2016 Pharmacotherapy Specialty Examination Review Course...
Transcript of 2016 Pharmacotherapy Specialty Examination Review Course...
2016 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:
Select the appropriate treatment and monitoring of a complex patient with multiple conditions,
including breast cancer, febrile neutropenia, and pulmonary embolism.
Compare and contrast current breast cancer screening recommendations.
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 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 450‐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.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 1
PATIENT CASE Date: March 1, 2016
Initials LK DOB/Age
54
Sex
F
Race/Ethnicity
Chinese
Source
Patient and medical
records
Chief Complaint/History of Present Illness:
“My husband felt a lump in my right breast.”
The patient presents to a multidisciplinary breast cancer clinic at your comprehensive cancer center
to establish a treatment plan for her newly diagnosed right breast cancer.
Past Medical History
None
From Medical Record
Breast Cancer, Stage IIB
• Diagnosed March 2016 in her right breast
• Stage IIB (T2 N1 M0)
• ER and PR positive
• HER2 negative
• Postmenopausal (menopause at age 51)
Breast Cancer Treatment
• 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
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 2
Current Prescription/OTC Medications
Start Date Drug Name/Strength/Regimen Indication
6/2016 Ondansetron 8 mg orally every 8 hr prn Nausea/vomiting
6/2016 Prochlorperazine 10 mg orally every 6 hr
prn
Nausea/vomiting
6/2016 Lorazepam 0.5‐1 mg orally every 6 hr prn Nausea/vomiting; anxiety
6/2016 Palonosetron 0.25 mg IV and
dexamethasone 10 mg IV every 2 weeks
pre‐chemotherapy
Prevention of nausea and
vomiting
6/2016 Doxorubicin 60 mg/m2 IV and
cyclophosphamide 60 mg/m2 IV every 2
weeks
Adjuvant breast cancer
treatment
Vaccinations: Influenza vaccine fall 2015 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; Mother 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: None
Smoking: 1 pack per day from age 18 to 30 EtOH: None
Illicit Drugs: None Language: Mandarin speaking,
minimal English
Education: high school in China Family/Social Environment: Lives with
husband; 2 daughters, one in college,
and one in graduate school for
electrical engineering
Review of Systems: Per HPI /PE
Height 167 cm, Weight 78 kg, BSA 1.9 m2
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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Presentation Questions
1. Should LK have previously undergone screening with mammography prior to her diagnosis?
a. Yes, annually starting at age 20
b. Yes, due to her family history
c. No, because LK is under age 55
d. No, due to her family history
2. Which of the following should be monitored for our patient on this chemotherapy regimen?
a. CBC, liver function tests, renal function, and neurologic function
b. CBC, liver function tests, renal function, and signs and symptoms of hemorrhagic cystitis
c. CBC, liver function tests, and cardiac function
d. CBC, liver function tests, and signs and symptoms tumor lysis syndrome
3. What is the appropriate antiemetic regimen for LK 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
4. Which of the following should be initiated as empiric therapy for febrile neutropenia in LK?
a. Ciprofloxacin 500 mg IV every 8 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. Imipenem 500 mg IV every 6 hours
5. What factors for LK should be considered when deciding if vancomycin should be added to LK’s
regimen?
a. All FN patients should receive vancomycin
b. Presence of a central venous catheter
c. Prior ciprofloxacin prophylaxis
d. Reported symptom of cough
6. Which of the following is the best choice for empiric antifungal coverage for LK?
a. Micafungin 50 mg IV once daily
b. Micafungin 100 mg IV once daily
c. Fluconazole 200 mg IV once daily
d. Voriconazole 6 mg/kg IV every 12 hours
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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7. Which of the following is a risk factor for venous thromboembolism (VTE) in LK?
a. Metastatic Breast Cancer
b. Nausea and vomiting
c. Presence of a Central Venous Catheter
d. Depression
8. Which of the following therapies should be initiated in LK 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
9. LK’s oncologist asks you for a conversion to a long‐acting opioid as LK has escalated her
hydrocodone use and is still reporting poor pain control with inability to sleep. Which of the
following is the best regimen for LK?
a. Fentanyl TDS 100 mcg/hr every 72 hr
b. Morphine SR 15 mg po every 8 hr
c. Morphine SR 15 mg po every 12 hr
d. Morphine SR 30 mg po every 12 hr
10. LK’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 hr
b. Morphine IR 15 mg po every 4‐6 hr
c. Morphine IR 30 mg po every 6 hr
d. Oxycodone 2.5 mg po every 6 hr
11. Which of these therapies is a possible treatment option for LK?
a. Palbociclib and fulvestrant
b. Ado‐trastuzumab emtansine
c. Pertuzumab, trastuzumab, and paclitaxel
d. Palbociclib and docetaxel
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 5
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.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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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.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 7
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 patients 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).
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 8
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, apixaban
and edoxaban in oncology patients. In 2016, the American College of Chest Physicians provided a
guideline update on antithrombotic therapy for venous thromboembolism disease that suggests low
molecular weight heparin (LMWH) over these newer agents for long‐term treatment (first 3 months)
of cancer‐associated thrombosis, with an evidence level of 2C.
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.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 9
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
Advanced age
o Treatment‐related risk factors
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.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 10
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
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 11
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
Two newer oral agents approved for highly and moderately emetogenic chemotherapy
regimens include rolapitant 180 mg (NK1 antagonist) and netupitant 300 mg/palonosetron
0.5mg (combination NK1 antagonist and 5HT3 antagonist).
Highly emetogenic intravenous agents are listed in the slide set
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 12
Moderately Emetogenic Agents
MASCC NCCN® ASCO
Intravenous
Agents
Oxaliplatin
Cytarabine > 1000 mg/m2
Carboplatin
Ifosfamide
Cyclophosphamide <
1500 mg/m2
Azacitidine
Alemtuzumab
Doxorubicin
Daunorubicin
Epirubicin
Idarubicin
Irinotecan
Bendamustine
Clofarabine
Aldesleukin > 12‐15
million IU/m2
Amifostine >300 mg/m2
Arsenic trioxide
Azacitidine
Bendamustine
Busulfan
Carboplatin
Carmustine ≤ 250mg/m2
Clofarabine
Cyclophosphamide ≤
1500 mg/m2
Cytarabine > 200 mg/m2
Dactinomycin
Daunorubicin
Doxorubicin < 60 mg/m2
Epirubicin ≤ 90mg/m2
Idarubicin
Ifosfamide < 2000
mg/m2/dose
Interferon alfa > 10
million IU/m2
Irinotecan
Melphalan
Methotrexate ≥ 250
mg/m2
Oxaliplatin
Temozolomide
Azacitidine
Alemtuzumab
Bendamustine
Carboplatin
Clofarabine
Cyclophosphamide <
1500 mg/m2
Cytarabine > 1000 mg/m2
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Ifosfamide
Irinotecan
Oxaliplatin
Oral Agents Cyclophosphamide
Temozolomide
Vinorelbine
Imatinib
Moderate to High:
Altretamine
Busulfan (≥ 4 mg/day)
Crizotinib
Cyclophosphamide (≥100
mg/m2/day)
Estramustine
Etoposide
Lomustine (single day)
Mitotane
Procarbazine
Temozolomide (≥75
mg/m2/day)
Vismodegib
Ceritinib
Lenvatinib
Olaparib
Panobinostat
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 13
Low Emetogenicity Agents
MASCC NCCN® ASCO
Intravenous Agents Paclitaxel
Docetaxel
Mitoxantrone
Topotecan
Etoposide
Pemetrexed
Methotrexate
Doxorubicin HCl
liposome injection
Temsirolimus
Ixabepilone
Mitomycin
Gemcitabine
Cytarabine < 1000 mg/m2
5‐fluorouracil
Bortezomib
Cetuximab
Trastuzumab
Catumaxomab
Panitumumab
Temsirolimus
Ado‐trastuzumab
emtansine
Amifostine ≤ 300mg/m2
Aldesleukin ≤ 12 million
IU/m2
Brentuximab
Cabazitaxel
Carfilzomib
Cytarabine (low dose)
100‐200 mg/m2
Docetaxel
Doxorubicin (liposomal)
Eribulin
Etoposide
5‐fluorouracil
Floxuridine
Gemcitabine
Interferon alfa >5 <10
million international
units/m2
Methotrexate >50 mg/m2
<250 mg/m2
Mitomycin
Mitoxantrone
Omacetaxine
Paclitaxel
Paclitaxel‐albumin
Pemtrexed
Pentostatin
Pralatrexate
Romidepsin
Thiotepa
Topotecan
Ziv‐aflibercept
Belinostat
Blinatumomab
5‐fluorouracil
Bortezomib
Cabazitaxel
Catumaxomab
Cytarabine ≤ 1000 mg/m2
Docetaxel
Doxorubicin (liposomal)
Etoposide
Gemcitabine
Ixabepilone
Methotrexate
Mitomycin
Mitoxantrone
Paclitaxel
Panitumumab
Pemetrexed
Temsirolimus
Topotecan
Trastuzumab
Oral Agents Capecitabine
Tegafur‐uracil
Etoposide
Sunitinib
Fludarabine
Everolimus
Lapatinib
Low to Minimal:
Axitinib
Bexarotene
Bosunitinib
Busulfan (<4 mg/day)
Cabozantinib
Capecitabine
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 14
Lenalidomide
Thalidomide
Chlorambucil
Cyclophosphamide (<100
mg/m2/day)
Dasatinib
Dabrafenib
Erlotinib
Everolimus
Fludarabine
Gefitinib
Hydroxyurea
Imatinib
Lapatinib
Lenalidomide
Melphalan
Mercaptopurine
Methotrexate
Nilotinib
Pazopanib
Pomalidomide
Potaninib
Regorafenib
Ruxolitinib
Sorafenib
Sunitinib
Temozolomide (≤75
mg/m2/day)
Thalidomide
Thioguanine
Topotecan
Trametanib
Tretinoin
Vandetanib
Vemurafenib
Vorinostat
Afatinib
Ibrutinib
Idelalisib
Palbociclib
Breakthrough nausea and vomiting
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
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 15
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):
24‐hr Oral Morphine Dose (mg) Fentanyl TDS dose (mcg/hr)
60‐134 25
135‐224 50
225‐314 75
315‐404 100
405‐494 125
495‐584 150
585‐674 175
675‐764 200
765‐854 225
855‐944 250
945‐1034 275
1035‐1124 300
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 16
Fentanyl TDS Pearls
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
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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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
Nulliparity
Lack of breast feeding
Oral contraceptives
Hormone‐replacement therapy
o Alcohol use
o Obesity
o Lack of physical activity
Guidelines on breast cancer screening in average risk women have recently been updated, but there
is no clear consensus on the age for initiation of screening or the screening frequency
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
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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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)
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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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
Lymph node negative, hormone receptor positive 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 or aromatase inhibitor
for an additional 5 years (up to 10 years of therapy). 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 aromatase inhibitor plus ovarian ablation or
suppression or tamoxifen +/‐ ovarian ablation or suppression X 5
years, consider an additional 5 years of tamoxifen or aromatase
inhibitor (if initially treated with tamoxifen)
Patients who become postmenopausal can complete 5
years of AI therapy, then consider an additional 5 years of
tamoxifen
Chemotherapy – preferred regimens all evaluated in Phase III trials (NCCN®
designates preferred vs. other based on efficacy and toxicity)
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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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 (+/‐ pertuzumab)
o AC followed by paclitaxel with trastuzumab for 1 year starting with
the first dose of paclitaxel
o Consider docetaxel and carboplatin (TCH) for patients 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 +/‐ pertuzumab 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
(ONJ)
Postmenopausal endocrine therapy options: anastrozole, letrozole,
exemestane, tamoxifen, toremifene, fulvestrant, megestrol acetate,
fluoxymesterone, ethinyl estradiol
o The combination of everolimus and exemestane can be utilized in
patients that have failed nonsteroidal aromatase inhibitors
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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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 or with fulvestrant after progression on another endocrine
therapy
Premenopausal patients should receive ovarian suppression or ablation and
follow postmenopausal options for treatment
Chemotherapy
o For hormone receptor negative tumors not localized to bone,
symptomatic visceral metastases, refractory to endocrine therapy
o NCCN® preferred single agents
Anthracyclines – doxorubicin, liposomal doxorubicin
Taxanes – paclitaxel, docetaxel, albumin‐bound paclitaxel
Antimetabolites – capecitabine, gemcitabine
Non‐taxane microtubule inhibitors – vinorelbine, eribulin
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
treatment naïve (preferred, Category 1) (with paclitaxel, Category
2A)
o “Other 1st line options;” trastuzumab with nonanthracycline
chemotherapy
o Ado‐trastuzumab emtansine in patients that have previously
received trastuzumab (preferred)
o “Other” regimes for trastuzumab exposed patients include
pertuzumab and trastuzumab (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)
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 22
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).
2. National Comprehensive Cancer Network. NCCN® clinical practice guidelines in oncology: prevention
and treatment of cancer‐related infections. Version 2.2015. Available at:
http://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Referenced with permission
from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prevention and
Treatment of Cancer‐Related Infections V.2.2015 © National Comprehensive Cancer Network, Inc
2015. All rights reserved. Accessed [November 1, 2015].
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)
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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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).
3. National Comprehensive Cancer Network. NCCN® clinical practice guidelines in oncology: venous
thromboembolic disease. Version 1.2015. Available at:
http://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Referenced with permission from
the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Venous Thromboembolic
Disease V.1.2015 © National Comprehensive Cancer Network, Inc 2014. All rights reserved.
Accessed [November 1 2015].
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. Lee AYY, Kamphuisen PW, Meyer G et al. Tinzaparin vs warfarin for treatment of acute venous
thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015; 314:677‐
86. http://jama.jamanetwork.com/article.aspx?articleid=2428955&resultClick=3 (accessed 2016
February 21).
6. Kearon C, Akl EA, Ornelas J et al. Antithrombotic therapy for VTE disease: CHEST guideline and
expert panel report. Chest. 2016; 149: 315‐52.
http://journal.publications.chestnet.org/article.aspx?articleid=2479255 (accessed 2016 February
21).
Nausea and Vomiting
1. Hesketh PJ, Bohlke K, Lyman GH et al. Antiemetics: American Society of Clinical Oncology focused
guideline update. J Clin Oncol. 2016; 34:381‐86.
http://jco.ascopubs.org/content/early/2015/10/26/JCO.2015.64.3635.full (accessed 2016 Feb 8)
2. Gralla RJ, Rolia F, Tonato M et al. MASCC/ESMO antiemetic guidelines 2013. Available at:
http://www.mascc.org/antiemetic‐guidelines.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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3. National Comprehensive Cancer Network. NCCN® clinical practice guidelines in oncology:
antiemesis. Version 2.2015. Available at:
http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Referenced with permission
from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2015
© National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed [February 8,
2016].
4. Hesketh PJ. Chemotherapy induced nausea and vomiting. N Engl J Med. 2008; 358:2482‐94.
http://www.motilitysociety.org/clinician/manuscripts/drugNV_nejm.pdf (accessed 2014 May 21)
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
cancer pain. Version 2.2015. Available at:
http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf. Referenced with permission from
the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Adult Cancer Pain
V.2.2015 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed
[November 1, 2015].
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.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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Breast Cancer
1. National Comprehensive Cancer Network. NCCN® clinical practice guidelines in oncology: breast
cancer. Version 1.2016. Available at:
http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Referenced with permission from
the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2016 ©
National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed [February 28,
2016].
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, trastuzumab, and docetaxel in HER2 positive
metastatic breast cancer. N Engl J Med. 2015; 372: 724‐34.
7. Turner NC, Ro J, Andre F, et al. Palbociclib in hormone‐receptor‐positive advanced breast cancer. N
Engl J Med. 2015; 373:209‐19.
8. 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.
9. 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.
10. Oeffinger KC, Fontham ETH, Etzioni R et al. Breast cancer screening for women at average risk: 2015
guideline update from the American Cancer Society. JAMA. 2015; 314: 1599‐1614.
11. Siu AL, US Preventive Services Task Force. Screening for breast cancer: US Preventive Services Task
Force recommendation statement. Ann Intern Med. 2016; 164: 279‐96.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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12. National Comprehensive Cancer Network. NCCN® clinical practice guidelines in oncology: breast
cancer screening and diagnosis. Version 1.2015. Available at:
http://www.nccn.org/professionals/physician_gls/pdf/breast‐screening.pdf. Referenced with
permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast
Cancer Screening and Diagnosis V.1.2015 © National Comprehensive Cancer Network, Inc 2015. All
rights reserved. Accessed [February 21, 2016].
Safety in Cancer Patients
1. Verma S, Madarnas Y, Shedev S et al. Patient adherence to aromatase inhibitor treatment in the
adjuvant setting. Current Oncology. 2011; 18(Suppl 1):S3‐9.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119895/ (accessed 2014 May 21)
2. Holbrook AM, Pereira JA, Labiris R et al. Systemic overview of warfarin and its drug and food
interactions. Arch Intern Med. 2005; 165:1095‐106.
http://www.ncbi.nlm.nih.gov/pubmed/15911722 (accessed 2014 May 21).
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).
2. NCCN® Guidelines for Patients (http://www.nccn.org/patients/default.asp). Referenced with
permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Patients
© National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed [February 28,
2016].
3. ASCO Website for Patients (http://www.cancer.net)
4. American Cancer Society (http://www.cancer.org/)
5. LIVESTRONG Foundation (http://www.livestrong.org/)
6. Clinical Trials (www.clinicaltrials.gov)
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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Complex Breast Cancer Case
Helen M. Marshall, Pharm.D., BCPS, BCOPClinical Pharmacist, Hematopoietic Stem Cell Transplant
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
• Select the appropriate treatment and monitoring of a complex patient‐case with multiple conditions, including breast cancer, febrile neutropenia, and pulmonary embolism.
• Compare and contrast current breast cancer screening recommendations.
• Develop a plan to manage pain and nausea/vomiting in a patient with cancer.
Learning Objectives
• Determine how to manage drug‐drug and drug‐disease interactions in a cancer patient.
• Discuss safety issues in this population.
• Identify and recommend appropriate resource organizations/groups to assist a specific patient.
Our Patient (HPI)• LK is a 54 year old female who presents to a multidisciplinary breast cancer clinic at your comprehensive cancer center to establish a treatment plan for her newly diagnosed right breast cancer
• Right breast lump discovered by LK’s husband
• Work up revealed localized breast cancer
• LK reports no associated symptoms
• LK has no primary care physician and reports no previous health conditions
She has not had a menstrual cycle in the last 3 years
LK Continued
• FH: Father: MI s/p CABG X 2 at age 55; Mother has a history of stage I breast cancer s/p mastectomy with reconstruction and no recurrence; Brother has MS
• SH: Lives at home with husband, 2 daughters in college; completed high school in China; speaks Mandarin; former smoker (1 pack per day from age 18‐30), no alcohol use
• NKDA
• Height 167 cm, Weight 78 kg, BSA 1.9
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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LK Continued
• Breast Cancer, Stage IIB
Diagnosed March 2016 in her right breast
Stage IIB (T2 N1 M0)
ER and PR positive
HER2 negative
Postmenopausal (menopause at age 51)
Question 1: Should LK have previously undergone screening with mammography prior to her diagnosis?
A. Yes, annually starting at age 20
B. Yes, due to her family history
C. No, because LK is under age 55
D. No, due to her family history
Breast Cancer Screening with Mammography• BENEFITS
Decrease in breast cancer mortality
—For women age 40‐74, screening is associated with a 15‐20% relative risk reduction in mortality
—Based on 25 year follow up of the Canadian National Breast Cancer Screening Study (RCT), there is uncertainty about the magnitude of benefit (2014)
• RISKS
Overdiagnosis and resulting treatment of insignificant cancers
False positives with additional testing and anxiety
False negatives with a false sense of security and potential delay in diagnosis
Radiation‐induced breast cancer Nelson HD, et al. Ann Intern Med. 2009;151:727‐37.Miller AB, et al. BMJ. 2014;348:g366.
National Cancer Institute PDQ® Breast Cancer Screening. Bethesda, MD: National Cancer Institute. Date last modified 01/08/2016. Available at: http://www.cancer.gov/types/breast/hp/breast‐screening‐pdq. Accessed 01/31/2016.
American Cancer Society (ACS) Key Recommendations for Women at Average Risk• Regular screening mammography starting at age 45 years (strong)
• Women aged 45 to 54 years should be screened annually (qualified)
• Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified)
• Women should have the opportunity to begin annual screening between the ages of 40 and 44 years (qualified)
• Continue screening mammography as long as overall health is good and they have a life expectancy of 10 years or longer (qualified)
• ACS does not recommend clinical breast examination for screening at any age (qualified)
• Last update 2003
Oeffinger KC et al. JAMA. 2015; 314:1599‐1614.
US Preventive Services Task Force (USPSTF) Recommendation (for Average Risk Women)• Biennial screening mammography for women aged 50 to 74 years (B recommendation)
• The decision to start screening mammography in women prior to age 50 years should be an individual one. Women who place a higher value on the potential benefit than the potential harms may choose to begin biennial screening between the ages of 40 and 49 years (C recommendation)
• Current evidence is insufficient to assess the balance of benefits and harms of screening mammography in women aged 75 years or older (I statement)
• Last update 2009
Siu AL. Ann Intern Med. 2016; 164:279‐96.
National Comprehensive Cancer Network (NCCN) Guidelines® Breast Cancer Screening and Diagnosis (Average Risk Women)
• Age ≥ 40 years
Annual clinical breast exam
Annual screening mammogram (Category 1)
Breast awareness
• Age ≥ 25 but < 40 years
Clinical breast exam every 1 to 3 years
Breast awareness
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer Screening and Diagnosis V.1.2015 © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed [February 21, 2016].
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 29
LK ‐ Planned Breast Cancer Treatment
• Surgery
Mastectomy with axillary lymph node dissection
4 positive lymph nodes
• Radiation
Chest wall and regional lymph nodes
Planned Breast Cancer Treatment• 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
• Prevention of nausea and vomiting
Palonosetron 0.25 mg IV pre‐chemotherapy day 1
Dexamethasone 10 mg IV pre‐chemotherapy day 1
Question 2: Which of the following should be monitored for our patient on this chemotherapy regimen?
A. CBC, liver function tests, renal function, and neurologic function
B. CBC, liver function tests, renal function, and signs and symptoms of hemorrhagic cystitis
C. CBC, liver function tests, and cardiac function
D. CBC, liver function tests, and signs and symptoms tumor lysis syndrome
Evaluating and Monitoring Chemotherapy
• Patient
• Regimen
• Organ function
• Numbers
• Toxicity
Adverse effects
Supportive care
• Drug‐drug interactions
Question 3: What is the appropriate antiemetic regimen for LK 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
Chemotherapy Induced Nausea and Vomiting (CINV)• Acute Emesis within the first 24 hours after treatment
• Delayed Emesis occurring at least 24 hours after treatment
• Neurotransmitters dopamine, 5‐HT, and substance P play a role in CINV
• Prevention and treatment governed by multiple sets of guidelines MASCC ASCO NCCN®
Hesketh PJ. N Engl J Med. 2008; 358:2482‐94.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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CINV Risk Factors
• Young age
• Female sex
• Expectation of severe nausea
• Chemotherapy
Dose
Emetogenicity
• History of alcohol consumption (inverse)
Hesketh PJ. N Engl J Med. 2008; 358:2482‐94.
Highly Emetogenic Chemotherapy Agents
MASCC NCCN® ASCO
AGENTS CisplatinMechlorethamineStreptozocinCyclophosphamide > 1500 mg/m2
CarmustineDacarbazine
AC (doxorubicin or epirubicin with cyclophosphamide)Carmustine > 250 mg/m2
CisplatinCyclophosphamide > 1500 mg/m2DacarbazineDoxorubicin ≥ 60mg/m2
Epirubicin . 90 mg/m2
Ifosfamide ≥ 2 g/m2/doseMechlorethamineStreptozocin
CarmustineCisplatinCyclophosphamide ≥ 1500mg/m2
DacarbazineDactinomycinMechlorethamineStreptozocin
Specifics on the AC Regimen
Lists Anthracycline + Cyclophosphamide as its own category and is considered a highly emetogenic regimen
See above Asterisks anthracyclines (moderate level) and states highly emetogenic when combined with cyclophosphamide
Highly Emetogenic is defined as likely to cause N/V in >90% of patients
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2015 © National Comprehensive Cancer Network, Inc. 2015. All rights reserved. Accessed [November 1, 2015].
Basch E et al. J Clin Oncol. 2011; 29:4189‐98.Gralla RJ et al. MASCC/ESMO Antiemetic Guidelines. 2013.
Prevention of CINV (Highly Emetogenic)
MASCC NCCN® ASCO
Day 1 of Chemo
NK1 Antagonist Fosaprepitant 150 mg IVAprepitant 125 mg PO
Fosaprepitant 150 mg IV*Aprepitant 125 mg PONetupitant 300mg/Palonosetron 0.5mg PORolapitant 180 mg PO**
Fosaprepitant 150 mg IVAprepitant 125 mg PONetupitant 300mg/Palonosetron 0.5mg PO
5HT3 Antagonist See next slide Palonosetron 0.25mg IV (preferred) See next slidePalonosetron preferred
Corticosteroid Dexamethasone 12 mg IV/PO
Dexamethasone 12 mg IV/PODexamethasone 20 mg IV/PO**
Dexamethasone 12 mg IV/PO
Subsequent Days
NK1 Antagonist Aprepitant 80 mg Days 2 and 3
Aprepitant 80 mg Days 2 and 3 Aprepitant 80 mg Days 2 and 3
Corticosteroid Dexamethasone 8 mg PO daily for 3‐4 days
Dexamethasone 8 mg PO Day 2 then 8 mg po BID Days 3‐4*Dexamethasone 8 mg IV/PO Days 2‐4
Dexamethasone 8 mg IV/PO Days 2‐3 or 2‐4
Additional Recommendations
+/‐ 0.5‐2 mg lorazepam Q 6 hours+/‐ H2 blocker or PPI
Notes Olanzapine based regimen also available
5HT3 Antagonist Options• In all three guidelines
• Dolasetron 100 mg PO ONLY (QT prolongation)
• Palonosetron 0.25 mg IV
• Granisetron 0.01mg/kg IV (1mg), 2 mg PO
• In ASCO and MASCC
• Palonosetron 0.5 mg PO
• Ondansetron 8 mg IV or 0.15mg/kg IV
• In NCCN®
• Ondansetron 16‐24 mg PO or 8‐16 mg IV
• Granisetron 1 mg po BID or transdermal patch 3.1mg/24 hour applied 24‐48 hours pre chemo, max 7 days
• In ASCO
• Ondansetron 8 mg PO BID
• In MASCC• Ondanseton 16 mg PO (8 mg po BID in randomized studies)
Breakthrough N/V Management• Limited prospective data
• Lack of consensus despite guidelines
• Treatment is largely empiric
• Agents frequently used Benzodiazepines
Phenothiazines
• Consider changing original preventative regimen
• NCCN® states the principle is to add an additional agent from a different drug class to the current regimen
Hesketh PJ. N Engl J Med. 2008; 358:2482‐94. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2015 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed [February 8,
2016].
Additional Agents for Breakthrough N/V• Phenothiazines
Prochlorperazine* 10 mg PO every 6 hours
Promethazine* 12.5‐25 mg PO (IV if central line only) every 4 hours
• Others
Haloperidol* 0.5‐2 mg PO/IV every 4‐6 hours
Metoclopramide* 10‐40 mg PO/IV every 4 to 6 hours
Scopolamine transdermal patch every 72 hours
• Atypical Antipsychotics
Olanzapine 10 mg po daily X 3 days
• Benzodiazepine
Lorazepam 0.5 – 2 mg PO/IV every 4‐6 hours
• Cannabinoid
Dronabinol 5‐10 mg PO every 3 or 6 hours
Nabilone 1‐2 mg PO BID
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2015 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed
[February 8, 2016].
* Monitor for dystonic reactions; treat with diphenhydramine
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 31
LK’s Medications
• Chemo and premedication
• Ondansetron 8 mg po every 8 hours prn nausea and vomiting (N/V)
• Prochlorperazine 10 mg po every 6 hours prn N/V
• Lorazepam 0.5‐1 mg po every 6 hours prn N/V, anxiety
Interval History• 7 days after Cycle 3 of AC chemotherapy, LK calls into clinic with fever 101.2°F
• She reports sweats and chills, cough, and feeling poorly
• 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
Labs
—BMP: 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;LFTs WNL
—CBC: WBC 0.9 thou/microL, Hgb 10.8 g/dL, Hct 27%, Plts 79 thou/microL, ANC 0.38 thou/microL
Vitals: RR 23, BP 87/62, HR 122, Temp 101.4°F
Question 4: Which of the following should be initiated for empiric therapy for febrile neutropenia for LK?
A. Ciprofloxacin 500 mg IV every 8 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/clavulanate500 mg PO every 8 hours
D. Imipenem 500 mg IV every 6 hours
Febrile Neutropenia (FN)• Definition
ANC <0.5 X 109/L or an ANC that is expected to decrease to <0.5 X 109/L during the next 48 hours and
A single oral temperature >101°F (38.3°C) or >100.4° F (>38°C) for at least 1 hour
• Common source of cancer‐related morbidity and mortality
• Fever is only reliable indicator of infection Beware of masking fever with acetaminophen (APAP)/NSAIDs
• Primary sites of infection GI tract Lungs, sinuses Skin
Freifeld AG et al. Clin Infect Dis. 2011; 52:ee56‐93. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN
Guidelines®) for Prevention and Treatment of Cancer‐Related Infections V.2.2015 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed [November 1, 2015 ].
Risk Factors for FN
• Age
• Performance status
• Chemotherapy dose intensity
• Nutritional status
• Low baseline blood counts
Lyman GH et al. Oncologist. 2005; 10:427‐37.
Treatment of FN
• Immediate
• Utilize bactericidal agents
• Design guidelines based on your antibiogram and antimicrobial cost
• Utilize the MASCC, IDSA, and NCCN® guidelines to guide therapy
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prevention and Treatment of Cancer‐Related Infections V.2.2015© National Comprehensive Cancer Network, Inc
2015. All rights reserved. Accessed [November 1, 2015].Freifeld AG et al. Clin Infect Dis. 2011; 52:e56‐93.Klastersky J et al. J Clin Oncol. 2000; 18:3038‐51.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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Guideline Comparison: FN Risk Stratification MASCC Scoring Index Characteristic Score NCCN® Low Risk
Extent of Illness No Symptoms 5
Mild Symptoms 5
Moderate Symptoms 3
SBP ≥ 90 mm Hg 5
No COPD 4 No acute comorbid illness
Score ≥ 21 indicates low risk
Solid tumor (or heme malignancy w/o previous fungal infection)
4Anticipated short duration of neutropenia (<0.1 X109/L < 7 days)
No dehydration 3 No hepatic or renal insufficiency
Outpatient at fever onset 3 Outpatient at fever onset
Age < 60 yr 2 ECOG Performance Status 0‐1
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prevention and Treatment of Cancer‐Related Infections V.2.2015 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed [November 1, 2015].
Klastersky J et al. J Clin Oncol. 2000; 18:3038‐51. Freifeld AG et al. Clin Infect Dis. 2011; 52:e56‐93.
Guideline Comparison: FN Risk Stratification MASCC Scoring Index Characteristic Score NCCN® Low Risk
Extent of Illness No Symptoms 5
Mild Symptoms 5
Moderate Symptoms 3
SBP ≥ 90 mm Hg 5
No COPD 4 No acute comorbid illness
Score ≥ 21 indicates low risk
Solid tumor (or heme malignancy w/o previous fungal infection)
4Anticipated short duration of neutropenia (<0.1 X109/L < 7 days)
No dehydration 3 No hepatic or renal insufficiency
Outpatient at fever onset 3 Outpatient at fever onset
Age < 60 yr 2 ECOG Performance Status 0‐1
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prevention and Treatment of Cancer‐Related Infections V.2.2015 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed [November 1, 2015].
Klastersky J et al. J Clin Oncol. 2000; 18:3038‐51. Freifeld AG et al. Clin Infect Dis. 2011; 52:e56‐93.
ASCO Guidelines: Antimicrobial Prophylaxis & Outpatient Management of Fever and Neutropenia
PROPHYLAXIS OUTPATIENT FN• Only use antibacterial and antifungal
prophylaxis if neutrophils are expected to remain <100/µL for > 7 days (unless other factors increase risk for complications/mortality)
Oral fluoroquinolone
Oral triazole
• Interventions such as neutropenic diet, surgical/respiratory masks, supplements are not recommended (no data)
• Assess risk for medical complications in patients with FN
MASCC score (≥21)
Talcott’s rules (Talcott group 4)
No additional risk factors
• Oral fluoroquinolone plus amoxicillin/clavulanate (clindamycin for PCN allergic)
Unless FQ prophylaxis used prior to fever development
Give within 1 hour of triage
• Monitor patient for 4 hours to determine suitability of outpatient management
In 2014, NCCN® added moxifloxacin as a Category 1 recommendation for low risk FN treatment. Note moxifloxacin lacks Pseudomonas coverage.
Treatment of FN: High Risk
• Monotherapy
Anti‐Pseudomonal penicillin +/‐ ‐lactamase inhibitor or
Extended‐spectrum cephalosporin or
Carbapenem
• Combination therapy
Aminoglycoside + anti‐Pseudomonal penicillin +/‐ ‐lactamase inhibitor
Aminoglycoside + extended‐spectrum cephalosporin
Ciprofloxacin + anti‐Pseudomonal penicillin
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prevention and Treatment of Cancer‐Related Infections V.2.20145© National Comprehensive Cancer Network, Inc
2015. All rights reserved. Accessed [November 1, 2015].Freifeld AG et al. Clin Infect Dis. 2011; 52:e56‐93.
Question 5: What factors for LK should be considered when deciding if vancomycin should be added to LK’s regimen?
A. All FN patients should receive vancomycin
B. Presence of a central venous catheter
C. Prior ciprofloxacin prophylaxis
D. Reported symptom of cough
FN Treatment: Addition of Vancomycin
• 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
• Reassess therapy 24‐72 hours after initiation
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prevention and Treatment of Cancer‐Related Infections V.2.2015 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed [November 1, 2015].
Freifeld AG et al. Clin Infect Dis. 2011; 52:e56‐93.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 33
Hospital Course for LK
• Day 1
Respiratory rate improves, blood pressure improves with fluids
LK spikes a fever at 101.9° F
Blood and urine cultures are drawn again
Patient complains of tenderness at port site, which is red on examination
• Broaden Antibiotic Coverage
Imipenem 500 mg IV Q 6 hours
Add vancomycin 15 mg/kg loading dose then 1 g IV Q 12 hours
Check vancomycin trough level prior to 4th dose
Trough goal 15 mcg/ml
Hospital Course for LK• Days 2‐4
LK continues to run low grade fevers (100.3‐101°F)
Vitals remain stable
ANC remains < 0.5 X 109/L
• Day 5
Fever spikes to 103.4° F
Blood pressure drops to 89/54, heart rate 105
Initiate antifungal coverage
Cultures show no growth to date
Next set of blood cultures drawn
ANC rises to 0.5 X 109/L
Labs for LKOn Admission Day 1 Day 2 Day 3 Day 4 Day 5
Na (mEq/L) 138 140 139 138 140 140
K (mEq/L) 4.2 4.1 4.2 4 4.2 4
Cl (mEq/L) 105 102 103 100 100 102
CO2 (mEq/L) 28 28 27 26 28 28
BUN (mg/dL) 25 28 28 30 30 30
SCr (mg/dL) 1.1 1.3 1.3 1.4 1.4 1.3
Glucose (mg/dL) 99 120 121 108 114 115
WBC(X 109/L)
1.7 1.3 1.3 1.2 1.3 1.5
HgB (g/dL) 11.2 11 10.7 10.6 10.3 10
Hct (%) 30 29 28 28 27 27
Plts(X 109/L)
96 90 89 90 71 89
ANC (X 109/L) 0.6 0.4 0.4 0.3 0.4 0.5
Question 6: Which of the following is the best choice for empiric antifungal coverage for LK?
A. Micafungin 50 mg IV once daily
B. Micafungin 100 mg IV once daily
C. Fluconazole 200 mg IV once daily
D. Voriconazole 6 mg/kg IV every 12 hours
FN Treatment: Addition of Antifungal Coverage
• Most invasive fungal infections are due to Candida or Aspergillosis
• Fungal infections are uncommon early in FN such that treatment is usually delayed
• Candida Therapy
NCCN® – echinocandins
IDSA – insufficient evidence for one agent (FN guidelines); amphotericin B is the “old standard”
• Aspergillosis Therapy
NCCN® ‐ voriconazole
IDSA – voriconazole
• IDSA Guidelines available for Aspergillosis (2008) and Candidiasis(2009)
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prevention and Treatment of Cancer‐Related Infections V.2.2015 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed [November 1, 2015].
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 University Press.
Enlarged slide at back of handout.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 34
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 University Press.
Management of Candidemia
• Remove the long‐term catheter (port)
• An echinocandin should be used to treat critically‐illpatients until fungal isolate is identified
• Fluconazole may be used empirically for thefollowing patients
No azole exposure in the previous 3 months
Setting with low risk of C. krusei or C. glabrata
Mermel LA et al. Clin Infect Dis. 2009; 49:1‐45.
Treatment Options for Candida
Drug DoseDosage
AdjustmentsRecommendation
Fluconazole400 mg daily
Renal impairment
If susceptible
Caspofungin 70 mg loading dose then 50 mg
daily
Hepatic Impairment
Preferred
Anidulafungin 200 mg loading dose then 100 mg
dailyNone Preferred
Micafungin 100 mg daily None Preferred
LiposomalAmphotericin B
3‐5 mg/kg daily None Alternative
Note: all agents are intravenous except fluconazole which is also available as an oral formulation.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prevention and Treatment of Cancer‐Related Infections V.2.2015 © National Comprehensive Cancer Network, Inc
2015. All rights reserved. Accessed [November 1, 2015].
Culture Results for LK
Blood cultures(unless otherwise specified)
Admit Peripheral No Growth
Admit Central No Growth
Urine C & S 1+ mixed Gram‐positive flora
Day 2 Central No Growth
Day 2 Peripheral No Growth
Day 5 Central 4 + Yeast
Day 5 Peripheral 3 + Yeast
Hospital Course for LK• Days 6 – 8
No further fevers
Vitals stabilized
ANC recovers to > 1 X 109/L
• Day 9
Fungal cultures return positive for C. albicans, sensitive to fluconazole
Discontinue imipenem, vancomycin
Follow Up for LK
• LK was discharged and completed her course offluconazole without complications
• Her port was removed and she refused replacement;the remainder of her chemotherapy was given peripherally (carefully)
• Successfully completes chemotherapy without incidence
Last week of paclitaxel was not given due to peripheral neuropathy
• Initiated on adjuvant anastrozole 1 mg PO daily (planfor 5 years of therapy)
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 35
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.
Barriers to Adherence: Adjuvant Aromatase Inhibitor Therapy
Patient‐specific Factors Provider‐related Factors Treatment‐related Factors
Health beliefs (lack of belief in therapy)
Importance of adherence may not be emphasized
Adverse effects
Depression/Antidepressant use Difficulties of long term adherence may not be discussed
Underestimation of side effects by physician
Mastectomy Lack of support for dealing with side effects
Unexpected effects associated with non‐adherence
Poor awareness of therapeutic benefit
Dissatisfaction with provider
Remembering to take medication(Older and younger age groups associated with non‐adherence)
Inconvenience
Difficulty swallowing pills
Verma S et al. Curr Oncol. 2011 May; 18 Suppl 1:S3‐9.
Fast forward 4 years…
• LK has remained adherent to her anastrozole therapy
• In January 2017, her primary care physician startedher on paroxetine 20 mg orally daily as LK became more socially isolated, had difficulty sleeping and worried constantly about her cancer coming back
• In June 2020, she presents to the Emergency Department with sudden, severe, new onset chestand lower back pain. She is short of breath (RR 25)and tachycardic (HR 109).
Labs• CK Index 1• CK‐MB 1 ng/ml• Total CK 41 ng/ml• Troponin 0.2 ng/ml
• WBC 5.3 thou/microL• Hgb 13.2 g/dL• Hct 32%• Plts 144 thou/microL• ANC 2.7 thou/microL
• Na 135 mEq/L• K 4.0 mEq/L• Cl 100 mEq/L• CO2 30 mEq/L• BUN 17 mg/dL• SCr 0.87 mg/dL• Glucose 99 mg/dL
• AST 25 units/L• ALT 18 units/L• Alk Phos 105 units/L• T bili 1.0 mg/dL• TP 7.1 g/dL• Albumin 3.9 g/dL
• Spiral CT reveals bilateral pulmonary embolism
Small pulmonary embolus in the distal right lower lobe arterial tree
Large pulmonary embolus in the left upper lobe
• MRI Thoracic and Lumbar Spine
Compression fractures at T11, L1 and L2
Multiple small lesions throughout T7 to L3
• LDH 456 units/L
• Calcium 10.5 mg/dL
Tests Question 7: Which of the following are risk factors for venous thromboembolism (VTE) in LK?
A. Metastatic Breast Cancer
B. Nausea and Vomiting
C. Presence of Central Venous Catheter
D. Depression
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 36
VTE in Malignancy
• Endothelial injury
Central catheter
Chemotherapy
Surgery
• Circulatory Stasis
Prolonged bed rest
Vascular invasion by tumor cells
• Hypercoagulable state
Procoagulants from tumor
Release of cytokines
Direct cell‐to‐cell interaction between endothelial cells, leukocytes and platelets
Question 8: Which of the following therapies should be initiated in LK for her pulmonary embolism?
A. Warfarin 5 mg orally daily
B. Apixaban 10 mg orally twice daily
C. Dalteparin 12,500 units subcutaneous every 24 hr
D. Enoxaparin 80 mg subcutaneous every 12 hr
Low Molecular Weight Heparin (LMWH) vs. a Coumarin (CLOT Study)
• All patients initiated on dalteparin subcutaneous 200 units/kg/day
• N = 336 continued on dalteparin subcutaneous 200 units/kg/day X 1 month then dalteparin subcutaneous 150 units/kg/day X 5 months
• N = 336 received dalteparin subcutaneous X 5‐7 days with a coumarin derivative orally X 6 months with target INR = 2.5
• Primary outcome: Recurrent DVT and/or PE
• Secondary outcomes: Clinically overt bleeding, death
Lee AYY et al. N Engl J Med. 2003; 349:146‐53.
CLOT Results
• Primary outcome
Recurrence rates at 6 months: 8% in dalteparin group vs. 16% in the warfarin group
• Secondary outcomes
No significant difference in the rate of major bleeding (6% in the dalteparin group vs. 4% in the oral anticoagulant group)
Mortality rate at 6 months was 39% vs. 41% in the dalteparin and oral anticoagulant arms
Lee AYY et al. N Engl J Med. 2003; 349:146-53.
CATCH
• N= 449 Tinzaparin 175 IU/kg subcutaneous once daily X 6 months
• N= 451 Tinzaparin 175 IU/kg subcutaneous once daily X 5‐10 days then warfarin orally once daily (goal INR 2‐3) X 6 months
• Primary outcome: Recurrent thrombosis
6‐month cumulative incidence, 7.2% for tinzaparin vs 10.5% for warfarin; HR 0.65 [95%CI, 0.41‐1.03]; P = .07
• Secondary safety outcomes: major bleeding, clinically relevant nonmajor bleeding, and overall mortality
Significant reduction in clinically relevant nonmajor bleeding with tinzaparin (49 of 449 patients for tinzaparinvs 69 of 451 patients for warfarin; HR, 0.58 [95%CI, 0.40‐0.84]; P = .004) Lee AYY, et al. JAMA. 2015;314(7):677‐686.
Thrombosis in Malignancy:Current Recommendations• Initial Phase (5‐7 days)
Dalteparin 200 units/kg subcutaneous Q 24 hours OR
Enoxaparin 1 mg/kg subcutaneous Q 12 hours
• Subacute Phase (3‐6 months)
Dalteparin 200 units/kg subcutaneous Q 24 hours X 1 month then 150 units/kg Q 24 hours OR
Enoxaparin 1 mg/kg subcutaneous Q 12 hours or 1.5 mg/kg Q 24 hours
• Chronic Phase (6 months to indefinite)
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
V.1.2015 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed [November, 2015].
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
____________________________________________________________________________________________________________ 37
LK’s ED Course
• LK is initiated on enoxaparin 80 mg subcutaneous Q12 hours
She demonstrates the ability to give herself injections
LK is counseled on signs and symptoms of over and under anticoagulation
A referral for follow up at the cancer center’s pharmacist‐run anticoagulation clinic is made
—Monitor for heparin‐induced thrombocytopenia (HIT) (platelet checks)
—Assess for symptoms of improvement
LK’s ED Course
• Vitals at hour 3 in the ED
RR 20, BP 130/82, HR 100, Temp 98.1°F
• LK completes a NS 500 mL fluid bolus
• Hydromorphone 2 mg IV X 2 is administered, patientreports improvement of back pain
• She reports resolution of shortness of breath and chestpain
• For pain control she is prescribed hydromorphone 1 mgorally every 4 hours as needed
• Follow up with her oncologist for breast cancer recurrence
Interval History• LK comes to clinic 1 week after her ED visit to discusstherapy options for her recurrent breast cancer
• She reports adherence to enoxaparin, but “hates the shots”
Her oncologist says that they can discuss changing to warfarin after 6 months of injections
• Platelet count, renal function are stable on labs
• She continues to struggle with pack pain
The pain is worse at night as she cannot sleep comfortably
She has been taking two tablets of hydrocodone at 8am, noon, 4pm but three hydrocodone tablets at bedtime and 2‐3 times per night when she wakes up
Question 9: LK’s oncologist asks you for a conversion to a long‐acting opioid as LK has escalated her hydrocodone use and is still reporting poor pain control with inability to sleep. Which of the following is the best regimen for LK?
A. Fentanyl TDS 100 mcg/hr every 72 hours
B. Morphine SR 15 mg poQ 8 hours
C. Morphine SR 15 mg poQ 12 hours
D. Oxycodone SR 30 mg po Q 12 hours
Pain
• “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in such terms”
International Association for the Study of Pain 1994
• Whatever the patient says it is
Prevalence of Types of Cancer Pain (Pathophysiology)
Pain Type Percentage
Somatic 32‐35%
Visceral 15‐17%
Neuropathic 8‐9%
Somatic & Visceral 11‐13%
Somatic & Neuropathic 21‐23%
Visceral & Neuropathic 2‐4%
Breakthrough 65%
Chang VT et al. J Palliat Med. 2006; 9:1414‐34.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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World Health Organization (WHO) Principles of Pharmacologic Management
• By the mouth
• By the clock
• By the ladder
• For the individual
• With attention to detail
World Health Organization 1996; 2nd Edition.
Adapted from WHO Pain Relief Ladder.Palliative Pharmacy Care edited by Jennifer Strickland, published in 2009 by ASHP.
“Strong” opioids+/‐ APAP/NSAIDs+/‐ adjuvants
“Weak” opioids+/‐ APAP/NSAIDs+/‐ adjuvants
Acetaminophen+/‐ NSAIDs+/‐ adjuvants
APAP = acetaminophen
“Weak” opioids: e.g., codeine, hydrocodone, oxycodone/APAP“Strong” opioids: e.g., morphine, hydromorphone, oxycodone
WHO Pain Relief Ladder
Therapy Options• Non‐Opioid
Acetaminophen (APAP)
NSAIDs
COX‐2 Selective Agents
• Opioids
See upcoming slides
• Adjuvants
Note: Use is off‐label Antidepressants Anticonvulsants Consider risk of suicide
Local Anesthetics Bisphosphonates Calcitonin Corticosteroids Hydroxyzine
Pereira A et al. Pain 2013; 154:345‐9.
Opioids: What to UseMild‐Moderate Pain
• Hydrocodone/APAP*
• Oxycodone/APAP*
• Codeine
• *Combo products have variable amounts of opioid
Severe Pain
• Morphine
• Oxycodone
• Hydromorphone
• Methadone
• Fentanyl
• Oxymorphone
Opioids: Essential Considerations
• Medication allergies
• Previous opioid exposure and preference
• Severity and nature of disease
• Age of patient
• Extent of cancer, particularly hepatic and renalinvolvement altering opioid pharmacokinetics
• Comorbid disease states
• Dosage form and route of administration
Opioid Dose Titration• Patients currently on opioids
No consensus or guidelines available
• Severe pain (7‐10)** Consider increasing dose by 50‐100%
• Moderate pain (4‐6)** Consider increasing dose by 25‐50%
• Minimal pain (1‐3)** No increase in dose if controlled with current breakthrough pain (BTP) medication
Consider increasing dose by 25%
• End‐of‐dose failure Shorten dosing interval
**On a 10‐point scale with 10 for the worst pain imaginable for the three severity ratings on this slide
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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Opioids: Equianalgesic Dosing
• Incomplete cross tolerance between opioids
• Wide interindividual variability
• Several different equianalgesia charts available Derived from single‐dose studies
Do not reflect long‐term opioid exposure or changes made due to ineffective analgesia or toxicity
• If pain poorly controlled, use aggressive conversion 75‐100% of dose
• If pain well controlled, use conservative conversion 50‐75% of dose
Opioids: Equianalgesic DosingOPIOID ORAL DOSE PARENTERAL DOSE
Codeine 200 mg N/A
Hydrocodone 30 ‐ 45 mg N/A
Oxycodone 15‐20 mg N/A
Morphine 30 mg 10 mg
Hydromorphone 7.5 mg 1.5 mg
Methadone* * *
Fentanyl** N/A 100 mcg
Oxymorphone 10 mg 1 mg
*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
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Adult Cancer Pain V.2.2015 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed
[November 1, 2015].
Stepwise Approach to Conversion
1. Comprehensive pain assessment
Current level of pain control
Functional status
2. Determine total daily opioid use
3. Use conversion table to convert to new opioid
4. Individualize dose
More aggressive conversion for uncontrolled pain
Less aggressive conversion for well controlled pain
5. Follow‐up and continual reassessment
Question 9 Revisited: LK’s oncologist asks you for a conversion to a long‐acting opioid as LK has escalated her hydrocodone use and is still reporting poor pain control with inability to sleep. Which of the following is the best regimen for LK?
A. Fentanyl TDS 100 mcg/hr every 72 hours
B. Morphine SR 15 mg po Q 8 hours
C. Morphine SR 15 mg po Q 12 hours
D. Oxycodone SR 30 mg po Q 12 hours
Question 10: LK’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 poevery 1‐2 hours
B. Morphine IR 15 mg poevery 4‐6 hours
C. Morphine IR 30 mg poevery 6 hours
D. Oxycodone 2.5 mg poevery 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
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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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)
CIPN: Chemotherapy-induced peripheral neuropathyHershman DL, et al. J Clin Oncol 2014; 32:1941-1967.
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 2.2015.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Adult Cancer Pain V.2.2054 © National Comprehensive Cancer Network, Inc 2015. All rights reserved. Accessed November 1, 2015].
Breast Cancer Epidemiology
• 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 8,2016.
Individualized Drug Therapy in Breast Cancer• Menopausal Status
Potential for use of tamoxifen vs. aromatase inhibitors
Need for ovarian suppression or ablation
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 in postmenopausal patients with ER+Her2‐metastatic breast cancer (1st line therapy)
In combination with fulvestrant in patients with ER+Her2‐ advanced/metastatic breast cancer after progression on endocrine 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
• With letrozole: Median PFS 20.2 months (95% CI 13.8‐27.5) vs. 10.2 months (95% CI 5.7‐12.6) with letrozole alone, HR 0.488 (95% CI 0.319‐0.784)
• With fulvestrant: Median PFS 9.2 months (95% CI, 7.5 to not estimable) vs. 3.8 months (95% CI, 3.5 to 5.5) with fulvestrant alone, HR 0.42 (95% CI, 0.32 to 0.56; P<0.001)
Finn RS et al. Lancet Oncol. 2015; 16: 25-35.Turner NC et al. N Engl J Med. 2015:373: 209-19.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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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
HER2 Targeted Therapy• Lapatinib
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 option for LK?
A. Palbociclib and fulvestrant
B. Ado‐trastuzumabemtansine
C. Pertuzumab, trastuzumab and paclitaxel
D. Palbociclib and docetaxel
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
• Symptomatic visceral disease
Proceed with chemotherapy
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2016 © National Comprehensive Cancer Network, Inc 2016. All rights reserved. Accessed [March 6, 2016].
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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Examples of Safety Issues in Our Patient Case• Medication Adherence
Hormonal therapies (other oral therapies)
• Safe use of anticoagulant therapy
Warfarin drug‐drug interactions
—Consider influence of active cancer and chemotherapy on bleeding risk
• Extravasation
LK’s need for a central venous catheter
• Cardiotoxicity
Anthracycline (others include HER2 agents)
Ambulatory Health Care National Patient Safety Goal (NPSG.03.05.01)
• Reduce the likelihood of patient harm associated with the use of anticoagulant therapy
• Applies to organizations that provide anticoagulant therapy and/or long‐term anticoagulation prophylaxis where the clinical expectation is that the patient’s laboratory values for coagulation will remain outside normal values
• Elements of performance
Use approved protocols for the initiation and maintenance of anticoagulant therapy
Before starting a patient on warfarin, assess the patient’s baseline coagulation status; for all patients receiving warfarin therapy, use a current INR to adjust this therapy
Provide education regarding anticoagulant therapy to prescribers, staff, patients, and families
Evaluate anticoagulation safety practices, take action to improve practices, and measure the effectiveness of those actions in a time frame determined by the organization
Available at: http://www.jointcommission.org/assets/1/6/2016_NPSG_AHC.pdf. Accessed February 28, 2016.
Warfarin Drug Interactions• Too many for this slide!
Substrate of CYP1A2, 2C19, 2C9 (major), and 3A4
Weak inhibitor of CYP2C19 and 2C9
Common agents for cancer patients (e.g., antibiotics, chemotherapy)
• Increased bleeding risk
Thrombocytopenia
Disease related
Chemotherapy
Bleeding tumors
• Intensive monitoring required for cancer patients
Changes in appetite
Fatigue
Nausea/vomiting
Example: increased fall risk due to chemotherapy‐induced peripheral neuropathy
Extravasation• Symptoms can be delayed or immediate
Pain, burning
Swelling
Erythema
Loss of blood return
• Determine if agent binds to DNA for direct vs. indirect effect
• Results in partial or full thickness skin loss
• Minimal evidence base for treatment
Schulmeister L. J Clin Oncol Nurs. 2007; 11(3):387‐95. Wickham R et al. Oncology Nursing Forum. 2006; 33:1143‐50.
Schrijvers DL. Annals of Oncology. 2003; 14 (supplement 3): iii26‐30.Photos from: N Engl J Med, Vano‐Galvan S, Jaen P, Extravasation of Epirubicin, 360,
2117. Copyright © 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Treatment of ExtravasationAgent Antidote Comments
Anthracyclines Dexrazoxane1000 mg/m2 IV within 5 hours on Day 1, repeat Day 2 then 500 mg/m2 IV on Day 3
DMSO Apply locally ASAP and repeat Q 8 hours X 7 days
Cold packs Vasoconstriction decreases local drug uptake
Nitrogen Mustards Sodium thiosulfate2 mL of a solution of 4 mL sodium thiosulfate and 6 mL sterile water
Vinca Alkaloids Hyaluronidase 50‐1500 units subcutaneous
Warm Packs Vasodilation to enhance drug uptake
Taxanes Normal saline Exerts dilutional effect
DMSO
Cold packs ?
Surgical intervention may also be warranted
Wickham R et al. Oncology Nursing Forum. 2006; 33:1143‐50.Schrijvers DL. Annals of Oncology. 2003; 14 (supplement 3): iii26‐30.
Cardiotoxicity
• Anthracycline Induced ‐ Cardiomyopathy
Delayed
Cumulative
Dose‐related (Lifetime maximum dose)
Risk factors include heart disease, HTN, mediastinal radiation, prior anthracycline
• Trastuzumab Induced
Additive with anthracyclines
• Recommendations for monitoring for our patient’s initial chemotherapy regimen
Cardiac monitoring at baseline, 3, 6 and 9 months
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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Pharmacist’s Role in Complex Oncology Patients
• Drug therapy recommendations
Chemotherapy
Supportive care
• Anticoagulation management
• Pain Management
• Medication safety, especially chemotherapy
• Medication access
• Monitoring
• Patient and family education
Cancer Patient Resources
• NCCN® Guidelines for Patients (http://www.nccn.org/patients/default.asp) Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Patients © National Comprehensive Cancer Network, Inc 2014. All rights reserved. Accessed [November 19, 2014].
• ASCO Website for Patients (http://www.cancer.net)
• American Cancer Society (http://www.cancer.org/)
• LIVESTRONG (http://www.livestrong.org/)
• Clinical Trials (www.clinicaltrials.gov)
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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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 University Press.
©2016 American Society of Health-System Pharmacists, Inc. All rights reserved.
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