2016 Pharmacotherapy Specialty Examination Review Course ...elearning.ashp.org/Files/Org/c52850f8e2e14ca8b14b... · 2016 Pharmacotherapy Specialty Examination Review Course: Complex

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


____________________________________________________________________________________________________________ 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


____________________________________________________________________________________________________________ 3

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


____________________________________________________________________________________________________________ 4

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


____________________________________________________________________________________________________________ 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.


____________________________________________________________________________________________________________ 6

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.


____________________________________________________________________________________________________________ 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).


____________________________________________________________________________________________________________ 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.


____________________________________________________________________________________________________________ 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.


____________________________________________________________________________________________________________ 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


____________________________________________________________________________________________________________ 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


____________________________________________________________________________________________________________ 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


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


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


____________________________________________________________________________________________________________ 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


____________________________________________________________________________________________________________ 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


____________________________________________________________________________________________________________ 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


____________________________________________________________________________________________________________ 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


____________________________________________________________________________________________________________ 17

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


____________________________________________________________________________________________________________ 18

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)


____________________________________________________________________________________________________________ 19

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)


____________________________________________________________________________________________________________ 20

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


____________________________________________________________________________________________________________ 21

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)


____________________________________________________________________________________________________________ 22

References and Recommended Readings

Febrile Neutropenia

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in neutropenic patients with cancer: 2010 update by the Infectious Disease Society of America. Clin

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2014 May 21).

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Infectious Diseases Society of America. Clin Infect Dis. 2008; 46:327‐60.

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7. Flowers CR, Seidenfeld J, Bow EJ et al. Antimicrobial prophylaxis and outpatient management of

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____________________________________________________________________________________________________________ 23

Anticoagulation

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Nausea and Vomiting

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guideline update. J Clin Oncol. 2016; 34:381‐86.

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2. Gralla RJ, Rolia F, Tonato M et al. MASCC/ESMO antiemetic guidelines 2013. Available at:

http://www.mascc.org/antiemetic‐guidelines.


____________________________________________________________________________________________________________ 24

3. National Comprehensive Cancer Network. NCCN® clinical practice guidelines in oncology:

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Pain Management

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[November 1, 2015].

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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

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____________________________________________________________________________________________________________ 25

Breast Cancer

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cancer. Version 1.2016. Available at:

http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Referenced with permission from

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2016].

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positive breast cancer. N Engl J Med. 2005; 353:1673‐84.

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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.

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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.


____________________________________________________________________________________________________________ 26

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.


3. Schulmeister L. Extravasation management: clinical update. Semin Oncol Nurs. 2011; 27:82‐90.


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

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2002; 3:629‐37. http://www.thelancet.com/journals/lanonc/article/PIIS1470‐2045(02)00877‐

X/abstract (accessed 2014 May 21).

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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)


____________________________________________________________________________________________________________ 27

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


____________________________________________________________________________________________________________ 28

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].


____________________________________________________________________________________________________________ 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.


____________________________________________________________________________________________________________ 30

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


____________________________________________________________________________________________________________ 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.


____________________________________________________________________________________________________________ 32

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


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


Freifeld AG et al. Clin Infect Dis. 2011; 52:e56‐93.


____________________________________________________________________________________________________________ 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)


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.


____________________________________________________________________________________________________________ 34




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)


____________________________________________________________________________________________________________ 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


____________________________________________________________________________________________________________ 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].


____________________________________________________________________________________________________________ 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.


____________________________________________________________________________________________________________ 38

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


____________________________________________________________________________________________________________ 39

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


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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.


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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].


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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


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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)


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