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2015 Pharmacotherapy Specialty Examination Review Course: Complex Breast Cancer Case
Helen M. Marshall, Pharm.D., BCPS, BCOP Clinical Pharmacist, Hematology/Oncology
Seattle Cancer Care Alliance/University of Washington Medical Center Clinical Assistant Professor
University of Washington School of Pharmacy Seattle, Washington
Learning Objectives: At the end of the presentation, the pharmacist should be able to:
• Correctly answer case-based questions about appropriate treatment and monitoring of a complex patient with multiple conditions, including breast cancer, febrile neutropenia, and pulmonary embolism.
• Develop a plan to manage pain and nausea/vomiting in a patient with cancer. • Determine how to manage drug-drug and drug-disease interactions in a cancer patient. • Discuss ethical, cultural, health literacy, legal, economic, quality of life, or safety issues in this
population. • Identify and recommend appropriate resource organizations/groups to assist a specific patient.
Format: This session will use a series of audience response questions to engage the audience and to prepare participants to answer similar questions on the pharmacotherapy board certification examination. The speaker will discuss drug therapy management in a cancer patient and discuss the rationale and guidelines driving therapeutic decisions. Premise: You are a clinical pharmacist in a large, 800-bed institution. You also participate in a continuity clinic one afternoon per week in an ambulatory, multidisciplinary breast cancer clinic. You are responsible for drug therapy monitoring in both settings and ensuring patient safety for both chemotherapy and supportive care. You have online access to an integrated medical record that is shared in both the inpatient and outpatient settings. NOTE: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are referenced with permission from the National Comprehensive Cancer Network® (NCCN®). To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
PATIENT CASE #1 Date: June 1, 2015 Initials GE DOB/Age
53 Sex F
Race/Ethnicity Caucasian
Source Patient and medical records
Chief Complaint/History of Present Illness: “I feel awful. I’m very short of breath and I can’t stop vomiting.” The patient is being treated for breast cancer and presents to the ED with acute onset of chest pain and shortness of breath. She also feels dizzy and weak. She has been unable to eat for the past day. Triage and work up begin immediately.
Past Medical History (major illnesses and surgeries)
From Medical Record Hypertension Depression Hypothyroidism Breast Cancer, Stage IIB
• Diagnosed January 2015 in her right breast • Stage IIB (T2 N1 M0) • ER and PR positive • HER2 negative • Postmenopausal (menopause at age 51)
Breast Cancer Treatment to Date
• Surgery ▫ Mastectomy with axillary lymph node dissection ▫ 4 positive lymph nodes
• Radiation ▫ Chest wall and regional lymph nodes
• Chemotherapy ▫ Dose-dense AC (Adriamycin [doxorubicin] and cyclophosphamide) ▫ Doxorubicin 60 mg/m2 IV day 1 ▫ Cyclophosphamide 600 mg/m2 IV day 1 ▫ Every 14 days X 4 cycles ▫ Dose-dense AC requires growth factor support ▫ Followed by paclitaxel ▫ Paclitaxel 80 mg/m2 IV day 1 weekly X 12 cycles
• GE received cycle 2 of doxorubicin and cyclophosphamide 2 days ago
Levothyroxine 88 mcg orally once daily Hypothyroidism
5/2015 Ondansetron 8 mg orally every 8 hr prn Nausea/vomiting 5/2015 Prochlorperazine 10 mg orally every 6 hr
prn Nausea/vomiting
5/2015 Lorazepam 0.5-1 mg orally every 6 hr prn Nausea/vomiting; anxiety 5/2015 Ondansetron 8 mg IV and dexamethasone
10 mg IV every 2 weeks pre-chemotherapy Prevention of nausea and vomiting
5/2015 Doxorubicin 60mg/m2 IV and cyclophosphamide 60mg/m2 IV every 2 weeks
Adjuvant breast cancer treatment
Vaccinations: Influenza vaccine fall 2014 Pharmacy(ies) Used: local community pharmacy, cancer center
RX Payment: Private (15% co-insurance) Meds Admin by: Self Drug Allergies/Adverse Effects: NKDA Family Medical History: Father: MI s/p CABG X 2 at age 55; Grandmother has a history of stage I breast cancer s/p mastectomy with reconstruction and no recurrence; Brother has MS Social History
Residence: lives at home w/ husband
Occupation: Elementary school teacher
Smoking: Previously smoked 1 ppd x 2 years in college
EtOH: 1-2 glasses of wine with dinner 2-3 times/week
Illicit Drugs: Marijuana in college only Diet: Vegetarian Education: college graduate Family/Social Environment: Lives with
Objective Data (observations/vital signs/physical examination/labs)
General: Ill appearing female that is acutely SOB; A&0 x 3 RR 25/min, BP 90/52 mm Hg, HR 105 bpm, Temp 98.4 °F Wt 76 kg, Ht 166 cm Physical Exam – Diminished breath sounds on the left and right, left > right; tachycardic; skin and oral mucous membranes are dry. All other systems are negative/noncontributory. Laboratory Tests (drawn in ED) – Na 129 mEq/L K 3.3 mEq/L Cl 100 mEq/L CO2 32 mEq/L BUN 25 mg/dL SCr 1.2 mg/dL Glucose 95 mg/dL AST 27 units/L ALT 18 units/L Alk Phos 105 units/L T bili 0.8 mg/dL TP 7.1 g/dL Albumin 3.2 g/dL WBC 1.7 X 109/L Hgb 11.2 g/dL Hct 30% Plts 96 X 109/L ANC 0.6 X 109/L CK Index 1 CK-MB 1 ng/mL Total CK 41 ng/mL Troponin 0.2 ng/mL
1. Which of the following should be monitored for our patient on this chemotherapy regimen?
a. Cognitive function b. Pulmonary function c. Cardiac function d. Thyroid function
2. Which of the following is a risk factor for venous thromboembolism (VTE) in GE?
a. Febrile neutropenia b. Nausea and vomiting c. Presence of central venous catheter d. Hypertension
3. Which of the following therapies should be initiated in GE for her pulmonary embolism?
a. Warfarin 5 mg orally daily b. Apixaban 10 mg orally twice daily c. Dalteparin 12,500 units subcut every 24 hr d. Enoxaparin 80 mg subcut every 12 hr
4. What is the appropriate antiemetic regimen for GE while receiving treatment with dose-dense AC?
a. Ondansetron 8 mg IV and dexamethasone 12 mg IV day 1 followed by dexamethasone 4 mg PO BID days 2-4
b. Fosaprepitant 150 mg IV, ondansetron 8 mg IV, and dexamethasone 12 mg IV day 1 followed by dexamethasone 4 mg PO BID days 2-4
c. Fosaprepitant 150 mg IV, ondansetron 8 mg IV, and dexamethasone 12 mg IV day 1 d. Palonosetron 0.25 mg IV and dexamethasone 10 mg IV day 1 followed by dexamethasone 4 mg
PO BID days 2-4
5. Which of the following is a therapeutic option for anticoagulation in a patient with suspected HIT?
a. Argatroban b. Dalteparin c. Dabigatran d. Clopidogrel
6. Which of the following should be initiated as empiric therapy for febrile neutropenia in GE?
a. Imipenem 500 mg IV every 6 hours b. Ciprofloxacin 500 mg PO every 8 hours and clindamycin 450 mg PO every 8 hours c. Ciprofloxacin 500 mg PO every 8 hours and amoxicillin/clavulanate 500 mg PO every 8 hours d. Ciprofloxacin 500 mg IV every 8 hours
7. Which of the following considerations enters into the decision about whether vancomycin should be added to GE’s regimen?
a. Guidelines recommending empiric vancomycin for all patients with FN b. Presence of a central venous catheter c. Prior use of ciprofloxacin prophylaxis d. Reported symptom of cough
8. GE’s oncologist asks you for a conversion to a long-acting opioid because GE has escalated her oxycodone use to 5 mg every 3 hours around the clock and is still reporting poor pain control. Which of the following is the best regimen for GE?
a. Fentanyl TDS 100 mcg/hr every 72 hours b. Morphine SR 45 mg po every 8 hours c. Morphine SR 15 mg po every 12 hours d. Morphine SR 30 mg po every 12 hours
9. GE’s oncologist follows your advice and initiates the long acting pain regimen that was
recommended. Which of the following is the best breakthrough pain regimen for her?
a. Morphine IR 15 mg po every 1-2 hours b. Morphine IR 15 mg po every 4-6 hours c. Morphine IR 30 mg po every 6 hours d. Oxycodone 2.5 mg po every 6 hours
10. Which of GE’s medications poses a concern if initiating therapy with tamoxifen?
a. Lisinopril b. Levothyroxine c. Paroxetine d. Morphine
11. Which of the following is a possible treatment option for GE if her cancer returns (metastatic to the
bone) during treatment with tamoxifen?
a. Exemestane and everolimus b. Ado-trastuzumab emtansine c. Pertuzumab, trastuzumab, and paclitaxel d. Tamoxifen (complete 5 years)
Additional Information on Breast Cancer Febrile Neutropenia Pearls • A clinical practice guideline for the use of antimicrobial agents in patients with febrile neutropenia
and cancer was published by the Infectious Diseases Society of America (IDSA) in 2011. Some of the changes in this guideline include an emphasis on risk stratification of patients with FN, improved guidance on which patients benefit from prophylaxis (antibacterial, antiviral, and antifungal), and discussion of the use of empiric vs. preemptive antifungal therapy and emerging resistance problems.
• Main algorithms are below:
Frefield AG, Bow EJ, Sepkowitz KA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Disease Society of America. Clin Infect Dis. 2011; 52:e56-93. http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/idsaneutropenicfever2010.pdf (accessed 2015 May 19). Clinical infectious diseases by Infectious Diseases Society of America. Reproduced with permission of Oxford University Press in the format Journal via Copyright Clearance Center.
Frefield AG, Bow EJ, Sepkowitz KA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Disease Society of America. Clin Infect Dis. 2011; 52:e56-93. http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/idsaneutropenicfever2010.pdf (accessed 2015 May 19). Clinical infectious diseases by Infectious Diseases Society of America. Reproduced with permission of Oxford University Press in the format Journal via Copyright Clearance Center. • Modifications to initial antibiotics based on resistance.
o MRSA consider early addition of vancomycin, linezolid or daptomycin o VRE consider early addition of linezolid or daptomycin o ESBLs consider early use of a carbapenem o KPCs consider early use of polymyxin-colistin or tigecycline
• Duration of therapy is dictated by organism/site if documented infection; or at least until ANC recovers (>0.5 thou/microL) or longer depending on clinical situation.
• ASCO published guidelines for antimicrobial prophylaxis and outpatient management of FN o In patients with FN, those that meet MASCC criteria, those in Talcott group 4, and without
additional risk factors may be managed with empiric fluoroquinolone and amoxicillin/clavulanate (clindamycin for pateints with a penicillin allergy)
• NCCN® also lists moxifloxacin as an outpatient option for low risk FN patients • Fluoroquinolone prophylaxis may be used for patients at high risk with expected duration of
neutropenia ≤ 0.1 thou/microL for > 7 days. • Empiric antifungal coverage for persistent/recurrent fever after 4-7 days of antibiotics for
neutropenia expected to be > 7 days; preemptive therapy is acceptable for high-risk patients. • Antifungal prophylaxis should be used
o Against Candida for allogeneic stem cell transplant patients or undergoing intensive reinduction or salvage chemotherapy for acute leukemia (fluconazole, itraconazole, voriconazole, micafungin or caspofungin)
o Against Aspergillus for patients ≥ 13 years of age undergoing intensive therapy for acute leukemia or myelodysplastic syndrome with high risk of invasive aspergillosis (use posaconazole). May also use antifungal prophylaxis pre-engraftment in transplant patients with history of invasive aspergillosis, prolonged neutropenia ≥ 14 days, or prolonged period of neutropenia prior to transplant.
• Antiviral Prophylaxis o Acyclovir for herpes simplex virus (HSV)-seropositive patients undergoing allogeneic stem
cell transplant or leukemia induction therapy o Yearly influenza vaccination for all patients being treated for cancer o No other routine prophylaxis, but appropriate treatment if infection develops
• Myeloid growth factors are not recommended for established fever and neutropenia • Central line-associated bloodstream infections (CLABSI) in patients with FN
o Differential time to positivity > 120 minutes after blood cultures drawn from both the central line and peripherally suggests a CLABSI
o Infections caused by Staphylococcus aureus, Pseudomonas aeruginosa, fungi or mycobacteria Remove the catheter Systemic therapy for at least 14 days
o If caused by coagulase-negative Staphylococci, may maintain central line and treat with systemic therapy with or without antibiotic lock therapy
o Use duration of therapy of 4-6 weeks for deep tissue infection, endocarditis, septic thrombosis or persistent bacteremia/fungemia > 72 hours after catheter removal
• IDSA guidelines are also available (see reference list) for the treatment of candidiasis (2009) and catheter-related infections (2009).
Anticoagulation Pearls • Oncology patients should be provided education about the signs and symptoms of VTE • Anticoagulation should not be used to extend survival in patients with cancer in the absence of
other indications • At this time, there are insufficient data to recommend the use of dabigatran, rivaroxaban, and
apixaban in oncology patients. • Low molecular weight heparin (LMWH) remains the cornerstone of therapy.
• Anti-factor Xa monitoring is not routinely recommended, but it is used by some clinicians. The goal trough concentration is < 0.5 units/mL. You may consider this type of monitoring in special situations, such as changing renal function, pregnancy, or obesity.
• Routine monitoring of LMWH should include weight, SCr/CrCl, hematocrit and platelets. • In patients receiving extended anticoagulant therapy, the need for continued treatment should be
periodically reevaluated. • In patients with active cancer, extended anticoagulant therapy is recommended (beyond 3 months
of therapy) even when the risk for bleeding is high. • In patients with acute pulmonary embolism (PE) treated with LMWH, use a once-daily regimen
instead of a twice-daily regimen if possible to minimize the number of injections. • In patients with upper extremity DVT (UEDVT) associated with a central venous catheter, the
catheter should not be removed if it is functional and there is an ongoing need for it. • In cancer patients with UEDVT in whom the catheter is removed, 3 months of anticoagulant therapy
is suggested over extended therapy (Grade 2C). • In cancer patients with UEDVT in whom the catheter is not removed, anticoagulation should
continue for as long as the catheter remains (at least 3 months). • Hospitalized patients with cancer should receive prophylactic anticoagulation unless there is a
contraindication. Prophylactic anticoagulant therapy is recommended in the postoperative setting for 4 weeks, especially for high-risk abdominal or pelvic cancer surgery.
• Prophylactic anticoagulant therapy is recommended in high-risk ambulatory settings o Multiple myeloma patients receiving lenalidomide or thalidomide in combination with high-
dose dexamethasone or a multi-agent doxorubicin-containing regimen or multiple myeloma patients with other risk factors Prophylactic LMWH (i.e., enoxaparin 40 mg subcutaneously every 24 hours) Warfarin to target international normalized ratio (INR) 2-3
o Low-risk myeloma patients may receive prophylaxis with aspirin 81-325 mg once daily o Select the prophylactic agent based on cost, Food and Drug Administration (FDA)-approved
indication, ease of administration, reversibility, monitoring requirements, and presence of renal failure
• In the setting of heparin-induced thrombocytopenia (HIT), treatment with a direct thrombin inhibitor (DTI) or fondaparinux should overlap with warfarin therapy for a minimum of 5 days, and be continued until the INR is >2 for at least 24 hours.
• If argatroban is used, the target INR should be 4 before the drug is discontinued, and then the INR should be repeated within 3-6 hours after discontinuation of argatroban.
• Chromogenic factor X could be used to monitor the INR during DTI therapy because it is not affected by the DTI.
• Patients with cancer should be periodically assessed for venous thromboembolism (VTE) risk • Risk factors for VTE in malignancy
o General Patient Active cancer Advanced stage of cancer Types: brain, pancreas, stomach, bladder, gynecologic, lung, lymphoma,
myeloproliferative disease, kidney, metastatic Regional bulky lymphadenopathy with extrinsic vascular compression Familial and/or acquired hypercoagulability Medical comorbidities, including infection, renal disease, pulmonary disease,
congestive heart failure, or arterial thromboembolism Poor performance status
Major surgery Central catheter/IV catheter Chemotherapy, especially bevacizumab or thalidomide/lenalidomide with
dexamethasone Exogenous estrogen, including hormone-replacement therapy, contraceptives,
tamoxifen/raloxifene, diethylstilbestrol o Modifiable risk factors
Smoking Obesity Exercise (lack of)
o Multiple myeloma patient risk factors M spike > 1.6 g/dL Hyperviscosity Progressive disease
o High-risk outpatients on chemotherapy (based on risk factor combinations) Active cancer with high risk of DVT (See above) Pre-chemotherapy platelet count > 300 thou/microL Pre-chemotherapy WBC > 11 thou/microL Hemoglobin <10 g/dL Use of erythropoiesis-stimulating agents BMI ≥ 35 kg/m2 Prior VTE
• NCCN® also has recommendations for managing therapeutic failure of anticoagulation, which does occur in the oncology population.
Chemotherapy Induced Nausea and Vomiting (CINV) Pearls
• Risk factors for CINV include o Young age o Sex (female increases risk) o Expectation of severe nausea o Chemotherapy
Dose Emetogenicity
o History of alcohol intake • There are three main sets of guidelines utilized in clinical practice (MASCC, ASCO, and NCCN®,
see references). There are some differences in each guideline in regards to classification of emetogenicity risk of each chemotherapeutic agent as well as recommendations for prophylaxis/treatment.
• Definitions: Emetic Risk Groups o High = Risk in > 90% of patients; cisplatin is a key example and frequently used in clinical
trials o Moderate = Risk in 30% to 90% of patients o Low = Risk in 10% to 30% of patients o Minimal – Risk in <10% of patients
• The combination of anthracycline and cyclophosphamide was reclassified to highly emetogenic in the 2011 update of the ASCO guideline.
• The guidelines also provide guidance for radiation-induced nausea/vomiting. • Acute emesis occurs within 24 hours of treatment • Delayed emesis occurs at least 24 hours after treatment • Antiemetic treatment for patients receiving combination chemotherapy should be determined
based on the agent with the highest emetic risk. • NCCN® Principles of Emesis Control
o Prevention is the goal o Risk of N/V for patients receiving highly or moderately emetogenic regimens lasts 3 days
for high regimens and 2 days for moderate regimens; use prophylaxis throughout o Oral and intravenous 5HT3 antagonists are equally effective at appropriate doses o Consider the toxicity of the selected agents (e.g., constipation with 5HT3 antagonists) o Choice of antiemetic should be based on regimen emetogenicity, patient factors and
prior antiemetic history o Consider other factors causing N/V in patients with malignancy o Consider H2 antagonist or PPI use to decrease dyspepsia which can exacerbate nausea o Lifestyle measures (e.g., small, frequent meals) may be useful
• Recommendations for Prophylaxis Emetic Risk Category Acute Delayed Notes High NK1 Antagonist AND
5HT3 Antagonist AND Dexamethasone
Dexamethasone (and aprepitant if used)
NCCN®: Consider adding lorazepam, H2 antagonist or PPI; also provides an olanzapine-based regimen
Moderate Palonosetron AND Dexamethasone
Dexamethasone NCCN® notes as above
Low 5HT3 Antagonist OR Dexamethasone OR Dopamine Receptor Antagonist
No routine prophylaxis NCCN®: Consider adding lorazepam, H2 antagonist or PPI ASCO: dexamethasone is recommended
Minimal No routine prophylaxis No routine prophylaxis
• Dexamethasone and 5HT3 antagonist are both recommended for high-dose chemotherapy (frequently used in bone marrow transplant)
• The ASCO guideline focuses on intravenous therapy; oral chemotherapy is discussed in NCCN® and MASCC
• Highly emetogenic agents are listed in the slide set
o Occurs despite prophylaxis (re-evaluate) o Treatment is largely empiric, without strong data or consensus recommendations o Drug classes frequently used include phenothiazines and benzodiazepines o Consider adding an additional class of medication to the current regimen o ASCO suggests olanzapine, high-dose intravenous metoclopramide, benzodiazepine
or dopamine antagonist • Anticipatory nausea and vomiting
o Use most active, appropriate regimen for prophylaxis o Consider behavioral therapy/desensitization o Consider benzodiazepine
Pain Management Pearls • Note that charts and tables of analgesic agents with equianalgesic dosing information are variable.
Doses recommended were obtained from studies of single doses for acute pain, were not bi-directional, and did not account for inter-patient variability in response.
• In addition to pharmacologic treatment of cancer pain, interventional (e.g., celiac plexus block, placement of an intrathecal catheter), behavioral, cognitive, rehabilitative and integrative modalities for management of cancer pain are available.
• Prescription drug abuse has continued to rise in the United States, and many states are enacting legislation to promote the safe use of opioid analgesics. In many states, cancer patients are exempt from legal requirements, but legislation in some states may apply to cancer patients with non-cancer chronic pain (e.g., low back pain).
• There is no upper dose limit for opioids in cancer pain. The correct dose controls the patient’s pain and does not cause unacceptable side effects.
• Opioids to avoid in patients with cancer pain: meperidine, pentazocine, butorphanol, nalbuphine, and buprenorphine.
• Hydrocodone has been reclassified to CII (2014) • Requirements for risk evaluation and mitigation strategies (REMS) have been established by FDA for
some opioids, including the newer extended-release hydromorphone product (available at: http://www.exalgorems.com/) and all immediate-release transmucosal fentanyl products (available at: https://www.tirfremsaccess.com/TirfUI/rems/home.action). Prescribers, patients, and pharmacies must be registered for outpatient use of these products.
• Conversion to fentanyl transdermal systems (TDS) can be accomplished using morphine equivalents (do not use the following table to convert from fentanyl to another opioid):
o Patients need to be on an oral morphine equivalent of at least 60 mg daily to start using transdermal systems
o The onset of action is approximately 12 hours o Removal of the TDS results in continued fentanyl exposure for approximately 17 hours o The system should be removed and replaced by a fresh one every 72 hours o The TDS is useful in patients with chronic, stable pain as well as patients who cannot
swallow solid oral dosage forms (e.g., patients with head or neck cancer) o Counseling patients on proper use and disposal of the TDS is imperative
• Methadone Clinical Pearls o Useful and inexpensive agent for oncology patients o Thought to provide additional pain relief by antagonizing N-methyl d-aspartate (NMDA)
receptors in the dorsal horn of the spinal cord o Analgesic duration (approximately 4-8 hours) and drug half-life (15-30 hours) are very
different o Drug accumulation may occur o Equianalgesic conversion is not linear, and very challenging o Doses should not be titrated faster than once every 5 days o Prolongs the QTc interval on the ECG (see the article by Krantz MJ et al in the pain
management section of the reference list in this handout for suggested monitoring parameters)
• Opioid Rotation (this is a more complex and conservative example than that provided during the presentation, but it illustrates the point that conversion from one agent to another is not straightforward; see the article by Portenoy (Lancet) in the pain management section of the reference list in this handout)
o Step 1 Select agent based on previous patient experience, availability, cost, etc Calculate equianalgesic dose For opioids other than methadone and fentanyl, identify a 25-50% dose reduction
window lower than the calculated dose • For methadone, the dose reduction window is 75-90%, rarely converting to
methadone at doses higher than 100 mg per day • For transdermal fentanyl, use the package insert
Select dose closer to the lower bound (25%) or upper bound (50%) based on how applicable the conversion is to the regimen and patient
• Upper bound if patient is on a fairly high dose, is not white, elderly or medically frail
• Lower bound if otherwise and especially if switching route of administration o Step 2
On the basis of assessment of pain severity and other medical/psychosocial patient characteristics, increase or decrease the calculated dose by 15-30% to improve the likelihood that the initial dose will be effective and/or prevent adverse effects/withdrawal
Assess response and titrate as necessary to optimize outcome • ASCO released guidelines for prevention and management of chemotherapy-induced peripheral
neuropathy in survivors of adult cancer (2014). There is a lack of evidence for preventative therapy. The guidelines make a moderate recommendation for the use of duloxetine based on a randomized controlled trial for 5 weeks duration that resulted in a decrease in average pain intensity score in the duloxetine arm of 1.06 (95% CI, 0.72-1.40) vs. 0.34 (95% CI, 0.01-0.66) in the placebo arm (P = .003; effect size, 0.513).
Breast Cancer Pearls • Most common malignancy in women (approximately 231, 840 new cases expected in 2015), and
second leading cancer killer behind lung cancer. Mortality from breast cancer appears to be declining.
• Risk factors o Gender (please remember that breast cancer can occur in men) o Advanced age o Genetics (BRAC1/2, others) o Family history, personal history o Race (Caucasian women have slightly higher incidence, but African-American women have a
higher mortality; Asian, Hispanic, and Native-American women have a lower risk) o Dense breast tissue o Benign breast conditions o Lobular carcinoma in situ (LCIS) o Menarche at age < 12 and menopause at age > 55 (more hormonal exposure) o Diethylstilbestrol exposure o Increased hormone exposure
Lack of breast feeding Oral contraceptives Hormone-replacement therapy
o Alcohol use o Obesity o Lack of physical activity
• Cancers may arise from the ducts or lobules (85-90% of invasive are ductal) • Test all tumors for estrogen receptor (ER), progesterone receptor (PR) and HER2 status • Treatment includes local therapy with surgery and/or radiation therapy and the treatment of
systemic disease with chemotherapy, endocrine therapy, biologic therapy, or combinations of these modalities.
• Factors that influence treatment include: o Tumor histology o Clinical and pathologic characteristics of the tumor o Axillary node status o Tumor hormone receptor content o Tumor HER2 status o Multi-gene testing o Patient factors: comorbid conditions, age, and menopausal status
• Patients stratified for treatment: o Pure noninvasive carcinomas: LCIS and ductal carcinoma in situ (DCIS) (Clinical Stage 0) o Operable, local-regional invasive carcinomas with or without associated noninvasive
carcinoma (Clinical Stage I, Stage IIA, Stage IIB, and some Stage IIIA) o Inoperable local-regional invasive carcinoma with or without associated noninvasive
carcinoma (Clinical Stage IIIB, Stage IIIC, and some Stage IIIA) o Metastatic (Clinical Stage IV) or recurrent carcinoma
• Survival Data (Based on 2001-2002 diagnoses, American Cancer Society)
Stage 5-Year Overall Survival (%)
0 93
I 88
IIA 81
IIB 74
IIIA 67
IIIB 41
IIIC 49
IV 15
• Treatment o LCIS
Surveillance Risk reduction counseling
o DCIS Lumpectomy + radiation (Category 1, but no survival advantage) Mastectomy +/- reconstruction Lumpectomy alone with observation
Consider tamoxifen for ER positive o Stage I, IIA, IIB, some IIIA
Mastectomy with axillary lymph node dissection OR breast-conserving therapy with lumpectomy, axillary dissection, and whole breast irradiation (Stages I, II)
Consider neoadjuvant therapy for large IIA, IIB and T3N1M0 tumors when patients want to undergo breast-conserving therapy (sentinel lymph node dissection should be completed before neoadjuvant therapy)
• Neoadjuvant pertuzumab and trastuzumab-based regimens should be added to chemotherapy for patients with HER2 positive tumors
Individualized endocrine therapy (if ER/PR positive), chemotherapy Node status
• 4 positive – high risk for recurrence prophylactic chest wall/regional lymph node radiation after mastectomy and chemotherapy (can be given with endocrine therapy, HER2-targeted therapy)
• 1-3 positive – controversial; radiation recommended for large (>5 cm) tumors and/or positive margins
• Node negative – radiation for large tumors and/or positive margins Adjuvant Therapy
• Data for chemotherapy not definitive over age 70 • Online decision making tool (www.adjuvantonline.com) can be used to
assess need for adjuvant therapy (endocrine, chemotherapy) • Gene expression profile (DNA microarray technology) may be used to guide
therapy; trials ongoing • Not needed for small tumors <0.5 cm with no nodal involvement • Lymph node negative, hormone receptor negative tumor > 1 cm
chemotherapy and endocrine therapy • Lymph node positive chemotherapy (and endocrine therapy if hormone
receptor positive) • Endocrine receptor positive
o Adjuvant therapy should follow chemotherapy • Postmenopausal tamoxifen for 4.5-6 years or aromatase
inhibitor(AI) for 5 years. Consider tamoxifen for an additional 5 years.
• Women with a contraindication to or who are intolerant to or decline therapy with aromatase inhibitors: tamoxifen for 5 years or consider tamoxifen for up to 10 years
o Premenopausal tamoxifen X 5 years, consider an additional 5 years of tamoxifen Patients who become postmenopausal can complete 5
years of AI therapy, then consider an additional 5 years of tamoxifen
Data is emerging regarding the role of ovarian ablation • Chemotherapy – preferred regimens all evaluated in Phase III trials (NCCN®
designates preferred vs. other based on efficacy and toxicity) o Dose-dense AC followed by sequential paclitaxel every 2 weeks o Dose-dense AC followed by weekly paclitaxel
o TC (docetaxel and cyclophosphamide) o Many “other” options
• Adjuvant trastuzumab therapy for HER2-positive disease X 1 year for tumors > 1 cm
o AC followed by paclitaxel with trastuzumab for 1 year starting with the first dose of paclitaxel
o Consider docetaxel and carboplatin (TCH) for patiients with risk factors for cardiac toxicity
o Inoperable Stage III Invasive Tumors Neoadjuvant anthracycline-based chemotherapy with or without a taxane Preoperative trastuzumab if HER2-positive Total mastectomy with axillary lymph node dissection with or without delayed
breast reconstruction OR lumpectomy and axillary dissection No matter what surgery, patients are at high risk for recurrence and therefore
should receive adjuvant radiation Completion of chemotherapy course if not all given preoperatively Endocrine therapy and/or trastuzumab as above for those with hormone receptor-
positive disease and/or HER2-positive disease, respectively o Metastatic (Stage IV) or Recurrent
Local recurrence • Previous mastectomy only salvage surgery if possible and radiation • Previous mastectomy + radiation limited duration systemic therapy • Previous breast-conserving therapy mastectomy, axillary lymph node
dissection if not done prior • Systemic therapy using the principles of adjuvant therapy
Systemic disease • Endocrine therapy preferred due to improved toxicity profile in the
palliative setting • Patients are stratified by presence of bone metastases then hormone
receptor and HER2 status • Initiate bisphosphonate or RANK ligand therapy for those with bone disease
o Monitoring includes serum calcium, phosphate, magnesium, renal function
o Use calcium and vitamin D supplementation o Bone-modifying therapies associated with osteonecrosis of the jaw
o The combination of everolimus and exemestane can be utilized in patients that have failed nonsteroidal aromatase inhibitors
o The combination of palbociclib, a novel oral cyclin-dependent kinase (CDK) inhibitor that blocks transition from the G1 to S phase of the cell cycle, can be used in combination with letrozole in 1st line therapy (not yet in NCCN® Guidelines)
o Preferred combination regimens CAF (cyclophosphamide, doxorubicin, fluorouracil) FEC (fluorouracil, epirubicin, cyclophosphamide) AC (doxorubicin, cyclophosphamide) EC (epirubicin, cyclophosphamide) CMF (cyclophosphamide, methotrexate, fluorouracil) Docetaxel and capecitabine GT (gemcitabine and paclitaxel) Gemcitabine and carboplatin Paclitaxel and bevacizumab (no OS benefit)
o Failure to achieve a tumor response with 3 sequential chemotherapy regimens or ECOG performance status ≥ 3 is an indication for supportive care
• Add HER2-targeted therapies for HER2-positive disease o Trastuzumab + pertuzumab + docetaxel in patients who are
o “Other 1st line options;” single agent trastuzumab or with chemotherapy
o Ado-trastuzumab emtansine in patients that have previously received trastuzumab (preferred)
o “Other” regimes for trastuzumab exposed patiens include pertzumab and transtuzumab (if no previous pertuzumab) +/- chemotherapy; capecitabine and lapatinib; lapatinib and letrozole
o Do not use trastuzumab in combination with AC because of high risk for cardiotoxicity (27% is considered to be too high for the palliative setting)
References and Recommended Readings Febrile Neutropenia 1. Frefield AG, Bow EJ, Sepkowitz KA et al. Clinical practice guideline for the use of antimicrobial agents
in neutropenic patients with cancer: 2010 update by the Infectious Disease Society of America. Clin Infect Dis. 2011; 52:e56-93. http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/idsaneutropenicfever2010.pdf (accessed 2015 May 19).
3. Mermel LA, Allon M, Bouza E et al. Clinical practice guidelines for the diagnosis and management of
intravascular catheter-related infection: 2009 update by the Infectious Disease Society of America. Clin Infect Dis. 2009; 49:1-45. http://www.ncbi.nlm.nih.gov/pubmed/19489710 (accessed 2012 May 31).
4. Pappas PG, Kauffman CA, Andes D et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009; 48:503-35. http://www.ncbi.nlm.nih.gov/pubmed/19191635 (accessed 2014 May 21).
5. Klastersky J, Paesmans M, Rubenstein EB et al. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000; 18:3038-51. http://www.ncbi.nlm.nih.gov/pubmed/10944139 (accessed 2014 May 21).
6. Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008; 46:327-60. http://www.uphs.upenn.edu/bugdrug/antibiotic_manual/idsa-aspergilloisrx-2008guidelines.pdf (accessed 2014 May 21).
7. Flowers CR, Seidenfeld J, Bow EJ et al. Antimicrobial prophylaxis and outpatient management of
fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013; 31:794-810. http://jco.ascopubs.org/content/31/6/794.long (accessed 2014 May 21)
Anticoagulation 1. Lee AYY, Levine MN, Baker RI et al. Low-molecular-weight heparin versus a coumarin for the
prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003; 349:146-53. http://www.nejm.org/doi/full/10.1056/NEJMoa025313 (accessed 2014 May 21).
2. Kearon C, Akl EA, Comerota AJ et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th Ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(2 suppl):419S-94S. http://www.ncbi.nlm.nih.gov/pubmed/22315268 (accessed 2014 May 21).
4. Lyman GH, Khorana AA., Kuderer NM et al. Venous thromboembolism prophylaxis and treatment in
patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013; 31:2189-204. http://jco.ascopubs.org/content/31/17/2189.long (accessed 2014 May 21).
5. Linkins LA, Dans AL, Moores LK et al. Treatment and prevention of heparin-induced
thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th Ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012; 141(2 suppl):495S-530S. http://www.ncbi.nlm.nih.gov/pubmed/22315270 (accessed 2014 May 21).
6. Lo GK, Juhl D, Warkentin TE et al. Evaluation of pretest clinical score (4T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006; 4:759-65. http://www.ncbi.nlm.nih.gov/pubmed/16634744 (accessed 2014 May 21).
Nausea and Vomiting 1. Basch E, Pestrud AA, Hesketh PJ et al. Antiemetics: American Society of Clinical Oncology clinical
practice guideline update. J Clin Oncol. 2011; 29:4189-98. http://jco.ascopubs.org/content/29/31/4189.long (accessed 2014 May 21)
2. Gralla RJ, Rolia F, Tonato M et al. MASCC/ESMO antiemetic guidelines 2013. Available
at: http://www.mascc.org/antiemetic-guidelines. 3. National Comprehensive Cancer Network. NCCN® clinical practice guidelines in oncology:
Pain Management 1. World Health Organization. Cancer pain relief: with a guide to opioid availability. 2nd ed. Geneva;
1996. Available at http://whqlibdoc.who.int/publications/9241544821.pdf
2. Portenoy RK. Treatment of cancer pain. Lancet. 2011; 377:2236-47. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60236-5/fulltext (accessed 2014 May 21).
3. Krantz MJ, Martin J, Stimmel B et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009; 150:387-95. http://www.ncbi.nlm.nih.gov/pubmed/19153406 (accessed 2014 May 21).
4. National Comprehensive Cancer Network. NCCN® clinical practice guidelines in oncology: adult
5. Portenoy RK, Ahmend E. Principles of opioid use in cancer pain. J Clin Oncol. 2014; 32: 1662-70. 6. Hui D, Bruera E. A personalized approach to assessing and managing pain in patients with cancer. .
J Clin Oncol. 2014; 32: 1640-46. 7. Hershman DL, Lacchetti C, Dworkin RH, et al. Prevention and management of chemotherapy-
induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2014; 32:1941-67.
Breast Cancer 1. National Comprehensive Cancer Network. NCCN® clinical practice guidelines in oncology: breast
2. Burnstein HJ, Temin S, Anderson H et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update.. J Clin Oncol. 2014; 32:2255-69.
3. Ellis GK, Livingston, RB, Gralow JR et al. Dose-dense anthracycline-based chemotherapy for node-positive breast cancer. J Clin Oncol. 2002; 20:3637-43. http://jco.ascopubs.org/content/20/17/3637.long (accessed 2014 May 21).
4. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005; 353:1673-84. http://www.nejm.org/doi/full/10.1056/NEJMoa052122 (accessed 2014 May 21).
5. Irvin W Jr, Muss HB, Mayer DK. Symptom management in metastatic breast cancer. Oncologist. 2011; 16:1203-14. http://www.ncbi.nlm.nih.gov/pubmed/21880861 (accessed 2014 May 21).
6. Swain SM, Basegla J, Kim SJ, et al. Pertuzumab, transtuzumab, and docetaxel in HER2 positive
metaststic breast cancer. N Engl J Med. 2015; 372: 724-34. 7. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human
epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology practice guideline. J Clin Oncol. 2014; 32: 2078-99.
8. Partridge AH, Rumble RB, Carey AL, et al. Chemotherapy and targeted therapy for women with
human epidermal growth factor receptor-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology practice guideline. J Clin Oncol. 2014; 32: 3307-29.
3. Schulmeister L. Extravasation management: clinical update. Semin Oncol Nurs. 2011; 27:82-90. http://www.ncbi.nlm.nih.gov/pubmed/21255716 (accessed 2014 May 21).
4. Senkus E, Jassem J. Cardiovascular effects of systemic cancer treatment. Cancer Treat Rev. 2011; 37:300-11. http://www.ncbi.nlm.nih.gov/pubmed/21126826 (accessed 2014 May 21).
Patient Resources 1. Jefford M, Tattersall MHN. Informing and involving cancer patients in their own care. Lancet Oncol.
2002; 3:629-37. http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(02)00877-X/abstract (accessed 2014 May 21).
Helen M. Marshall, Pharm.D., BCPS, BCOPClinical Pharmacist, Hematology/Oncology
Seattle Cancer Care Alliance ‐ University of Washington Medical Center
Clinical Assistant Professor
University of Washington School of Pharmacy
Seattle, Washington
• I have nothing to disclose related to the content of this presentation.
Disclosure
Learning Objectives
• Correctly answer case‐based questions about appropriate treatment and monitoring of a complex patient with multiple conditions, including breast cancer, febrile neutropenia, and pulmonary embolism.
• Develop a plan to manage pain and nausea/vomiting in a patient with cancer.
• Determine how to manage drug‐drug and drug‐disease interactions in a cancer patient.
Learning Objectives
• Discuss safety issues in this population.
• Identify and recommend appropriate resource organizations/groups to assist a specific patient.
Our Patient (HPI)
• GE is a 53 year old female being treated for breast cancer who presents to the ED with acute onset chest pain and shortness of breath
• GE reports that she has been vomiting for the last 24 hours and is unable to eat
Continue anticoagulation long term or until malignancy resolves
— LMWH
— Warfarin with INR 2‐3 Kearon C et. al. Chest 2012; 141(2 suppl):419S‐94S. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Venous Thromboembolic Disease
GE’s Treatment Continued• GE follows up with the anticoagulation clinic the day after her ED visit
• She receives further education
• Platelet monitoring is initiated every 3 days
• She returns to clinic for Cycle 3 of doxorubicin and cyclophosphamide
Relevant Labs ED visit
(Chemo D3)
Day 7 Day 10 Day 14
(Cycle 3 of AC)
Platelets(thou/microL)
96 89 56 33
WBC(thou/microL)
2.7 3.7
ANC(thou/microL)
0.9 1.5
SCr (mg/dL) 1.1 0.8
Heparin‐Induced Thrombocytopenia (HIT, Type II)• Antibody‐mediated adverse drug reaction
• Thrombotic complications
Pulmonary embolism
Ischemic limb necrosis requiring amputation
Acute myocardial infarction
Stroke
• If risk of HIT is > 1%, monitor platelets every 2‐3 days from Day 4‐14 (or until heparin is stopped)
• Do not start warfarin until platelets have recovered (>150 X 109/L) and use low doses initially (5 mg/day)
Linkins LA et al. Chest. 2012; 141(2 suppl):495S‐530S.
The 4T Score: An example of PreTest Probability Scoring for HIT
Category 2 Points 1 Point 0 Points
ThrombocytopeniaPlatelet count fall > 50% with nadir ≥20 X 109/L
Platelet count fall 30‐50% or nadir 10‐19 X 109/L
Platelet count fall < 30% or nadir < 10 X 109/L
Timing of Fall of PlateletCount
Onset between Days 5 –10 or platelet fall ≤ 1 day (with heparin exposure in last 30 days)
Consistent with days 5–10 fall, but unclear (e.g. missing platelet counts) or onset after day 10 or fall ≤ 1 day (prior heparin exposure 30–100 days ago)
Platelet count fall < 4 days without recent heparin exposure
Thrombosis or Sequelae
New thrombosis (confirmed) or skin necrosis at heparin injection sites or acute systemic reaction after intravenous heparin bolus
Progressive or recurrent thrombosis or nonnecrotizing (erythematous) skin lesions or suspected thrombosis (not proven)
None
Other Causes for Thrombocytopenia
None Possible Definite
The 4T Score
• Total Score
≤ 3 points = Low Probability of HIT
4‐5 points = Intermediate Probability of HIT
≥ 6 points = High Probability of HIT
Lo GK et al. J Thromb Haemost. 2006; 4:759–65.
Question 5: Which of the following are therapeutic options for anticoagulation for suspected HIT?
a. Argatroban
b. Dalteparin
c. Dabigatran
d. Clopidogrel
Direct Thrombin Inhibitors (DTIs)Name Bivalirudin Argatroban
Starting Dose 0.15 mg/kg/hr 2 mcg/kg/min
Dose Modifications
0.5‐1.2 mcg/kg/min inpts with heartfailure, multi‐organsystem failure,severe anasarca orpost‐cardiacsurgery
Dosing in Renal Impairment Reduction for CrCl < 60 ml/min None
Dosing in Hepatic Impairment NoneInitial dose for moderate impairment is 0.5 mcg/kg/min
Fondaparinux: An Outpatient Option• An outpatient option for patients with malignancy
• Labeling for DVT/PE is in conjunction with warfarin
• Fondaparinux causes inhibition of Factor Xa, and dosing is weight‐based
• Limitations:
Not studied (further study recommended in ACCP guidelines)
Long half‐life
Lacks reversal agent
• Use is restricted to patients with HIT or allergy to heparin/LMWH
Linkins LA et al. Chest. 2012; 141(2 suppl):495S‐530S.
GE’s HIT Management
• Enoxaparin immediately discontinued
• Initiated on fondaparinux 7.5 mg subcut Q 24 hours
• Continuation of fondaparinux was discussed by the oncologist, but the patient’s copay was over $1000, and she was not eligible for patient assistance (patient paid for a 7‐day supply)
• Initiated on warfarin 5 mg po daily after platelets recovered
• HIT Antibody was positive
Interval History• 7 days after Cycle 3 of AC chemotherapy, GE calls into clinic with fever 101.2°F
• She reports sweats and chills, cough, and feeling very “worn down”
• She asks to take acetaminophen, but her nurse recommends she come into clinic for evaluation
2 sets of blood cultures drawn (one from port, one peripherally), urine cultures obtained
Inc 2014. All rights reserved. Accessed [February 16, 2015].Freifeld AG et al. Clin Infect Dis. 2011; 52:e56‐93.Klastersky J et al. J Clin Oncol. 2000; 18:3038‐51.
• 15 mg/kg IV Q12 hours should be added if Risk factor for Streptococcus viridans
—Prophylaxis (fluoroquinolone or trimethoprim‐sulfamethoxazole)
—Severe mucositis
Colonization with resistant Streptococci or Staphylococci Catheter‐related infection Blood culture positive for gram‐positive bacteria Hypotension/sepsis Skin or Soft‐tissue infection Pneumonia
Freifeld AG et al. Clin Infect Dis. 2011; 52:e56‐93.Pappas PG et al. Clin Infect Dis. 2009; 48:503‐35. Walsh TJ. Clin Infect Dis. 2008; 46:327‐60.
Approach to a Port‐Related Bloodstream Infection
Mermel LA et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter‐related infection: 2009 update by the Infectious Disease Society of America. Clin Infect Dis. 2009; 49:1‐45.
Clinical infectious diseases: an official publication of the Infectious Diseases Society of America by INFECTIOUS DISEASES SOCIETY OF AMERICA . Reproduced with permission of Oxford.
Follow Up for GE
• GE completed her course of oral antibiotics without complications, no organisms were grown on culture
• Successfully completes 12 cycles of weekly paclitaxelwithout incidence
• Initiated on adjuvant anastrozole 1 mg PO daily (planfor 5 years of therapy)
• Warfarin was discontinued after 6 months ofanticoagulation
Interval History
• 2 months into therapy with anastrozole, GE returns toher oncologist complaining of severe muscle and jointpain
• The oncologist initiates her on naproxen 500 mg PO BID
• GE returns to clinic in 1 week without relief. She has notbeen working due to pain and spends 75% of her day in bed
• GE is switched to letrozole 2.5 mg po daily, without relieffrom severe arthralgias and myalgias
• She is prescribed oxycodone 5 mg orally every 4‐6 hours prn pain
Question 8: GE’s oncologist asks you for a conversion to a long‐acting opioid as GE has escalated her oxycodone use to 5 mg every 3 hours around the clock and is still reporting poor pain control with inability to return to work. Which of the following is the best regimen for GE?
*Ratio may range from 1:1 at low doses of oral morphine up to 20:1 for patients receiving high doses of oral morphine (~300mg/day)**Fentanyl transdermal systems 25mcg/hr 60mg PO morphine
Less aggressive conversion for well controlled pain
5. Follow‐up and continual reassessment
a. Fentanyl TDS 100 mcg/hr every 72 hours
b. Morphine SR 45 mg po Q 8 hours
c. Morphine SR 15 mg po Q 12 hours
d. Morphine SR 30 mg po Q 12 hours
Question 8 Revisited:GE’s oncologist asks you for a conversion to a long acting opioid as GE has escalated her oxycodone use to 5 mg every 3 hours around the clock and is still reporting poor pain control with an inability to return to work. Which of the following is the best regimen for GE?
Question 9: GE’s oncologist follows your advice and initiates the long acting pain regimen that was recommended. Which of the following is the best BTP regimen for her?
a. Morphine IR 15 mg po every 1‐2 hours
b. Morphine IR 15 mg po every 4‐6 hours
c. Morphine IR 30 mg po every 6 hours
d. Oxycodone 2.5 mg po every 6 hours
Breakthrough Pain (BTP)
• A fluctuation in pain intensity that interrupts a tolerable background pain.
• 3 types Idiopathic
Incident (predictable and unpredictable)
End‐of‐dose failure
• Characterized by Moderate to severe intensity
Rapid onset (<3 minutes)
Relatively short duration (< 1 hour)
Frequency averaging 1‐6 episodes per day
Breakthrough Pain• The Ideal BTP Medication
Rapid onset (immediate release)
Easy to titrate
Short duration
Cost effective
Minimal side effects
• PO Dose: 10‐20% of daily dose q3hr PRN, OR
• PRN dose given as immediate release product during a given interval equals the total scheduled dose of a sustained release product given in the same interval e.g., morphine SR 90mg PO Q12h = morphine IR 30mg PO q4h
Cancer‐Related Neuropathic Pain
• NCCN® Guidelines
Antidepressants and anticonvulsants are 1st line adjuvant medications
Derived from data in non‐cancer patients
• ASCO Guidelines for CIPN
No agents recommended for prevention
Moderate recommendation for treatment with duloxetine
• N=231
• 5 week treatment course: duloxetine 30 mg X 1 week then 60 mg X 4 weeks vs. placebo
• Primary outcome: average pain intensity (0‐10 scale)
Duloxetine arm: mean decrease in average pain of 1.06 (95% CI, 0.72‐1.40) vs. placebo arm: 0.34 (95% CI, 0.01‐0.66) (P = .003; effect size, 0.513)
Smith EM et al. JAMA. 2013 Apr 3;309(13):1359-67.National Comprehensive Cancer Network. NCCN® clinical practice guidelines in oncology: adult cancer pain. Version 2.2014.
• 231,840 new cases of invasive breast cancer expected in 2015
• 40,290 women expected to die from breast cancer this year
• Incidence rates decreased 7% from 2002‐2003
Women’s Health Initiative published in 2002
Decline in use of hormone replacement therapy
Incidence rates stable recently
• 2nd leading cause of cancer death in women
• 2.8 million survivors in the United States
American Cancer Society. Available at: http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-key-statistics. February 16,2015.
Individualized Drug Therapy in Breast Cancer• Menopausal Status
Potential for use of tamoxifen vs. aromatase inhibitors
Need for ovarian suppression
Fertility preservation
• Hormone Receptor Status (ER/PR)
Use of hormonal therapies
• HER2 Status
Use of trastuzumab, lapatinib, pertuzumab or ado‐trastuzumab emtansine
• Patient factors such as performance status, organ function, etc.
Hormonal Therapies
• Nonsteroidal Aromatase Inhibitors
Anastrozole
Letrozole
• Steroidal aromatase inactivator Exemestane
• Selective Estrogen Receptor Modulators
Tamoxifen
Toremifene
• Estrogen Receptor Antagonist Fulvestrant
• Others include megestrol acetate, fluoxymesterone, ethinyl estradiol
Palbociclib (Ibrance®)• Indication
In combination with letrozole
Postmenopausal patients with ER+Her2‐metastatic breast cancer (1st line therapy)
• MOA
Inhibits cyclin‐dependent kinase (CDK) 4 & 6
Deceases cell proliferation by blocking cell progression from G1 to S phase
• Dose: 125 mg po daily Days 1‐21 Q 28 days
• Median PFS 20.2 months (95% CI 13.8‐27.5) vs 10.2 months (95% CI5.7‐12.6) with letrozole alone, HR 0.488 (95% CI 0.319‐0.784) Finn RS et al. Lancet Oncol. 2015; 16: 25-35.
Active Antineoplastic Agents in Breast Cancer
Class Agents
Anthracyclines
Doxorubicin
Epirubicin
Liposomal doxorubicin
Taxanes
Paclitaxel
Docetaxel
Albumin‐bound paclitaxel
AntimetabolitesGemcitabine
Capecitabine
Other Microtubule InhibitorsVinorelbine
Eribulin
Other Active AgentsCyclophosphamide, mitoxantrone, cisplatin, carboplatin, etoposide, vinblastine, fluorouracil, ixabepilone
HER2 Targeted Therapy
• Trastuzumab Adjuvant Setting
—as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and a taxane
—with docetaxel and carboplatin
—single agent following multi‐modality anthracycline‐based therapy
Metastatic Setting—In combination with paclitaxel for 1st line treatment
—As a single agent for patients who have received one or more chemotherapy regimens for metastatic disease
With capecitabine, for the treatment of patients who have received prior therapy including an anthracycline, a taxane, and trastuzumab
With letrozole
• Pertuzumab
In combination with trastuzumab and docetaxel for patients with metastatic breast cancer who are treatment‐naïve
Neoadjuvant therapy (with trastuzumab and docetaxel) for early breast cancer
• Ado‐trastuzumab emtansine
As a single agent, for the treatment of patients who previously received trastuzumab and a taxane (separately or in combination)
CLEOPATRA
• Trastuzumab and docetaxel +/‐ pertuzumab in HER2+ metastatic breast cancer with no prior treatment
• Median overall survival was 56.5 months (95% CI, 49.3 to not reached) in the pertuzumab arm, compared with 40.8 months (95% CI, 35.8 to 48.3) in the placebo arm (HR favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001)
• 15.7 months difference
Swain SM, et al. N Engl J Med. 2015; 372:724-34.
Question 11: Which of these therapies is a possible treatment options for GE if her cancer returns (metastatic to the bone) during treatment with tamoxifen?
a. Exemestane with everolimus
b. Ado‐trastuzumabemtansine
c. Pertuzumab, trastuzumaband paclitaxel
d. Tamoxifen (complete 5 years)
Follow‐up Therapy for Endocrine Treatment of Recurrent or Stage IV Disease
• Continue endocrine therapy until progression or unacceptable toxicity
• If no clinical benefit after 3 sequential endocrine regimens OR
Consider influence of active cancer and chemotherapy on bleeding risk
• Extravasation
GE’s need for a central venous catheter
• Cardiotoxicity
Anthracycline
Endocrine Therapy Medication Adherence
• Data evaluating adherence are variable
Methods
Definitions
Endpoints
Duration of follow up
• Some studies show up to 50% discontinuation rates of endocrine therapies prior to completion of recommended course
• Discontinuation is linked to increased mortalityHershman DL et al. Breast Cancer Res Treat. 2011; 126: 529‐37.
McCowan C et al. Br J Cancer. 2008; 99:1763‐8.Dezentje VO et al. J Clin Oncol. 2010; 28(14):2423‐9.Hershman DL et al. J Clin Oncol. 2010; 28(27):4120‐8.
Mermel LA et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter‐related infection: 2009 update by the Infectious Disease Society of America. Clin Infect Dis. 2009; 49:1‐45.
Clinical infectious diseases: an official publication of the Infectious Diseases Society of America by INFECTIOUS DISEASES SOCIETY OF AMERICA . Reproduced with permission of Oxford.