnancies), inc. age, first kid >35, white, n.american, north europe, genetic, controversials—HRT, environmental, diet, ovulatory stim. drugs, Decreased: BOC(>5yrs) dec by 50%, >1 full term pregnancy, breast-feeding, oophorectemy, tubal ligation , Genetic: # of first degree relatives w/disease, Familial—5% if 1 1st degree relative, 7% if 2 1st degree; F at high risk(hered, BRCA1, BRCA2 positive)—pelvic exam, transvag. Ultrasound, CA-125 starting at age 25-35 (CA-125 < 35unitls/ml) P: oral conc., oophorectemy PATH: Epithial adenocarcinoma 90% cases, on surface of ovaries, histopathologic subtypes(serous-most common, mucinous, endometriod, clear-cell, Brenner), grade 1- grandular and well differentiated tumors(better prognosis), grade 2 – tumors w/grandular and solid areas, grade 3 – solid and poorly differentiated tumors; Sex cord-stromal tumors(hormone producing) grandulosa tumor; Germ-cell tumors(aggressive) age 15-25yo, >90%survival at 5yrs, includes dysgerminoma, malignant teratoma, embryonal carcinoma; Metastatic breast/colon SIGNS/SX: ab pain, change in bowel or bladder fx, bloating, vag bleedingGI-n/v/dyspepsia, diff. eating, pulm. SOB, ascites w/ poss. abd distention, pelvic mass, highCA-125DIAG: hx/physical, ab/pelvic pain, CA-125 (elevated in 85%), transvag ultrasound, imaging ovaries &abdomin—ultrasound, CT, MRI, colonoscopy or barium enema, chest xray, CBCs, LFTs, chemistryFIGO STAGING: (given) Stage 1(T1) mild –limited to ovaries, Stage 2—involves 1 or both ovaries w/pelvic extention, Stage 3(most dx)-involves one or both ovaries w/microscopically confirmed peritoneal metastasis and/or outside the pelvis and/or regional lymph node metastasis, superficial liver metastasis, tumor limited to pelvis but malignant extention to small bowel or omentum, Stage 4(M1) –growth involving 1 or more ovaries w/distant metastasis, parenchymal liver metastasis equal stage 4 disease, pleural effusion must have positive etiology for designation of stage 4MANAGEMENT: Surgery—cure/treatment; Chemo—cure/treatment; Radiation; HRT INITIAL TX: Stage 1comprehensive surgical staging for all pts., includes total abdominal hysterectomy(TAH), bilateral-salpingo-oophorectemy(BSO), complete abdominal exploration, intact tumor removal; possible pelvic and para-aortic lymph node sampling, appendectomy, omentectomy, perotineal biopsies, cytologic washings; unilateral salpingo-oophorectemy if stage 1A and pt desires fertility, must be done by gynecologic oncologist for accurate staging; If early stage, favorable features, and 1A/1B=only surgical staging; If unfavorable, grade 2 or 3, or 1C = Paclitaxel 175mg/m2 IV over 3h on day 1 & Carboplatin (AUC5-7) IV on day 1 given q21days for total of 6 cycles Stage 2,3,4 comprehensive surgical staging w/chemo, Preferred: Taxane(paclitaxel or docetaxel) + Platinum compound(carboplatin or cisplatin) for 6 cycles; Stage 3C or pts w/minimal residual disease (2cm) consider intraperotineal chemo w/ paclitaxel 135mg/m2 IV on day 1 + cisplatin 100mg/m2 IP on day 2 + paclitaxel 60mg/m2 IP on day 8 + neulasta; Extent of surgery—optimal cytoreduction (<1-2cm residual disease at end of surgery), sub-optimal (>2cm residual disease) Select Patients neoadjuvant chemo (prior to surgery) if pt. medically inoperable initially; secondary cytoreduction if initial surgery leaves sub-optimal disease start chemo 2-3 cycles followed by surgery again Monitoring Primary: pelvic exam q2 cycles, CA-125 prior to each cycle, CBC’s, platelets, chemistries, imaging if necessary; End of 6 cycles: complete pelvic/PE, CA-125 q 2-4 months for 2 years, then q6months for 3 years, then annually, imaging only in highly select patients TX RECURRENT: (6080% relapse), no standard therapy, treatment/prognosis go by initial response to chemo, Platinum sensitive (remission > 6 months) –first recurrence use Carbo + Pac, Carbo, Cis, Pac, Gemcitabine + Carbo; use other agents for subsequent; Platinum resistant (< 6 months remission) —salvage agents; use liposomal doxorubicin, topotecan, docetaxel, gemcitibine, bevacizumab, altretamine; Primary progressive(platinum refractory)—clinical trial agents PROGNOSTIC FACTORS: Stage(1 better than 4), vol. of residual disease at time of surgery(< 2cm), histologic subtype & grade, CA-125 CHEMO: Taxanes: MOA: enhances polymerization of tubulin & induces formation of stabile nonfunctional microtubules, blocks cells in late G2/M phases; Paclitaxel (Taxol®) Source: bark of pacific yew Dose: 175-225mg/m2/3weeks (3h) or 135mg/m2/3weeks (24h) Drug Int: Cyp450 Dose Adjust: Hepatic Premedications: Decadron 20mg po 12 & 6 hours prior to paclitaxel, decadron 20mg, diphenhydramine 50mgIV, famotidine20mg 30 min. prior to paclitaxel (cremophor) Toxicity: hypersens(flushing, bone pain, rash), hypotension, brady, neutropenia, peripheral neuro(3h), arth/myalgia, mild inc. LFTs, alopecia Docetaxel(Taxotere®) Dose: 750100mg/m2/3weeks (1h infusion) DI’s: Cyp450 Dose Adjust: hepatic Premeds: Decadron 8mg po bidx3-5days Toxicity: neutropenia, fluid retent, skin/nail toxic, alopecia, neurotoxic, myalgia, asthenia; Platinum analogues: MOA: aquation reaction w/H20 replacing Cl- groups to form +charged, reactive, electrophiles, active platinum species reacts w/DNA, covalent binding of platinum to DNA forms intra- inter-strand cross links Mechanism of resistence: reduced cellular drug accumulation, cytosolic inactivation of drug, DNA repair enhancement Cisplatin(Platinol®) Dose: 20-100mg/m2 IV, IP Toxicity: nephrotoxic(prevent w/ aggressive hydration, mannitol), n/v (acute/delayed), neurotoxic, ototoxic(peds), peripheral neuropathy, mild myelosuppression(good), e- abnorms dec Mg, K, Carboplatin(Paraplatin®) Dose: Calvert Formulamyelosupression (thrombocytopenia mainly, dose-limiting, neutro and anemia poss), n/v, hypersens.(>7cycles or hx) Desensitization: if sens. to Cisplatin, give Carbo 1:1000, 1:100, 1:10, 1:1 Oxaliplatin(Eloxatin®) Dose: 85-135mg/m2 Toxicity: acute neurotoxicity (w/in hours, avoid cold for 5 days, laryngopharyngeal spasm, infustion rate dependent), delayed sensory neuropathy(cumulative) Topotecan(Hycamtin®) MOA: topoisomerase inhibitor results in DNA single strand breaks Dose: 1.5mg/m2 IV dailyx5daysq21days or IVqweekx3weeks w/1 week off Elimination: renal Toxicity: neutropenic, alopecia, low-grade fever, n/v/d, rash, transient hepatic transaminitis Liposomal doxorubicin(Doxil®) MOA: intercalates b/w base pairs inhibiting DNA syn & DNA dependent RNA syn, inhibits protein synthesis, encapsulation improves therapeutic index & selective delivery of drug to tumor Dose: 40-50mg/m2 IV q3-4weeks Dose Adjust: impaired hepatic func, modify if pt has hand-foot syndrome, stomatitis, hematologic toxic Toxicity: less cardiac tox. than normal doxorubicin, hand-foot syndrome, myelosuppression, mucositis, mild n/v, acute infusion reaction(chills, fever, flushing) Gemcitabine(Gemzar®) MOA: antimetabolite, inhibits DNA polymerase and ribonucleotide reductase, specific for S-phase Dose: 1000mg/m2 IV once weekly x3weeks, repeat cycle q4weeks Toxicity: myelosuppression(dose limiting: all 3), fever, rash, alopecia, dyspnea, n/v/d, inc LFTs Bevacizumab(Avastin®): MOA: inhibits vascular endothelial growth factor, recombinant humanized monoclonal IgG1 Dose: 5-15mg/kg IV q2-3weeks, wait 28 days post surgery, Administration: 90 min infuse, then 60, then 30 if tolerated, T1/2 ~20days Toxicity: HTN, proteinuria, DVTorPE, would healing, hemorrhage, GI perf PAIN- Prev – Newly diag (28%), Active tx (50-70%), Adv. Disease (64-80%), >80% before dying- Uncontrolled– (1) disturb normal coping/adjustment; augment vulnerability, cause risk for catastrophic outcomes; (2) mood /beliefs ab/ meaning of pain; exacerbate perceived intensity & pain is a maj. factor in function/mood PAIN – unpleasant sensory/emotional experience assoc. w/ actual/potential tissue damage/described in terms like damage- Etiology –1/metastatic dx; develop pain to 1) surgery 2) radiation 3) chemo 4) (osteo, immob., infect.) Acute = several days, intermittent/ confined time & unpredictable; <3 mos., Ex: bone marrow biopsy, post op, chemo, WBC GF, bone pain Chronic-persistent cancer >3 mos, pain caused by dx (HIV, MS, ES organ failure), Ex: bone metastasis, nerve pain, post chemo, peripheral neuro., tumor infiltration Chronic non-malig-myofascial, neuropathic, complex regional, failed back, H/A, arthritis UNDERTX-ped/geriatric pt, communication, substance abuse, neuro pain, minorities, females, culture-Risks of Unrelieved - catabolic demands, RR, limb move (clot risk),GI motility,Na/water retention, tachycardia,BP, infection ,negative emotion, sleep, suffering- Onset, Location, Duration, Characteristics, Aggravating, Remitting, Temporal, Severity-Universal Screening-pain=0 (reassess later), pain>0(assess) A=Ask,Assess,B=Believe,C=Choose,D=Deliver E=Empower ACUTE -prevent, sched. analgesics, PRN breakthrough -mildNSAID, modlow-dose opoid+NSAID, severehigher opiod+NSAIDs (elevate opiods as needed, + adjuvants)-consider PCA (6-8 min), epidurals, nonpharm -general approach to tx-by mouth(pills), by clock by ladder , for individual, reassess frequently, balance pain relief and Ses Mild(13) no ASA -APAP=antipyretic, hepatotoxic, ≤4g, ceiling effect -NSAIDs=ceiling effect, antipyretic, antiPLT, renal/GI tox,LFTs Mod (4-6)start mild opiod -Codeine-limited N/C/allergy, dn exceed 1.5mg/kg b/c SEs -Hydrocodone- limited by APAP effect Severe(7-10)-start strong opiod-Morphine-standard use, caution renal dysfunction, N/V Hydromorphone-potency,caution in liver dysfunction-Oxycodone-no IV-Fentanyl-unique transmucosal,transdermal patch (never cut), lipophilic area, n for use in cachectic pt -Methadone-cheap,lasts 4-8hr, t½=15-48hr, tough to titrate-Agents NOT Rec.-meperidine,agonist-antagonist(pentazocine butorphanol,denocine,nalbuphine IM erratic absorp Salicylates P-Aminop. Derivatives Propionic acids ASA APAP 3-12 hr 2-4 hr 325mg PO q6h 325-650mg PO q6h Ibu Naproxen Nap Na Ketorolac PO(15,30,60) PO(5/325,5/ 500,7.5/500, 10/650) PO 100, 100/650 Many 1.8-2 hr 13 hr 13 hr 4-7hr 15-120 q4 2.5-10 q4 max-60qd 200-800 PO q6h 250-500 PO q12h 220-550 PO q12h 15-30mg IV q6h 2-3 3-4 N/C 2-3 3-4 w/ APAP and ASA 100 Q4 Max600qd 10-30 q4 and 1-4 IV q3-4 2-3 3-4 n routine use 2-3 3-4 Concent. Oral soln (20mg/ml) Hmorphone 2 mg 4 mg Oxycodone 5,15,30 mg Fentanyl Many 2-3 3-4 Tab, liquid 2-4 q4 and 0.2-0.6 IV q 3-4 2.5-10 q4 2-3 3-4 see morphine IV, Transmuc 25-100 IV q 1-2 and 200 TM start 1-2 1-3 1-2 Tramadol Tab 50-100 q4-6 Max400qd ~6 9 Mcg, breakthrough, F=0.5(buccal/ Oral) CNS Acetic Acid Codeine Hmorphone/ APAP Propoxy. Nap Morphine Opiate SEs-CONSTIPATION-tolerance dn develop, need fluids/ fiber/exercise, prophylaxis-docusate+senna (w/opoid), pharm-inc lax, PRN MOM, biscodyl,lactulose, sorbitol,mag cit,enemas NAUSEA-PRN (prochlorperazine), SEDATION-dose related, dose/frequency, methylphenidate RESP- w/ increasing doses URINARY RETENTION/BLADDER SPASMS- elderly, dose PRURITIS(Benadryl)SEIZURES- only with high doses - opoids no ceiling effect titrate up w/ inadeq relief, failure, breakthrough (≥3 PRN daily x 2-3d) total opoid (ATC+PRN) depending on pain scale; 50-100% for severe, 2550% for mod, 25% for mild -PRN should be 10% of daily dose, freq of titration q12-24h for chronic/oral opoids, q1-4h for acute/crisis/parenteral down titrate w/ no SEs/no pain, dec. pain source, no PRNs -down titrate 50% x 2d, 25% q 2d until preferred dose/no pain medication needed (can vary, gradual 1-7d, rapid 50-75% q12-24h) bone metastasis-bisphosphanates (pamidronate 60-90 IV q mo or zoledronic acid 4mg IV q mo), NSAIDs, Corticosteroids (dexamethasone), radiation, radiopharm (strom-89, sumar153)NEUROPATHIC-opiates, TCAs (amitrtiptylline), SSRIs (duloxetine 60mg BID, max 300/d), Anticonvulsants (gabapentin 100mg BID/TID, max 3600/d or Pregabalin 50mg TID, max 300d), Nerve blockCONVERSION IV Morphine to (Fentanyl)8-22mg=25mcg, 23-37= 50mcg, 38-52=75mcg, 53-67=100mcg, 68-82=125mcg, 82-97=150mcgCASE 1: 1. metastatic melanoma to liver/lungs 2. N/V (morphine induced)- modify pain SR Morphine MSContin-q12, q8 8-12 Rectal MSContin good therapy 3. cancer-related pain- MsContin, Morphine IR 2. Comp 15,30,60,100,200 for 8-12hr 10mg PO/25 PR (Mon- EPS (benadryl), excess sedation, HoTN, Kadian(can open)-qd,q12 12liver dysfunct, bone marrow aplasia). KW-180mg MsContin/day— 20,30,50,60,120 24 switch to Duragesic 50mcg/hr 1 patch Q72hrs (mon-n/v, resp SR Oxycodone, Oxycontin-q8h, q12h 12 depression, sedation, bp, don’t cut, no heat on patch, fatty area Oxycontin 10,20,40,80,160 absorb better). [OR switch to Oxycontin 180mg/day x 0.75 Transderm Fent Duragesic- q72h 72 Skin depot, 48 h in 12mcg/hr,25,50,75,100 some 135mg/day => oxycontin 40mg Q8hr.] KW also take 90mg Methadone Dolophene- tab-5,10mg 6-8 Long t½ , cheap, long morphine IR/day – 90/x=30/1.5 => Dilaudid 4.5mg IV x 0.75 = Q6 Q8 soln 1mg/ml, 10mg/ml 3.4mg/24hr =>0.14mg/hr cont infusion => dilaudid 0.56mg IV Levorphanol Oral: 2-4mg PO q6-8h PRN 6-8 Long t½ , refract N/V Q4hr prn (PO usage 90/x=30/7.5 => 22.5mg PO x 0.75 = IV: 1-2mg IV q6-8hr PRN 16.9mg/24hr =>dilaudid 2.8mg PO Q4H prn). If tolerated inc dilaudid dose to 28mg/24hr (22.5mg x 1.25) => 4.7mg PO Q4hr prn (mon- pain relief, resp/ment status, weakness, n/v/constipation)Case 2A(CrCl 74.5/1.92 m2) 1.Stage IIA Carboplatin(4) + Paclitaxel(2) 2.Mild (3/10) PN- Paclitaxel ADR determine Tx 3. N/V Px (5)- Palon ; Loraze; Dexa 4. Hx of abnormal pap smears- determine Tx 5. Anxiety- Sertraline 6. HTN- determine Tx 7. Dyslipid- Pravastatin 2.Switch to Paclitaxel 135mg/m2/3wks/24 hours (less PN, mon: myelosuppression) + Add Gabapentin 100 mg TID- titrate to 300mg TID (mon sedation) 4. screen for cervical cancer 6. monitor BP **Monitor: pelvic exam Q2 cycles; CA-125 before each cycle; CBC; platelets End of 6 cycles: pelvic exam and CA-125 Q2-4 mos for 2 yrs then Q6 mos for 3 yrs then Qyr. 2B (plat sensitive): 1. Stage IIIC -determine Tx 2. Anemia-11 gm/dL 3. Anxiety-Sertraline 1. Carboplatin + Pacletaxel (same dose, mon PN and neutropenia) N/V Px? 2. Consider Epoetin Alfa 40,000 U/wk mon: bp, Hgb/Hct.Case 3 (CrCl 142.03/2.1 m2): 1.relapsed non-hodgkins lymphoma- ESHAP + Ritux 2. N/V Px level 5- (risk-Hx of motion sickness) determine Tx 3. Anemic-12 gm/dL- determine Tx 4.Depression- paroxetine 5. GERD- pantoprazole 2. N/V px:dolestron 100 mg IV on Day 1 (30 mins prior to chemo) (mon: HA, constipation, somnolence, dizziness, serotonin syn) Methylpredn 500 mg IV Day 1 (30 mins prior) Continue Days 2-5 (mon: sugar, bp, electrolytes, mood, wt) Meclizine 12.5 mg PO Q12PRN (mon: drowsy, HA) Delayed: Comp 10 mg (mon: sedation, EPS, hypotn, BM, LFTs) Nonpharm: Relaxation, Guided Imagery, Densenstization, Hypnosis, Acupuncture 3. Mon Hgb/Hct Case 4: 1. recurrent invasive breast cancer- metastatic to bone 2. somatic (aching, throbbing) severe pain (7/10)- inadequate therapy - naproxen + oxycodone ATC 3. thrombocytopenia – 80K determine tx. 4. anemia – HgB-12 –determine tx. 5. depress – escitalopram. 6. nutrition– MVI*No morphine* D/C NSAID (min pain relief potential, antiplatelet effect). Since pain 7/10, increase dose by 50-100%. Long-acting— Oxycontin 20mg PO Q12hr also incr. interval of BTP med. to oxycodone IR 5mg PO Q4hr pp (mon- pain relief, resp/ment status, bp, n/v/constipation, pruitis). Zoledronic acid 4mg IV mos (monitor: edema, HoTN, fatigue, fever, risk of jaw osteonecrosis, renal function, electrolyte levels). thrombocytopenia- d/c NSAID. monitor plt until nadir. If plt count <50K, then consider Oprelvekin 50mcg/kg SC daily initiated 24hrs after chemo completion and cont 14-21days(max 21days) or plt count >50K. Many ADEs (cardiac, resp, edema, SOB, h/a, dizzy, thrombosis, myalgias)Case 5: Part 1- 1.AML – Idarubicin, Cytarabine. 2. Risk for TLS – (increase LDH, UA, blasts) determine treatment. 3. N/V px – deter tx. 4. anemia – HgB 9.2 5. heartburn – famotidine. 6. seasonal allergies- fexofenadine. TLS? rapid tumor cell lysis, releasing UA, K, Phos into blood which exceeds ability of norm compensatory mechs. At risk? hematologic malignancies (leukemia/lymphoma), tumors w/ high proliferative rates, large tumor burden, preexist renal insuff. TLS. – increased K, P, UA, Cr, LDH, wt. dec Ca, urine output. Pxof TLS- hydration-start 24-48hrs prior to tx (goal output >100mL/hr), alkalize urine-IV fluids +NaHCO3 goal urine pH >7 or acetazolamide, allopurinol 300mg PO QD start 24-48hr before chemo, rasburicase 3mg IV x 1as tx of TLS. N/V px(4) – aprepitant: 125mg on day 1, 80mg PO on day 2-3 (monitor fatigue, dizzy, hiccups, diarrhea), dolasetron 100mg PO/IV on day1, dexa 12mg PO/IV on day1, 8mg PO/IV days 2-4 tx Comp 10mg PO Q4-6H PRN Part2: 1. AML –day11of 1st chemo cycle. 2. neutropenic fever – determine tx. 3. thrombocytopenia. 4. anemia. 5. seasonal allergies. 6. heartburn. 7. Mild H/A – oxycodone/APAP ANC= 98. Cefepime 2gm IV Q8H until ANC>/=500cell/mm3 for 2 consecutive days, afebrile, negative cultures, no definite site of infection (monitor: hypersensitivity, rash, GI, negative cultures, h/a) (alternative; aminoglycoside + cefepime, or vanco 10-15mg/kg/dose IV Q12H) handwashing, minimize invasive proced, avoid crowds, fresh fruit. Consider antimicro/antifun/ antiviral px. Would filgrastim? No b/c of active leukemia. potential benefit once pt is in remission. Mild H/A – d/c percocet. Tramadol 50mg Q4-6H PRN H/A. (Monitor: pain relief, resp rate, bp, tolerance, cns effects, n/constipation)