Management of Patients Receiving Oral Chemotherapy

Siu Fun Wong, PharmD, FASHP, FCSHP Professor and Associate Dean Chapman University School of Pharmacy (CUSP) Irvine, CA Disclosure

I have no conflict of interest . Objectives

At the end of the presentation, the participants will be able to: 1. Recognize the difference in care required by patients receiving parenteral vs. oral chemotherapy 2. Deliver personalized care to patients receiving oral chemotherapy 3. Provide appropriate education relating to oral chemotherapy to patients and/or caregivers. Types of Oral Anti-cancer Chemotherapy

Cytotoxic Agents Hormone Agents Immunomodulators Differentiating Agents Targeted Therapy

Paradigm Change

The rise in the use of oral oncology drugs represents a major shift in the management of patient . Directly observed treatment to unsupervised self- administration setting . Intermittent to daily chronic therapy . Perception of less toxicity with oral route of administration – both patients and providers1 . Patient preference due to convenience without compromise for efficacy2 . Provider preference, especially in palliative or adjuvant setting where QOL is paramount3

1Sharma S & Saltz LB. The Oncologist 2000; 5:99-107 2 Liu G et al. J Clin Oncol1997; 15(1):110-115 3 Benjamin et al. Eur J Cancer 2012;48(6):912-920 Goal

How to empower patients to take the right dose at the right time under the right circumstances and to complete the treatment !!

Effective Use and Monitoring Key (Unique) Elements to Consider

Drug Administration Drug Interactions – Pharmacogenomics or genetic effect Adverse reaction management Adherence Safe handling Special Considerations for Oral Administration • Drug administration tolerability • Pharmacokinetics : Absorption, distribution, metabolism, excretion – Drug formulation, GI functions, drug interactions • Dosing regimen/scheduling • Specific patient considerations – safe handling Mechanisms of Drug Interactions

Where? Pharmacokinetic: Absorption, Distributions, Metabolism, Excretion Pharmacodynamic: change in the patient’s response to a drug without altering the PK of the object drug How? – Formulation incompatibility – Drug binding – Drug transporters – Protein binding – Receptor binding – Enzyme activities (lifestyle) – Genetic variations – Drug-disease interactions Clinical Drug Interactions - Absorption Oral Chemo Interactions/Mechanis Management m Afatinib, chlorambucil, Food -  bioavailability Empty stomach melphalen, 6-MP, (reduced AUC) capecitabine, temozolamide, sorafenib Vorinostat, regorafenib, Food - AUC Check study admin bosutinib, cabozantinib, condition to erlotinib, nilotinib, lapatinib, determine +/- food pazopanib, t-RA Estramustine Calcium-rich food – 1 hr before or 2 hrs impair absorption after Axitinib, bosutinib, crizotinib, pH-dependent solubility Separate antacids, dasatinib, nilotinib, erlotinib, – decrease AUC & H2 blockers, ponatinib, vismodegib avoid PPI Methotrexate, vismodegib, Dose-related saturation Separate daily tamoxifen PK dose Topotecan, vismodegib P-gp inhibitor – increase Avoid concurrent bioavailability administration Pharmacogenomic Effect Drugs Conditions or Biomarkers Clinical Effect Capecitabine Dihydropyrimidine ↑ toxicity dehydrogenase (DPD) deficiency (DPYD*2A) Crizotinib EML4-ALK fusion oncogene + Efficacy for crizotinib, ? ↓ erlotinib efficacy Everolimus Lapp lactase deficiency Diarrhea, malabsorption Erlotinib Epidermal Growth Factor ↑ treatment Receptor (EGFR) mutation+ response Kras mutation+ Poor response 6-MP Thiopurine methyltransferase ↑ myelo- (TPMP) deficiency suppression Tamoxifen CYP2D6*3 or *4 poor ↓ efficacy metabolizer Side Effects of Oral Anti-cancer Agents

• Hematologic Complications • Dermatologic toxicities • Neurologic • Ophthalmic • Cardiologic • Pulmonary • Gastrointestinal • Fluid retention • Lab Abnormalities/renal Hematologic Complications

• Myelosuppression -Neutropenia, anemia, thrombocytopenia • Cytotoxic agents, bosutinib, pazopanib • Hemorrhage - Bleeding, epistaxis • Bleeding: Cytotoxic agents, regorafenib, vandetanib, vorinostat (esp used w valproic acid) • Epistaxis: afatinib, cabozantinib • Thromboembolic events - PE, DVT • Tamoxifen, thalidomide, vorinostat • INR changes – concurrent use with warfarin • Erlotinib, nilotinib, sorafenib, vorinostat, Hematologic Complications Patient Management • Assess pt risks • Education for precautions • Neutropenia, anemia, thromobocytopenia • s/sx of conditions and potential complications • s/sx of DVT & PE • Prophylactic interventions • Laboratory monitoring • Supportive care Dermatologic Toxicities

• Hand-Foot Syndrome • Skin/Nail Reactions – Hypersensitivity reaction –maculopapular rash – Photosensitivity – Dermatitis – Papulopustular rash – Paronychia – Pigmentation changes – Radiation Recall Hand-Foot Syndrome

• aka palmar-plantar erythrodysesthesia • Agents: • Capecitabine, axitinib, cabozantinib, lapatinib, regorafenib, sorafenib, sunitinib • Onset can be from 2 to 12 days after initiation of therapy • May progress 3 to 4 days later into symmetrical edema and erythema of the palms and soles Hand –Foot Syndrome Grading Hand –Foot Syndrome Management • Systemic Agents – Pyridoxine or vitamin B6 – Dexamethasone – Amifostine – COX-2 inhibitors • Topical agents – Bag Balm, a topical petroleum-lanolin-based ointment with the antiseptic ingredient hydroxyquinoline sulfate. – Emollients, e.g. Biafine, Carmol 40 – Aloe vera lotion – Moisturizing creams. • Non-pharmacologic Interventions – Avoid undue pressure or rubbing of the skin – Avoid blood vessel dilation induced by hot showers or sun exposure – Cooling with cold water

Ann Oncol. 2007;18:1159-1164. Skin/Nail Reactions

• Hypersensitivity reaction –maculopapular rash • Photosensitivity • Dermatitis • Papulopustular rash • Paronychia • Pigmentation changes • Radiation Recall Dermatitis

• Capecitabine, axitinib, bosutinib, regorafenib, vandetanib • s/sx: Generalized skin rash +/- pruritis • Can be worsen by sun exposure • Use products with SPF > 30 • Apply 30-60 mins before sun exposure and reapply every 2 hours • Moisturizer • Dose reduction may help EGFRI-Induced Dermatologic Toxicity

Paronychia

Papulopustular Rash Trichomegaly EGFR Inhibitor – Induced Dermatologic Toxicity

• Erlotinib, afatinib, everolimus, vandetanib • Dermatologic toxicities include: – Papulopustular (Interfollicular and follicular-based erythematous papules and pustules) rash, xerosis, paronychial inflammation • Papulopustular Rash: – Onset: 1-2 weeks – Usually occur on face, scalp, and upper body – Symptoms: dry skin, pain/tenderness and pruritus – Inflammatory and infectious sequelae • Papulopustular Rash is common – 35-88% (all grades) – 16% (grade 3 or 4) – Dose reduction or discontinuation are recommended • Potential marker for drug activity and clinical outcome Pigmentation Changes

• Skin • Hyperpigmentation – busulfan, 6-MP • Skin discoloration (yellow) - sunitinib • Hair • Hair color change • Cabozantinib, panzopanib, sunitinib Neurologic Toxicities

• Seizure – hi dose busulfan, chlorambucil, vandetanib (RPLS – seizure, HA, visual disturbance, mental status changes) • Muscle spasm – vismodegib, vorinostat • Drowsiness, somnolence, tremor, peripheral neuropathy - thalodimide • Headache, dizziness – t-RA Ophthalmic

• Conjunctivitis • Associated with EGFRI • Steroid eye drops • Blurred vision • Crizotinib, vandetanib • Most likely secondary to keratitis Cardiac

• QT prolongation – Bosutinib, crizotinib, dasatinib, Imatinib, nilotinib, pazopanib, sorafenib, vandetanib – Increase risks: Concurrent QT prolongation drugs, low K+ and low Mg++ • CHF, ventricular dysfunction • Afatinib, lapatinib, panzopanib, vandetanib • Monitoring of EF with ECHO or MUGA, and S/Sx • Hypertension Hypertension

• Axitinib, cabozantinib, everolimus, panzopanib, regorafenib, sorafenib, sunitinib, vandetanib • MOA: Not completely known – ? abnormal endothelial function (RAF kinase inhibition) and angiogenesis (VEGF inhibition) • Onset usually within first 6 weeks after initiation of therapy • Management: – Monitor BP q week for first 6 week after initiation of therapy – Interruption and/or dose reduction should be considered – Permanent discontinuation is rare – Standard antihypertensive agents can be selected with caution to avoid agents with potential for CYP450 drug-drug interaction ( e.g. verapamil, diltiazem) – Agents with protection for proteinuria, such as ACE inhibitors are preferred Pulmonary • Interstitial Lung Disease (ILD) • Afatinib, erlotinib, lapatinib, topotecan, vandetanib • s/sx cough, dyspnea, can be fatal • Increase risk if prior ILD • Monitor • Interstitial pulmonary fibrosis • Busulfan, lomustine • Increase risk if >6 mos of therapy or cumulative dose • Cough • Bosutinib, crizotinib, everolimus, sorafenib, sunitinib, vorinostat • Usually associated with edema or pneumonitis • t-RA induced APL syndrome Gastrointestinal

• CINV • Mucositis • Diarrhea • GI perforation Anti-emetic Treatment Assessment for Acute CINV Chemotherapy Regimen: – Emetogenic potential of the chemotherapy regimen – Types of CINV (i.e. acute  delayed) Patient Assessment: – Patient risk factors – Patient history – Risk for anticipatory CINV MASCC/ESMO Antiemetic Guidelines 2016 Single Oral Agents CINV Management

• General Concepts: • Non-parenteral route: PO, PR, Transdermal • ATC schedule for high, mod, or refractory • Avoid long-term use of steroids and NK1 antagonist • Antiemetic Regimens: • High EP = hi dose 5HT3 antagonist +/- NK1 antagonist • Mod EP = mod dose 5HT3 antagonist • Low EP = 5HT3 antagonist prn • Adjunct drugs: lorazepam, prochlorperazine +/- diphenhydramine, olanzapine • Non-pharmacologic Mucositis

• Mucositis – Painful inflammation and ulceration of the mucous membranes lining of oral cavity and the digestive tract • Epithelial cells of oral and GI mucosal have high turn over rate of 7-14 days – Common sites for chemotherapy induced toxicity MASCC /ISOO Mucositis Guidelines (2014)

• Prevention: – Dental examination and treatment prior to cancer treatment – Basic oral care – Diet – Not recommended: chlorhexidine mouth wash, antimicrobial lozenges, acyclovir, sucralfate coating agent Mucositis Treatment

Assessment Management Patient history -Early interventions -Dose reduction of chemo Location of lesions (oral Topical vs. systemic vs.GI treatment Presence of pain Mild to moderate: topical Severe:: systemic Diet Diet modification if necessary Oral hygiene Salt and baking soda mouth rinse. DO NOT use hydrogen peroxide. Avoid EtOH- containing mouth rinses Mucositis-related infections

• Candidiasis- most common infection • Oral lesions should be cultured, but empiric treatment should be started • Mild infection (Grade 1 or 2 with no fever): topical antifungals • Clotrimazole troches 10 mg dissolve in mouth 5x per day or pastilles 200,000 U qid • Nystatin suspension 100,000 u/ml 4-6 ml swish and spit/swallow 4x/day • More Severe Infection – systemic anti-fungals Diarrhea

• All the oral targeted agents can cause diarrhea • Incidence: – All grade = up to 96% – Grade 3 & 4 = up to 16% • Gradual onset in 7-10 days • Management: – r/o other etiologies, especially infectious – Start with loperamide or lomotil 2 tabs PO q 6 hrs ATC – Monitor for fluid and electrolytes – Secondary agents: Paregoric, codeine sulfate, octreotide – Dose reduction or temporary interruption of oral targeted therapy in severe cases Fluid Retention

Overall <10%: Pleural, pericardial, ascites, & generalized edema Bosutinib, crizotinib, dasatinib, imatinib, nilotinib, everolimus, vorinostat, tamoxifen Management: – Monitor weight for sudden weight changes – Diuretic & corticosteroid as needed – Dose interruption or reduction Pleural Effusion Laboratory Abnormality

CBC Na K, Mg Ca P SCr Blood Glucose Afatinib ↓ Axitinib ↓ ↑, ↓ ↑ ↓ ↓ ↑ ↑, ↓ Bosutinib ↓ ↓ Cabozantinib ↓ ↓ ↓ ↓ ↓ Dasatinib* ↓ ↓ ↓ ↓ Everolimus ↓ ↓ ↑ ↑ Pazopanib ↓ ↓ ↓ ↑ Sorafenib* ↓ ↓ ↓ Tamoxifen ↑ t-RA ↑ ↑ Vandetanib ↓ ↓ ↓ ↑ ↓ Vismodegib ↓ ↓ ↑ Vorinostat ↓ ↓ ↑ ↑ Laboratory Abnormality

AST/AL T Alb T TG Lipase/Amylase INR TSH T Bili Chol Afatinib ↑ Axitinib ↑ ↓ ↑ ↑ Bosutinib ↑ ↑ Cabozantinib ↑ ↑ ↑ Capecitabine ↑ ↑ ↑ Crizotinib ↑ Dasatinib* ↑ ↑ Erlotinib ↑ ↑ ↑ Everolimus ↑ ↓ ↑ ↑ Lapatinib ↑ ↑ Pazopanib ↑ ↑ ↑ Sorafenib* ↑ ↓ ↑ ↑ t-RA ↑ ↑ ↑ Vandetanib ↑ ↑ Laboratory Abnormalities Management

• Monitor for abnormality and corrected as appropriate • Electrolyte (sodium, potassium, magnesium, phosphate, and calcium) and renal function should be evaluated prior to administration and replace accordingly, especially in patients at risk of or suffering from CINV, diarrhea, dehydration, or ECG changes ( e.g. QT prolongation) • Blood glucose for lessen risk of diabetes • Dyslipidemia may require anti-lipid therapy with ? effectiveness Adherence

o Early studies to assess adherence/persistence conducted with adjuvant hormonal therapy ( 5 years) for the treatment of breast cancer . 72-76% in clinical trial settings1 . 30-50% in non-trial setting2 . Contributory factors: concurrent IV chemo, MD visits, ?higher cost o Later reviews of adherence to oral chemotherapy in adults reported between 16 to 100%3 . Multiple contributory factors: patient, disease, provider

1 Howell A et al. Lancet 2005;365:60-2 2 Chlebowski RT & Geller ML. Oncology 2006;71:1-9 3 Ruddy K et cl. CA: a cancer journal for clinicians 2009;59:56- Impact of Non-adherence o Suboptimal adherence to oral therapy shown to worsen event free survival in patients with chronic myelogenous leukemia1,2 o “Over-adherent” also occurred in the presence of grade 3 or worse adverse events3 o Non-adherence in pts with chronic disorders estimated at $300 billions/yr4

1 Ganesan P et al. Am J Hematol 2011; 86(6):471-474. 2 Ibrahim AR, et al. Blood 2011; 117(14):3733-3736. 3 Patel K et cl. J Canc Edu 2013 July [Epub] 4DiMatteo MR. Med Care 2004; 42(3):200-209. Interventions – Patient Care

 Comprehensive Patient Assessment . Establish candidacy for oral administration . Identify risks of non-adherence and optimal tool to improve adherence . Evaluate psychosocial support  Proactive and Personalized education and management . Early interventions . Pt advocacy, minimize patient burden Safe Handling of Anti-cancer Drugs Occupational Safety and Health Administration (OSHA) guidelines Purpose: – Protect workers and workplace – Protect patients, caregivers, family, and public Rationale: – Genetic mutation – Secondary cancers – Fetal malformation – Fertility impairment Safe Handling of Oral Anti-cancer Agents • All oral anti-cancer agents must be stored in original container • Targeted agents are now classified as hazardous medications  same handling requirements • Crushing or breaking of the oral dosage form should be conducted in the Class II Type A biological safety cabinet • Separate equipment for dispensing or administration Protection at Home . Oral anti-cancer drugs should be handled by patient, if possible. Caregiver must use gloves to handle drugs and wash hands after handling. . Proper disposal container must be in place . Body fluids (vomitus, urine) may contain small amount of cytotoxic drugs and their active metabolites for 48 hours after patient receives chemotherapy . Contaminated linen should be handled with gloves and washed separately Summary

• Oral anti-cancer therapy is not less toxic • Many of these agents are administered on chronic continuous schedule with less supervision • Careful screening is essential to derive an optimal patient care plan • Empowering patients with good education to manage adverse effects can promote and enhance adherence • Safe handling education is essential to protect patients and caregivers in their home setting Question 1

Which can be expected in patients receiving oral chemotherapy?

A. Decrease risk of drug interaction B. Decrease risk of adverse events C. Increase risk of non-adherence D. Increase risk of anaphylactic reactions

Answer: C Question 2

Which toxicities can occurred with use of oral chemotherapy? (Select all that apply)

A. Diarrhea B. Extravasation C. Hematologic toxicity D. QT prolongation

Answer: A, C, and D Question 3

The best approach to support patients receiving oral chemotherapy is to provide a comprehensive, proactive and personalized education through direct patient contact.

A. True B. False

Answer: True Session Code: 1. Write down the course code. Space has been provided in the daily program-at- a-glance sections of your program book.

2. To claim credit: Go to www.cshp.org/cpe before December 1, 2016.