SUBMIT YOUR SYMPTOM MANAGEMENT UPDATE

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SYMPTOM MANAGEMENT OVERVIEW Section Editor: Joseph Bubalo, PharmD, BCPS, BCOP SUBMIT YOUR SYMPTOM MANAGEMENT UPDATE Readers are invited to submit brief updates with practice insights on the care of a

1 SYMPTOM MANAGEMENT OVERVIEW Section Editor: Joseph Bubalo, PharmD, BCPS, BCOP SUBMIT YOUR SYMPTOM MANAGEMENT UPDATE Readers are invited to submit brief updates with practice insights on the care of a specific symptom or a cluster of symptoms associated with a condition that is often seen in patients with cancer. The updates will be presented in the form of a How I Treat type of article. The goal of this section is to present a quick background to enhance providers understanding of the symptoms associated with a specific condition and their characteristic presentation(s) and etiology. The emphasis should be on a concise description of available treatments and current course of therapy. WHAT IS SYMPTOM MANAGEMENT OVERVIEW? Each review should provide a brief description of the symptom(s) associated with a common condition in oncology and its evidence-based management. ARTICLE FORMAT Length of article: words Tables: 1-3 Describe the symptom(s) Etiology Treatment options: dose(s), frequency, titration parameters Course of therapy: time to effect/symptom resolution, expected effects, special or target populations for specific therapies, side effects and their management, as appropriate References: minimum 5; maximum 15 HOW TO SUBMIT Submit a Word file of your article at 12 l Journal of Hematology Oncology Pharmacy l March 2015 l Vol 5, No 1

2 This section provides a quick update of symptomatic conditions in oncology and their management. Readers are invited to submit brief updates following the guidelines provided on page 12. Prevention and Treatment of Cytarabine- Induced Keratoconjunctivitis By Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine, Division of Hematology and Medical Oncology, Oncology Clinical Pharmacy Specialist, Oregon Health and Science University Hospital, OHSU Hospital and Clinics, Portland, OR SYMPTOM OVERVIEW Corneal toxicity with high-dose cytarabine is a wellestablished risk of therapy. 1 Routine prophylaxis with eye drops, usually topical corticosteroid drops, is an established part of high-dose cytarabine treatment protocols. 2 Without topical corticosteroid prophylaxis, incidences of keratoconjunctivitis have been reported in 85% to 100% of cases 3,4 ; the occurrence of clinically significant symptoms with the use of prophylaxis is reported in 8% to 16% of cases. 3 ETIOLOGY Cytarabine has a known ability to penetrate body fluids, including crossing the blood brain barrier, and can be found in the aqueous humor and in tears. 5 Corneal toxicity appears to be related to the concentration of cytarabine in tears, and the duration of exposure. Risk factors vary with high-dose cytarabine (Table 1), and duration of dosing is most strongly associated with the toxicity 4-6 ; few cases have been seen with intermittent or continuously administered intravenous, low-dose cytarabine (eg, <200 mg/m 2 /day). 5 Conjunctivitis has occurred as early as 3 days into therapy, and several days after therapy, with days 6 to 8 posttherapy the most commonly reported time of occurrence. 6-8 Findings at eye examinations have been described as bilateral corneal epithelial microcysts possibly more densely distributed in the center of the cornea than in the midperiphery, 5 conjunctival hyperemia, and fine corneal opacities. 9 There is often severe blepharospasm and moderate conjunctival inflammation however, the anterior chambers of the eyes are usually free of inflammation, and intraocular pressure is normal. 5 The TREATMENT OPTIONS Prophylaxis is generally not recommended at doses <1000 mg/m 2. 5 Suggested prophylaxis is corticosteroid eye drops 5,6,8 ; however, other agents and combinations have been used successfully. 8 These include a variety of preparations, including tear replacement solutions and Table 1 Risk Factors for Cytarabine-Induced Keratoconjunctivitis 4-6 Concurrent total body irradiation with high-dose cytarabine Cytarabine dose >1000 mg/m 2 ; cases reported as low as 400 mg/m 2 daily Duration of exposure variable with >5 days of high dose or >10 days at more moderate doses ( mg/m 2 ); very rare at <2 days mechanism of microcyst formation is currently unknown. Corneal epithelial stem cells have a long cycle time and are unlikely to be cytarabine-susceptible; however, they bring about more differentiated transient amplifying cells in the basal layer, which divide more frequently and may therefore be vulnerable to cytarabine toxicity. Common ocular symptoms include blurred vision, severe discomfort or burning pain, photophobia, 3,5,7 decreased visual acuity, tearing, 3,7 and foreign body sensation. 3 topical, nonsteroidal anti-inflammatory drops. 6,8 Every 4- or 6-hour administration on a strict schedule appears to provide the most benefit, and drops should be continued at least 48 hours after the last cytarabine dose. 6 The mechanism of conjunctivitis prevention is unclear, but Vol 5, No 1 l March l Journal of Hematology Oncology Pharmacy 13

3 may rely on a decreased replication rate induced by corticosteroids impacting DNA replication in corneal cells. 5 An additional mechanism of action may be a diluting effect on the cytarabine concentration; 1 trial showed benefits achieved from frequent use of artificial tears. 6 It is unclear whether components of eye solutions, especially preservatives, can exacerbate the conjunctivitis. Given the limited studies on this toxicity, preservative-free products would be preferred when available. 10 When conjunctivitis occurs there is no standard therapy, and treatment is often left to the local ophthalmologists, who generally apply additional corticosteroid eye drops, with other agents added in as needed. 5 See Table 2 for a list of prophylaxes and Table 3 for treatments for cytarabine-induced conjunctivitis. Dexamethasone eye drops are the most common agent used to treat conjunctivitis, and there may be additional benefits derived by adding a topical nonsteroidal anti-inflammatory drug (NSAID). 8 Dexamethasone has greater anti-inflammatory activity, and may have better corneal penetration than prednisolone. Pain, irritation, and other symptoms generally respond within days, with visual acuity returning to baseline by 2 weeks, and corneal opacities resolved by 4 weeks. 3 Additional symptom benefits may be obtained through the application of cold compresses to the eye, and by keeping lights at a low level. 6 Table 2 Prophylaxes for Cytarabine-Induced Conjunctivitis Agent Dose Duration Comments Betamethasone sodium phosphate 0.1% with natural tears or 0.1% sodium hyaluronate 4 Betamethasone sodium phosphate 0.1% with sterile saline eye rinse 10 1 drop of each every 6 hours 1 drop every 6 hours; rinse each eye with 3-4 ml of sterile saline in a commercial eye rinse cup Dexamethasone 0.1% 8 6 hours Dexamethasone 0.1% with diclofenac sodium 0.1% 8 Artificial tears 6 Natural tears 2 Prednisolone phosphate 1% 2,6 2 drops of dexamethasone in each eye every 6 hours, and 2 drops of diclofenac in each eye every 8 hours 8 hours Doses ranging from 2 drops in each eye every 8 hours to cytarabine and continue until 1 day after the last dose, or until complete resolution of any ocular symptoms cytarabine and continue until 1 day after, or until complete resolution of any ocular symptoms. Use sterile saline rinse every minutes during cytarabine infusion and for 2 hours after the last dose ( total) cytarabine and are continued for 4 days after the last dose cytarabine and continue for 4 days after the last dose HSCT indicates hematopoietic stem-cell transplantation; TBI, total body irradiation. Used in HSCT regimens as described below. This regimen is associated with 66% grade 2-3 keratoconjunctivitis Used as part of an HSCT conditioning regimen of TBI of 12 Gy following 4 days of cytarabine 3 g/m 2 every 12 hours. This regimen is associated with 17% grade 2-3 keratoconjunctivitis. No adverse effects were attributed to the saline rinse This regimen is associated with 92% grade 2-3 conjunctivitis. May be preferred over prednisolone because of higher anti-inflammatory activity This regimen is associated with 25% grade 2-3 conjunctivitis Possibly equal to prednisolone in efficacy when given on a rigorous administration schedule every Inferior to prednisolone in efficacy when given on the same schedule More effective than a natural tear control administered every 8 hours in the opposite eye, but possibly equal to them when given on a rigorous administration schedule every 14 l Journal of Hematology Oncology Pharmacy l March 2015 l Vol 5, No 1

4 Table 3 Treatments for Cytarabine-Induced Conjunctivitis Agent Dose Duration Comments Dexamethasone 0.1% 5,6 1-2 drops every 2 hours Drops continue until microcysts resolve, then become tapered over 1 week Taper during 1 week as tolerated Diclofenac sodium 0.1% 8 8 hours Combined with dexamethasone eye drops until symptoms resolved Symptoms resolved promptly (actual time not defined) when diclofenac was added to dexamethasone drops Although it has been well-documented for >30 years, cytarabine-induced keratoconjunctivitis continues to be a poorly studied and problematic adverse effect of cytarabine use. Even though evidence has been reported that deoxycytidine, a competitive inhibitor of cytarabine, may be an effective antidote, a commercially available product for patient use is still not available. 11 Unless a deoxycytidine product is developed and proven successful, the information currently available would support the addition of an NSAID eye drop to corticosteroids for high-risk or symptomatic patients. 8 Additional research is clearly warranted in this area. n References 1. Hopen G, Mondino BJ, Johnson BL, et al. Corneal toxicity with systemic cytarabine. Am J Ophthalmol. 1981;91: Lass JH, Lazarus HM, Reed MD, et al. Topical corticosteroid therapy for corneal toxicity from systemically administered cytarabine. Am J Ophthalmol. 1982;94: al-tweigeri T, Nabholtz JM, Mackey JR. Ocular toxicity and cancer chemotherapy. A review. Cancer. 1996;78: Mori T, Watanabe M, Kurotori-Sotome T, et al. Reduced efficacy of topical corticosteroid in preventing cytarabine-induced kerato-conjunctivitis in patients receiving high-dose cytarabine and total body irradiation for allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2008;42: Lochhead J, Salmon JF, Bron AJ. Cytarabine-induced corneal toxicity. Eye (Lond). 2003;17: Higa GM, Gockerman JP, Hunt AL, et al. The use of prophylactic eye drops during high-dose cytosine arabinoside therapy. Cancer. 1991;68: Ritch PS, Hansen RM, Heuer DK. Ocular toxicity from high-dose cytosine arabinoside. Cancer. 1983;51: Matteucci P, Carlo-Stella C, Di Nicola M, et al. Topical prophylaxis of conjunctivitis induced by high-dose cytosine arabinoside. Haematologica. 2006;91: Stentoft J. The toxicity of cytarabine. Drug Safety. 1990;5: Mori T, Kato J, Yamane A, et al. Prevention of cytarabine-induced kerato-conjunctivitis by eye rinse in patients receiving high-dose cytarabine and total body irradiation as a conditioning for hematopoietic stem cell transplantation. Int J Hematol. 2011;94: Gococo KO, Lazarus HM, Lass JH. The use of prophylactic eye drops during high dose cytosine arabinoside therapy. Cancer. 1992;69: VISIT OUR RECENTLY ENHANCED USER-FRIENDLY WEBSITE Read the most recent articles just published in the Journal of Hematology Oncology Pharmacy, the nation s first peer-reviewed clinical journal for oncology pharmacists Review key studies recently published relevant to hematology/ oncology pharmacists Submit an article to the journal Vol 5, No 1 l March l Journal of Hematology Oncology Pharmacy 15

Oncology Providers Practice and Personalized Medicine Trends Barbara L.

Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St.

the Experts Breakfast 8:00 am 8:15 am Introduction and Opening Remarks Barbara L. McAneny, MD, American Medical Association Sanjiv S.

Providers, Patients, and Payers Can All Benefit from Improving the Way We Pay for Cancer Treatment Harold Miller, Center for

Milliman 10:00 am 10:15 am Break 10:15 am 11:00 am Session 3 - Oncology Medical Home A Patient-Centric System for Delivering Quality

McAneny, MD, American Medical Association 11:00 am 11:45 am Session 4 - FDA on Testing and Personalized Medicine Speaker TBD 11:45

Exhibit Hall or Sponsored Lunch Presentation 1:15 pm 2:00 pm Session 6 - Keynote Session - Value-Based Cancer Care: How Do We Get

Michael Kolodziej, MD, Aetna 2:45 pm 3:30 pm Session 8 - The Precision Medicine Initiative: Deliverables from Those on the Front

to Meet the Needs of the Exponential Growth of the Molecular Testing Era Victoria Pratt, MD (Invited) 4:15 pm 5:00 pm Session 10 -

5 Oncology Providers Practice and Personalized Medicine Trends Barbara L. McAneny, MD Chair, Board of Trustees American Medical Association Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke s Cancer Center Omni Shoreham Hotel Washington, DC AGENDA MAY 5, 2015 * ANNUAL CONFERENCE TH ANNIVERSARY 7:00 am 8:00 am Meet the Experts Breakfast 8:00 am 8:15 am Introduction and Opening Remarks Barbara L. McAneny, MD, American Medical Association Sanjiv S. Agarwala, MD, Temple University School of Medicine 8:15 am 9:15 am Session 1 - Win-Win-Win Approaches to Oncology Care: How Providers, Patients, and Payers Can All Benefit from Improving the Way We Pay for Cancer Treatment Harold Miller, Center for Healthcare Quality and Payment Reform 9:15 am 10:00 am Session 2 - Pitfalls or Challenges of New Payment Models Bruce Pyenson, Milliman 10:00 am 10:15 am Break 10:15 am 11:00 am Session 3 - Oncology Medical Home A Patient-Centric System for Delivering Quality Cancer Care Barbara L. McAneny, MD, American Medical Association 11:00 am 11:45 am Session 4 - FDA on Testing and Personalized Medicine Speaker TBD 11:45 am 12:15 pm Session 5 - Revamping Research Raju Kucherlapati, PhD, Harvard Medical School 12:15 pm 1:15 pm Networking Lunch in Exhibit Hall or Sponsored Lunch Presentation 1:15 pm 2:00 pm Session 6 - Keynote Session - Value-Based Cancer Care: How Do We Get There in the Omics Era? Gary Palmer, MD, JD, MBA, MPH, Nanthealth 2:00 pm 2:45 pm Session 7 - Can We Afford Personalized Medicine? Michael Kolodziej, MD, Aetna 2:45 pm 3:30 pm Session 8 - The Precision Medicine Initiative: Deliverables from Those on the Front Lines of Personalizing Care Harold Varmus, MD, National Cancer Institute (Invited) 3:30 pm 4:15 pm Session 9 - Adapting Regulation to Meet the Needs of the Exponential Growth of the Molecular Testing Era Victoria Pratt, MD (Invited) 4:15 pm 5:00 pm Session 10 - Role of Pathologist in the Age of Personalized Medicine Pranil Chandra, DO, PathGroup (Invited) 5:00 pm 5:45 pm Session 11 - The Role of Immunotherapy in Personalizing Treatment James Allison, PhD, MD Anderson Cancer Center (Invited) 5:45 pm 6:00 pm Poster Award Q & A 6:00 pm 6:15 pm Closing Remarks 6:15 pm 8:15 pm Reception in Exhibit Hall *Agenda subject to change. AVBCConline.org/conference AVBCC395_Agenda5Asize021215

Overview & pathophysiology of Dry Eye and the use of cyclosporine eye drops in dry eye...

Overview & pathophysiology of Dry Eye and the use of cyclosporine eye drops in dry eye... This Allergan sponsored session was held on July 24, 2005, Hotel Satya Ashoka, Jabalpur. The session was followed