Methotrexate and Fluorouracil Toxicities: What Advanced Practitioners in Oncology Need to Know

CE INFORMATION

A continuing education activity for nurse practitioners, physician assistants, clinical nurse specialists, advanced degree nurses, oncology and hematology nurses, pharmacists, and physicians

Release date: March 15, 2015

Expiration date: March 15, 2016 Estimated time to complete activity: 1.00 hours

Meniscus Educational Institute Advanced Practitioner Society for Hematology and Oncology 100 Overlook Center, 2nd floor 100 Overlook Center, 2nd floor Princeton, NJ 08540 Princeton, NJ 08540 Voice: 609-246-5000 Voice: 609-246-5000 Fax: 609-449-7969 Fax: 609-449-7969 E-mail: [email protected] E-mail: [email protected]

Faculty Christopher J. Campen, PharmD, BCPS, BCOP, Arizona Cancer Center, University of Arizona Wendy H. Vogel, MSN, FNP, AOCNP®, Wellmont Cancer Institute Julie M. Vose, MD, MBA, University of Nebraska Medical Center

Activity Rationale and Purpose The journal supplement will focus on the prevention and management of methotrexate and fluorouracil- related toxicities, especially with regard to proper dosing, the current standard of care, collaborative models of assessment and monitoring, and continued high levels of supportive care. The supplement will also cover expanded access programs, including their purpose, benefits, and potential concerns. The goal is to provide the tools healthcare professionals need to expand delivery of state-of-the-art medical care, improve patient outcomes, and enhance the quality of life in patients with cancer, as well as reduce the barriers impacting the integration of therapies into practice and support adherence to current guidelines.

Intended Audience The activity’s target audience will consist of nurse practitioners, physician assistants, clinical nurse specialists, advanced degree nurses, oncology and hematology nurses, pharmacists, and physicians.

3 CE INFORMATION

Learning Objectives After completing this educational activity, participants should be able to: 1. Summarize the effects of methotrexate (MTX)- and fluorouracil (5-FU)–induced toxicities on managing cancer 2. Describe the appropriate strategies for managing MTX- and 5-FU–induced toxicities 3. Discuss collaborative practice initiatives for managing MTX- and 5-FU–induced toxicities 4. Become familiar with the clinical considerations regarding the use of glucarpidase for MTX toxicity and uridine triacetate for 5-FU overexposure 5. Review the most recent FDA guidelines on expanded access programs and their effect on clinical practice

Continuing Education

Statement of Credit—Participants who successfully complete this activity (including the submission of the post-test and evaluation form) will receive a statement of credit.

Physicians. The Meniscus Educational Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The Meniscus Educational Institute designates this journal article (271.012.1503-MJ) for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurses. This activity (271.012-1503-NJ) for 1.00 contact hours is provided by the Meniscus Educational Institute. The Meniscus Educational Institute is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Provider approved by the California Board of Registered Nursing, Provider No. 13164, for 1.00 contact hours. Pharmacists. The knowledge-based accredited education lectures are intended for pharmacists involved in the care of cancer patients. This educational activity is sponsored by the Meniscus Educational Institute. The Meniscus Educational Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. The ACPE Universal Activity Number assigned to this program, for 1.00 contact hours, is 0429-9999-15-003-H01-P.

Financial Disclosures All individuals in positions to control the content of this program (eg, planners, faculty, content reviewers) are expected to disclose all financial relationships with commercial interests that may have a direct bearing on the subject matter of this continuing education activity. Meniscus Educational Institute has identified and resolved all conflicts of interest in accordance with the MEI policies and procedures. Participants have the responsibility to assess the impact (if any) of the disclosed information on the educational value of the activity.

4 CE INFORMATION

PLANNERS FACULTY Christopher J. Campen, PharmD, BCPS, BCOP, Christopher J. Campen, PharmD, BCPS, BCOP, has owned stock from AbbVie. has owned stock from AbbVie. Jeannine Coronna has nothing to disclose. Wendy H. Vogel, MSN, FNP, AOCNP®, has been Joseph Cupolo has nothing to disclose. a part of speakers bureaus for Novartis, Celgene, Genentech, Lilly, Onyx/Bayer, and Regeneron/Sanofi. Claudine Kiffer has nothing to disclose. has received research Terry Logan, CHCP, has nothing to disclose. Julie M. Vose, MD, MBA, funding from Allos Therapeutics/Spectrum, Bristol- Susan Reckling has nothing to disclose. Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Molly Thompson has nothing to disclose. Incyte, Janssen Biotech, Pharmacyclics, and US Pamela Hallquist Viale, RN, MS, CNS, ANP, has Biotest. nothing to disclose. Wendy H. Vogel, MSN, FNP, AOCNP®, has been WRITERS a part of speakers bureaus for Novartis, Celgene, Joseph Cupolo has nothing to disclose. Genentech, Lilly, Onyx/Bayer, and Regeneron/Sanofi. Susan Reckling has nothing to disclose. Julie M. Vose, MD, MBA, has received research funding from Allos Therapeutics/Spectrum, CONTENT REVIEWERS Bristol-Myers Squibb, Celgene, Genentech, Margaret M. Fields, RN, ACNP-BC, AOCNP®, has GlaxoSmithKline, Incyte, Janssen Biotech, nothing to disclose. Pharmacyclics, and US Biotest. Claudine Kiffer has nothing to disclose. Allison Muller, PharmD, has nothing to disclose. LEAD NURSE PLANNER Moshe Ornstein, MD, MA, has nothing to disclose. Rita Wickham, PhD, RN, AOCN®, has received honoraria from Genentech.

Disclaimer This activity has been designed to provide continuing education that is focused on specific objectives. In selecting educational activities, clinicians should pay special attention to the relevance of those objectives and the application to their particular needs. The intent of all Meniscus Educational Institute educational opportunities is to provide learning that will improve patient care. Clinicians are encouraged to reflect on this activity and its applicability to their own patient population. The opinions expressed in this activity are those of the faculty and reviewers and do not represent an endorsement by Meniscus Educational Institute of any specific therapeutics or approaches to diagnosis or patient management.

Product Disclosure This educational activity may contain discussion of published as well as investigational uses of agents that are not approved by the US Food and Drug Administration. For additional information about approved uses, including approved indications, contraindications, and warnings, please refer to the prescribing information for each product.

How to Earn Credit To access the learning assessment and evaluation form online, visit www.meniscusce.com Statement of Credit: Participants who successfully complete this activity (including scoring of a minimum of 70% on the learning assessment and complete and submit the evaluation form with an E-mail address) will be able to download a statement of credit.

5 MEET THE PANEL

ased upon a roundtable discussion conducted at JADPRO Live at APSHO in Orlando, Florida, Bthis supplement centers on strategies for preventing and treating severe side effects associated with methotrexate and fluorouracil (5-FU) from the unique perspective and shared goals of key members of the health-care team: a clinical oncology pharmacist, a medical oncologist, and an oncology nurse practitioner. Representing these team members on the roundtable panel were:

Christopher J. Campen, PharmD, BCPS, BCOP: Dr. Campen is a clinical oncology pharmacist at the University of Arizona Cancer Center, Tucson. He is also an associate editor for the Journal of the Advanced Practitioner in Oncology.

Wendy H. Vogel, MSN, FNP, AOCNP®: Ms. Vogel is an oncology nurse practitioner at the Wellmont Cancer Institute in Kingsport, Tennessee. She is also an associate editor for the Journal of the Advanced Practitioner in Oncology.

Julie M. Vose, MD, MBA, FASCO: Dr. Vose is the Neumann M. and Mildred E. Harris Professorial Chair and Chief of the Oncology/ Hematology Division in the Department of Internal Medicine at the University of Nebraska Medical Center and the Associate Director of Clinical Research and Co-Chair of the Lymphoma Program at the Fred and Pamela Buffet Cancer Center, Omaha, Nebraska. She is also President of the American Society of Clinical Oncology.

Julie Vose, Christopher Campen, and Wendy Vogel discuss methotrexate and fluorouracil toxicities in Orlando, Florida, at JADPRO Live at APSHO.

6 INTRODUCTION

Methotrexate and Fluorouracil Toxicities: What Advanced Practitioners in Oncology Need to Know

Proceedings from a roundtable discussion presented at JADPRO Live at APSHO, October 31, 2014, in Orlando, Florida

INTRODUCTION The collaborative practice model is well known to improve patient care and enhance health-care delivery. Many different scenarios of collaborative practice have been described in the literature, often combining the teamwork of physicians, nurse practitioners, physician assistants, pharmacists, and nurses. The collaborative practice approach is optimal to educate patients and all members of the health-care team regarding potential adverse effects and to implement strategies to prevent and manage them. Additionally, collaborative practice models are essential to the care of patients in the management of rare toxicities or complications resulting from cancer treatment. In these settings, it is essential to develop strategies for team-based prevention, early recognition, and toxicity management. Based on an expert collaborative roundtable panel discussion—featuring Julie M. Vose, MD, MBA, FASCO; Wendy H. Vogel, MSN, FNP, AOCNP®; and Christopher J. Campen, PharmD, BCPS, BCOP— at the JADPRO Live at APSHO (Advanced Practitioner Society for Hematology and Oncology) conference in Orlando, Florida, in October/November 2014, the content of this supplement to JADPRO is intended to review collaborative strategies that should be employed to improve the care of patients treated with fluorouracil (5-FU) and high-dose methotrexate. Both 5-FU and methotrexate are widely used agents in oncology, with unique toxicity profiles that require collaborative prevention and management for optimal patient care. These agents and their associated toxicities will be reviewed extensively in this supplement, especially with regard to proper dosing, monitoring, and prompt intervention. In addition, expanded access programs, including their purpose, benefits, and potential concerns, will be discussed. The focused goal of the JADPRO Live at APSHO conference was for advanced practitioners and physicians to come together to discuss current treatment options and advances in the care of cancer patients and to help identify means to improve collaboration. With this goal in mind, BTG Interna- tional Inc. provided an educational grant to assemble this distinguished panel to review preventive and management strategies for patients who experience toxicities related to treatment with 5-FU and methotrexate. –Christopher J. Campen, PharmD, BCPS, BCOP

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dvanced practitioners in oncology, in- INDICATIONS FOR USE OF cluding oncology nurses, oncology METHOTREXATE AND 5-FU pharmacists, physician assistants, so- High-dose methotrexate has been used for cial workers, cancer navigators, genetic multiple tumor types, including acute lympho- counselors,A dieticians, and mental health profes- blastic leukemia (ALL), primary central ner- sionals, are being increasingly encouraged and ed- vous system lymphoma (PCNSL), and sarcomas. ucated to work together in a collaborative manner Methotrexate was the first drug to demonstrate to manage patients with cancer. One of the more curative anticancer activity when used alone, and beneficial aspects of this collaborative interpro- single-agent methotrexate is still a cornerstone of fessional practice approach is to educate patients, treatment for malignant gestational trophoblastic as well as advanced practitioners in oncology, re- disease (Yarris & Hunter, 2003). The broad range garding prevention and management of potential of antitumor activity of methotrexate is reflected adverse events. Prevention and management of in the large number of malignant diseases for side effects and adverse events associated with which it is included in treatment regimens. In ad- cancer therapy are keys to enabling patients to re- dition to antiproliferative activity, methotrexate main adherent to their treatment. One example of also has anti-inflammatory and immunomodulat- this strategic approach can be seen in the use of ing properties, which allow for its use in a wide two established cancer agents: high-dose metho- range of therapeutic indications across multiple trexate and fluorouracil (5-FU). specialties outside of oncology. Both agents have a long history in the treat- A key drug in the treatment of colorectal, pan- ment of cancer, and they are employed in a wide creatic, head and neck, and gastric cancers, 5-FU variety of dosing and administration schedules. is also used for many other tumor types and syner- Methotrexate has been used (alone or in combina- gistic with other anticancer drugs (Hou et al., 2013; tion with other agents) in the treatment of a host Mori et al., 2013). “5-FU is a drug that we are all fa- of different cancers in several different clinical miliar with,” noted Dr. Vose. “It has very broad an- settings. Similarly, the first intravenous drug ap- titumor activities and is often combined with other proved 50 years ago, 5-FU, remains the backbone drugs such as oxaliplatin or irinotecan. It is usually of many combination curative and palliative ther- given as a continuous IV infusion and used in can- apy regimens. cers of the colon, breast, stomach, and pancreas.” The National Institutes of Health (NIH) Federal Register reported that of the 275,000 WHEN TREATMENT BECOMES TOXIC patients in the United States who receive 5-FU One of the first questions addressed during annually, about 8,000 (2.9%) will experience a the roundtable was, “What constitutes high-dose toxic reaction that causes death in approximate- therapy?” The answer is not as straightforward as it ly 1,300 patients each year (BTG International would seem, in the opinion of the panel. In terms of Inc., 2011). Impaired clearance (usually caused methotrexate, it is difficult to define a specific dose by dihydropyrimidine dehydrogenase [DPD] defi- that would be considered high dose. According to ciency) and medication errors are usually respon- the literature, Dr. Campen added, high doses are sible for systemic overexposure of 5-FU (BTG 500 mg/m2, with the duration of infusion varying International Inc., 2011). from 0.3 to 24 hours. In treating patients with ag- It is imperative that all members of this gressive lymphomas or osteosarcomas, high-dose health-care team be familiar with potential risk methotrexate is typically > 10 g/m2. factors and strategies for preventing serious toxic Although the use of high-dose methotrexate effects from methotrexate and 5-FU. In this way, was the focus of the discussion, the panel agreed all health-care team members ideally would be that even a low or intermediate dose given to a on the same page regarding the assessment and patient who has pleural effusion or ascites can be grading of toxicities and would be informed about toxic. Thus, they emphasized the importance of a newer pharmacologic interventions for safely thorough evaluation for third-space fluids to pre- managing adverse events should they occur. vent such toxicity.

8 METHOTREXATE AND FLUOROURACIL TOXICITIES REVIEW

It is important for clinicians to be knowledge- infusions of 5-FU are typically still used for upper able about the pharmacokinetics of methotrexate, gastrointestinal malignancies such as esophageal as they vary considerably among patients due to or gastric cancer. Furthermore, continuous infu- an assortment of factors. Among these factors, im- sion 5-FU is occasionally used as a radiosensitizer paired renal function and concurrent medications in cases of rectal cancer. An oral prodrug of 5-FU may have the greatest impact. “With methotrexate (capecitabine) is often used to replace lengthy toxicity, approximately 2% of patients are at risk 5-FU infusions, given capecitabine’s similar phar- for acute kidney injury,” noted Dr. Campen. macokinetics and easier oral delivery system (Saif, The analysis of some methotrexate parameters Syrigos, & Katirtzoglou, 2009). related to measuring patients’ response to the drug, Considerations for using leucovorin in con- such as creatinine clearance, the plasma concen- junction with both methotrexate and 5-FU were tration-time curve (AUC), dose, dose intensity, and briefly mentioned during the roundtable discus- rate of infusion, may enable clinicians and advanced sion. In regard to methotrexate, leucovorin has a practitioners to identify subgroups of patients who clear rescue role (Table 2). Along with hyperhy- may have an increased risk of severe toxicity or dration and urine alkalization, pharmacokineti- may likely experience poor outcomes (Ferreri et al., cally guided leucovorin rescue is a key component 2004). In addition, sufficient methotrexate elimina- in the safe administration of high-dose methotrex- tion may be adversely affected in patients receiving ate in patients with normal renal function (Ham- concurrent nonsteroidal anti-inflammatory drugs mor & Hassan, 2013). (NSAIDs), benzimidazoles, and sulfonamides (nu- However, in regard to 5-FU, this is not the merous drugs that inhibit renal excretion of metho- case. Leucovorin actually potentiates the activity trexate have been identified; see Table 1). of 5-FU, because both are part of the same meta- As for 5-FU, the question of high dose also was bolic pathway within cells (Hammor & Hassan, debated, as was its delivery system. This agent is 2013). Leucovorin rescue is discussed further in one of a few drugs for which the qualitative spec- the section “Strategies for Managing Methotrex- trum of toxicity changes dramatically with the ate and 5-FU Toxicities” starting on page 15. route of administration (Di Paolo et al., 2008). For instance, diverse patterns of toxic effects are seen when bolus schedules are compared with infu- Table 1. Drugs That Inhibit Renal Excretion of sional schedules (Di Paolo et al., 2008). Further- Methotrexate more, many patients treated with a 5-FU–based Category Drug regimen have plasma 5-FU levels that are not in the appropriate therapeutic range (Gamelin et al., NSAIDs Ibuprofen, aspirin, naproxen 2008), so about 50% of patients are underdosed Antibiotics Penicillin, and 10% to 20% are overdosed (Saif, Choma, Sal- sulfamethoxazole/ amone, & Chu, 2009). trimethoprim Approximately 85% of 5-FU is converted to in- Proton pump inhibitors Omeprazole, active metabolites by DPD, and only 1% to 5% of lansoprazole, the original 5-FU dose exerts cytotoxic effects on rabeprazole, esomeprazole, tumor cells and normal tissues through anabolic pantoprazole, actions (Saif, Syrigos, & Katirtzoglou, 2009). An dexlansoprazole enzyme present in the liver, intestinal mucosa, and Antifungal Amphotericin various other tissues, DPD metabolizes 5-FU to Antiviral Acyclovir 5,6-dihydro-5-fluorouracil (Diasio & Harris, 1989). Prior platinum-based Carboplatin, cisplatin, Continuous infusion 5-FU may be admin- chemotherapy oxaliplatin istered at higher doses over 2 to 5 days and at lower doses continuously for weeks. A 48-hour Note. NSAIDs = nonsteroidal anti-inflammatory drugs. For more information, visit www.drugs.com/drug- infusion of 5-FU is often used in treating patients interactions/methrotrexate/html with colon cancer, said Dr. Vose, but 3- to 5-day

9 REVIEW METHOTREXATE AND FLUOROURACIL TOXICITIES

Table 2. Safety Guidelines for the Continuation sensitive to mild-to-moderate reductions in renal and Timing of Leucovorin Rescue function,” Ms. Vogel added. “The creatinine con- • Leucovorin should not be administered within 2 hours centration is used to estimate the GFR (glomeru- before or after glucarpidase dose because leucovorin is lar filtration rate), which is usually considered the a substrate for glucarpidase.a best measurement of renal function.” • For the first 48 hours after glucarpidase, administer the Both the dose and the route of administration of same leucovorin dose as given prior to glucarpidase. methotrexate and 5-FU play a major role in the occur- • Beyond 48 hours after glucarpidase, administer rence of serious complications in some patients. For leucovorin based on the measured methotrexate concentration. example, methotrexate can be given in higher doses over prolonged IV infusions, which require support- • Do not discontinue therapy with leucovorin based on the determination of a single methotrexate ive care measures to prevent unacceptable toxicity concentration below the leucovorin treatment (Hammor & Hassan, 2013; Asselin et al., 2011). threshold. As for 5-FU, exposure is influenced by the method • Therapy with leucovorin should be continued until the of administration, DPD activity, and renal function, patient’s methotrexate plasma concentration has been maintained below the leucovorin treatment threshold accounting for both interpatient and intrapatient for a minimum of 3 days. variability in 5-FU plasma concentrations during the • Continue hydration and alkalinization of the urine as course of administration (Gamelin et al., 2008). indicated. “The main thing with 5-FU is that dose and aBTG International Inc. (2013). duration have an important effect,” summarized Dr. Campen. “Fluorouracil is often given over longer durations, for example, 1,000 mg/m2 per day Types of Adverse Effects and Toxicities for 4 days, in head and neck cancers. If the total The panel discussed adverse effects that occur dose of the infusion is given for too short of a du- with high-dose methotrexate and 5-FU. According ration, it can lead to significant toxic effects. Thus, to Dr. Campen, renal toxicity is one of the biggest it is so important to have protocols and policies in concerns with high-dose methotrexate. The replace to deal with that and to have double-checks ported incidence of acute kidney injury with high- to ensure that there are no miscalculations in the dose methotrexate is 1.8% of patients (Hammor dose or miscalculations in the rate of infusion.” & Hassan, 2013). The rate may be higher among Crystal nephropathy may occur when metho- patients with diabetes or those who have poor re- trexate and its metabolites precipitate in the renal nal function prior to treatment. Dr. Vose noted, “It tubules (Figure 1; Hammor & Hassan, 2013). This ini- is particularly important to assess patients’ renal tially manifests as asymptomatic elevations in serum function, including its characteristics. We have to be very careful about impaired renal function, so I think that working with the health-care team, including the pharmacist and oncology nurse, is important to manage each individual patient.” Added Ms. Vogel, “Nursing plays a key role in the assessment of a patient’s renal function, such as observing for decreased urine production, edema, and changes in the level of consciousness. Nurses should monitor hypertension, dyspnea, increasing fatigue and lethargy, nausea and vomiting, abdominal pain, and complaints of metallic taste in the mouth. Signs of electrolyte imbalance should be promptly reported and managed.” “Serum creatinine concentration is the most commonly used diagnostic study to determine the Figure 1. Methotrexate crystal formation seen in level of renal function; however, it is relatively in- renal tubules.

10 METHOTREXATE AND FLUOROURACIL TOXICITIES REVIEW

creatinine levels but may progress to more severe renal injury and tubular necrosis (Hammor & Hassan, Most definitely. That’s when we're confront- 2013). Impairment in renal clearance of methotrex- ed with increased toxicities in our patients. ate causes toxic levels of methotrexate to accumulate, furthering adverse events (Hammor & Hassan, 2013). Most of the methotrexate toxicities that we Another manifestation of methotrexate toxicity encounter are more acute than chronic, is transient elevation of hepatic transaminases and, such as renal dysfunction, renal failure, in severe cases, multiorgan failure (Hammor & Has- problems with low blood counts, and diffi- san, 2013). Dermatologic reactions, ranging from culty with mucositis, especially if a patient mild erythematous eruptions to exfoliative derma- has any pleural effusion or ascites. titis, may occur in 10% of patients receiving high- dose methotrexate (Hammor & Hassan, 2013). Would you say renal dysfunction is the ma- Methotrexate may cause neurotoxicity, which jor consideration? may vary from brief, transient episodes to more severe, chronic complications; this variance is re- Renal dysfunction requires that we have lated to the route of administration and the cumu- protocols in place for following renal func- lative dose (Newton, 2012). Neurotoxic manifes- tion closely and ensuring that the hydra- tations may include confusional states, cerebellar tion status is addressed before the patient dysfunction, headache, and spinal cord damage starts methotrexate. We also need to en- with myelopathy (Newton, 2012). In fact, tran- sure that the pH is at the proper level, be- sient central nervous system (CNS) disturbances cause with high-dose methotrexate, if the (such as cortical blindness, hemiparesis, and sei- pH becomes too acidic, it can result in zure) have been reported in up to 15% of high-dose kidney damage. methotrexate courses (Hammor & Hassan, 2013). At our institution, we are using high-dose methotrexate for high-risk lymphomas and Collaborative Exchange: Risks and leukemias. Are there any others types of Toxicities Associated with High-Dose cancers for which high-dose methotrexate Methotrexate is used?

Wendy Vogel: We know the administration of Patients with CNS lymphomas as well as high-dose methotrexate can be an issue. How the more aggressive NHLs would be the would we describe high-dose methotrexate? biggest population for which we use high- dose methotrexate. Christopher Campen: When I think about high-dose methotrexate, it is any dose that is We also see some neurotoxicity. Have you considered to require leucovorin rescue. In experienced that particular side effect in many cases, this is 500 mg/m2 or greater, but your practice? in some cases, doses less than 500 mg/m2 may require leucovorin rescue. This is impor- It happens occasionally, but it is not as tant because the adverse effect profiles vary common as some of the other toxicities. significantly between low-, intermediate-, Still, the fact that it can occur is another and high-dose methotrexate. The dosing reason patients should be monitored very range of high-dose methotrexate is quite carefully and frequently, including neuro- variable, with doses often up to 12 g/m2. logic checks, blood tests, and methotrexate levels. Again, there needs to be a spe- Julie Vose: Do you see more toxicities at cific protocol in place for managing each of these higher levels of methotrexate? these side effects.

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“Nurses must be absolutely alert to the CNS enzyme that metabolizes 5-FU, resulting in the changes in their patients receiving methotrexate,” breakdown of approximately 80% of 5-FU,” noted said Ms. Vogel. “You cannot assume that it is a Dr. Campen. “Deficiency in DPD is basically push- sleeping pill or an antiemetic that is making them ing all of the elimination of the drug to the renal drowsy,” she added, emphasizing the importance elimination pathway, and by doing that, signifi- of performing frequent neurologic assessments. cantly elevated levels of 5-FU result.” Common adverse effects associated with 5-FU Hand-foot syndrome is another concern associ- include nausea, vomiting, oral mucositis, myelosup- ated with 5-FU administration. It has been report- pression, and diarrhea (Amstutz, Froehlich, & Lar- ed in 6% to 42% of patients treated with traditional giadèr, 2011), which typically occur between 3 and systemic chemotherapeutic agents such as 5-FU 8 days after 5-FU administration. Other possible (Pike, 2001). Symptoms of HFS may evolve as early adverse events are stomatitis, gastrointestinal (GI) as 24 hours after treatment initiation and as late as mucosal ulceration, and bleeding (Saif, Choma, Sal- 10 months after continued therapy (Agha, Kinahan, amone, & Chu, 2009). These effects may result in Bennett, & Lacouture, 2007). “We do see quite a bit dehydration and electrolyte imbalances, as well as of hand-foot syndrome in a certain population of enterocolitis, which can progress to systemic infec- our patients,” emphasized Ms. Vogel. tion, sepsis, and even death. “As for mucositis, we cannot overemphasize the importance of mouth PREVENTION AND MONITORING OF sores as a potential site of infection,” said Ms. Vogel. TOXICITIES Although symptomatic cardiotoxicity from The prevention and monitoring of toxicities 5-FU is uncommon (occurring in 1% to 18% of associated with methotrexate- and 5-FU–based patients; Kim et al., 2012; Kosmas et al., 2008), it chemotherapy regimens may present a challenge can be potentially fatal and, thus, warrants atten- to oncologists and advanced practitioners in oncol- tion. Some evidence suggests an increased risk for ogy. However, with methotrexate, more standard- cardiotoxicity with continuous infusion or when ized approaches to prevention and monitoring are 5-FU is administered with cisplatin (Polk, Vaage- becoming more commonplace. With high-dose Nilsen, Vistisen, & Nielsen, 2013). The most com- methotrexate, drug level assessment is routinely mon symptom of cardiotoxicity is chest pain, fol- performed. Standard practice includes schemas of lowed by palpitations, dyspnea, and hypotension prescheduled drug levels 24, 48, and 72 hours after (Polk et al., 2013). More severe events, including completion of methotrexate infusion. Careful and myocardial infarction, cardiogenic shock, or car- ongoing patient evaluation by oncology nurses is diac arrest, are reported in up to 2% of patients re- essential to identify early toxicities. ceiving 5-FU (Polk et al., 2013). As for 5-FU, pharmacokinetic evaluation has “Although we may see cardiotoxicity as an idio- been studied, but it is not yet part of routine stan- syncratic event, we do have to remove patients from dard practice, as few cancer centers are able to per- receiving 5-FU, even in potentially curative settings, form on-site testing. In addition, outsourcing to in- if cardiotoxicity occurs,” commented Dr. Campen. dependent test sites is expensive and the cost may The panel addressed the relationship between be eligible for reimbursement. The use of pharma- the occurrence of adverse effects and the method cokinetic guidance with 5-FU is continually being of 5-FU administration. According to Dr. Vose, studied, and in the future, it may become part of there are differences in toxicity profiles with con- standard practice. tinuous infusion and bolus delivery. “Specifically, you see a lot more hand-foot syndrome (HFS) and Prior to Methotrexate Administration less myelosuppression with continuous infusion The panel emphasized the importance of thor- than with IV bolus 5-FU,” she remarked. oughly assessing patients’ needs before high-dose Another issue associated with 5-FU adminis- methotrexate therapy is started. Patients should tration is the existence of DPD deficiency, a ge- be screened for adequate bone marrow, hepatic, netic inability to metabolize DPD (Amstutz et al., and renal function. Additionally, a patient’s uri- 2011). “Dihydropyrimidine dehydrogenase is an nary output should be > 100 mL/h, and his/her

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urinary pH must be maintained at > 7.0, as crystal- During Methotrexate Administration lization of methotrexate is less likely in an alkaline As methotrexate is predominately eliminated environment (Green, 2012). A detailed medication by the kidneys, assessment of renal function be- history should be taken to assess potential drug– fore and during infusion of each dose of high-dose drug interactions. methotrexate is necessary. Key measures of kidney Clinicians should be aware that drug elimi- function include serum creatinine, serum potas- nation may be reduced in patients with renal im- sium (severe renal failure may lead to life-threat- pairment, ascites, or pleural effusion. A baseline ening hyperkalemia), serum methotrexate, blood physical examination should be performed before urea nitrogen (BUN), urine output, and urine pH patients begin therapy and should be assessed fre- (Table 3; Al-Turkmani, Law, Narla, & Kellogg, quently during therapy. Important prophylactic 2010; Ahmed & Hasan, 2012; Nowicki, Bjornard, interventions are adequate hydration (2.5–3.5 L of Kudlowitz, Sandoval, & Jayabose, 2008). fluid/m2/24 hours), beginning 12 hours before the Plasma methotrexate levels should be monitored start of methotrexate and during methotrexate ad- closely to detect any delay in methotrexate clearance ministration (Green, 2012). (Warnick & Auger, 2009). Depending on the treat- Patients should be educated about the poten- ment protocol, plasma methotrexate assays may be tial side effects and informed that many of these appropriate at 24, 48, and 72 hours after the start of effects may resolve relative to time and/or treat- methotrexate infusion (Ahmed & Hasan, 2012). Se- ment interventions. “Patients and their caregivers rum methotrexate levels should be assessed with must have a thorough understanding of how and ongoing adjustment in hydration, alkalization, and when to take their medications, both treatment leucovorin rescue until the target level (< 0.05–0.1 medication and medications to manage side ef- μmol/L) is reached (Widemann & Adamson, 2006). fects,” emphasized Ms. Vogel. “It is helpful to have patients and caregivers repeat back this informa- Prior to 5-FU Administration tion to the health-care professional to demonstrate Appropriate preventive measures also should their understanding. Patients and their caregivers be implemented before patients begin 5-FU must know what symptoms to report to and how monotherapy or combination therapy. As 5-FU to get in touch with the health-care professional. is associated with possible cardiotoxicity, pre- Written information will facilitate understanding chemotherapy history and physical examination and recall for patients.” for careful evaluation of cardiovascular risk fac- As previously mentioned, clinicians should be tors that could be exacerbated by 5-FU are para- aware of common drug interactions associated with mount for all patients (Sorrentino, Kim, Foderaro, methotrexate. For instance, concomitant administra- & Truesdell, 2012). However, research has yet to tion of some NSAIDs with high-dose methotrexate provide conclusive evidence regarding the value may lead to elevated and prolonged serum metho- of prophylactic cardiac agents (i.e., calcium chan- trexate levels, which can result in death secondary to nel blockers and nitrates; Cianci et al., 2003). severe hematologic and GI toxicities (Green, Chow- dhary, Lombardi, Chalmers, & Chamberlain, 2006). Other adverse effects may include malaise, nausea, Table 3. Prevention of Nephrotoxicity From High-Dose Methotrexate vomiting, headaches, and mild alopecia, which are typically not life-threatening. • Aggressive hydration Oncologists and advanced practitioners • Urine alkalization to keep urine pH between 7.0 and 8.5 • Leucovorin rescue should review the patient’s current medications • Close monitoring prior to starting methotrexate and address any ♦ Urine output potential problematic drugs. “[Physicians] de- ♦ Fluid balance (avoid negative balance) pend on our clinical oncology pharmacist to pay ♦ Methotrexate levels attention to potential drug interactions, because ♦ Serum creatinine levels it is something that we may not do routinely,” Note. Information from Ahmed & Hasan (2012). said Dr. Vose.

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Although tests are available to determine the Unfortunately, although there is testing relative activity of the DPD enzyme (Ciccolini, available, I don’t find that we use it a whole Gross, Dahan, Lacarelle, & Mercier, 2010), they do lot in clinical practice. In our practice, usu- not always predict 5-FU toxicity. The issue with ally we have someone who received stan- DPD deficiency is a little bit confusing, the panel dard doses, and then all of a sudden, we agreed. However, the panel noted that DPD defi- see this huge hand-foot syndrome, horrible ciency testing, as with some other pharmacoge- mucositis, terrible diarrhea; at that point, netic testing, is underutilized. we may check for a DPD deficiency. I don’t Dr. Vose indicated, “DPD deficiency occurs know when that testing will become stan- in only about 3% to 5% of the general population, dard of care. Do you use this type of testing but up to 50% of toxicities with 5-FU may be at- in your practice? tributed to this (Moore, 2009). This test may be performed via whole-blood test or buccal swab No, we don't. We feel the same way, basi- and even may be self-ordered in some states by cally. If someone has an extreme toxic re- patients themselves.” action to 5-FU, severe diarrhea, and poten- “The difficulty with ordering DPD testing is tially a leukopenic fever, we would possibly how to interpret and act upon the results,” added Dr. test for DPD, and this often follows an inpa- Campen. “There are no standard recommendations tient admission. At this time, these are the for dose adjustments, and there are varying degrees only patients who we would test for poten- of DPD deficiency. Alternatively, 5-FU pharmacoki- tial DPD deficiency. netic analysis can be performed if the patient is receiving a continuous infusion, which can help guide appropriate treatment” (Goel et al., 2015). aware of potential problems associated with malfunction in pump usage. During 5-FU Administration Infusion errors and pump failures can cause Once 5-FU therapy is started, clinicians should serious harm and even death. According to one be aware of certain signs and symptoms of possible report, over a 4-year period, more than 56,000 toxicity. As 5-FU–based therapy is often adminis- adverse events and 710 deaths associated with tered via infusion pumps, clinicians alsoneed to be infusion devices were reported to the US Food and Drug Administration (FDA)—more than for any other medical technology (Association for Collaborative Exchange: Preventive the Advancement of Medical Instrumentation, Measures for 5-FU Toxicities 2010). This analysis takes into account only those adverse events and deaths that were reported. Wendy Vogel: We all realize that preventive Thus, a thorough education on pump functioning measures are huge, especially in preventing is needed for health-care professionals, patients, possible cardiotoxicity associated with 5-FU. and caregivers. It is important to look at the patient’s medi- Typical infusion pump problems include soft- cal history and to interview the patients to ware malfunctioning, alarm errors, inadequate determine whether there is any preexisting user-interface design, broken components, and cardiotoxicity or other side effects prior to battery failures (FDA, 2014a). Patients, especially chemotherapy. We should be looking for those receiving ambulatory IV infusions, should cardiovascular risk factors that may be exac- be instructed about symptoms to report to their erbated by 5-FU. I particularly want to deter- health-care team. Strategies to prevent problems mine the current hydration status. include having a backup plan in effect in case of an infusion pump failure; labeling the infusion Christopher Campen: So when do you con- pump channels and/or tubes with the name of sider looking for a DPD deficiency? the medication or fluid; verifying that the infusion pump is programmed for the right dosage, at

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the right rate, and the right volume to be infused; It’s less than a 10% change in the drug dose. obtaining an independent double-check of infu- The toxicity of administering a bolus amount sion pump settings; and using available resources of drug can often be significant when you cal- (FDA, 2014a). culate the amount of milligrams.

What type of monitoring does your institution do regarding infusion pump functioning? Collaborative Exchange: Infusion Pump Concerns With 5-FU All patients who are on a 5-FU pump are checked multiple times by attending staff. Wendy Vogel: Pump malfunction as a cause Basically, we have the prescriber or pre- of 5-FU overdosing is a concern in our prac- scribing advanced practitioner provide the tice. Can you provide insight on your expe- initial check on the prescription, followed riences with pump malfunction? by the clinical nurses. The nurses review and assess the prescribing order before it Christopher Campen: We have had our even reaches the pharmacy. In the pharma- share of that. Fortunately never with 5-FU, cy, we have double-checks in place. We but we have had pump malfunctions, and have two pharmacists sign off on every we have had pump errors. That is why we 5-FU pump that goes out, and there is also have double-checks in place. I cannot stress a technician involved in the process who enough how important it is to have written checks calculations, fills the pump, and cre- documentation of the rates that you use for ates the admixture. calculations and written assessments of how you basically program the dose. And if you have off-site clinics, you can use camera technology for double-checks. One study of great interest to me found Camera technology is an up-and-coming that over a 4-year period, there were more area, especially when groups are joining to- than 56,000 adverse events and 710 deaths gether. For example, at my institution, we attributed to 5-FU, mostly related to pump have an off-site pharmacist clinic where we failures or infusion programming errors. can take pictures and have them displayed Quite interesting and something we cer- at our primary site of pharmacy. We use our tainly never want to have happen in our camera technology not only for 5-FU, but practice. Also, I would be interested to also for double-checking when the techni- know what you do in your practice regard- cian has created a drug. ing residual drug remaining in the pump. There’s some controversy involved on how best to handle that. STRATEGIES FOR MANAGING METHOTREXATE AND 5-FU TOXICITIES Yes, residual drug remaining in the pump is Prevention of serious methotrexate and 5-FU something that everyone is aware of, espe- toxicities is clearly the ideal goal. However, when cially when you conduct a Saturday clinic un- adverse effects do occur, they require prompt iden- til, say, 2:00 p.m. and you have 4 hours of tification through accurate grading and knowl- drug remaining. I honestly don’t have the edge about effective pharmacologic interventions. perfect answer for that, and I don’t think any- All members of the health-care team need to have body does. We approach it on a patient-by- a firm grasp on the myriad challenges involved while patient basis. For instance, if it’s a 4-day working collaboratively to safely manage patients pump and there are 4 hours left, I would with these potentially life-threatening complications. definitely recommend stopping the infusion. “Obviously, we would prefer to prevent methotrexate and 5-FU toxicities,” noted Dr. Vose. “It’s

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really not that much fun when they happen. So, de- Methotrexate Nephrotoxicity: Glucarpidase veloping strategies to prevent toxicities is vital in Key steps to preventing methotrexate-in- any treatment center. This usually entails optimiz- duced nephrotoxicity center on leucovorin res- ing hydration, ensuring the dose is appropriate for cue, urine alkalization, and hydration (Rattu, the patient, and frequently checking to make sure Shah, Lee, Pham, & Marzella, 2013). Although the renal function and electrolyte levels are adequate.” majority of patients benefit from this standard approach, others experience prolonged, elevated Grading Toxicity plasma methotrexate concentrations and nephro- The panel discussed the difficulty of accurately toxicity. For these patients, the carboxypeptidase grading adverse effects of methotrexate and 5-FU enzyme glucarpidase is an effective therapeutic (such as diarrhea, neuropathy, mucositis, and skin approach (National Comprehensive Cancer Net- toxicity). Grading may be highly variable from one work [NCCN], 2014a). particular type of toxicity to another depending Glucarpidase, a recombinant bacterial enzyme, on whether the Eastern Cooperative Oncology hydrolyzes the carboxyl-terminal glutamate residue Group (ECOG) grading scale or the National Can- from folic acid and classic antifolates, such as metho- cer Institute’s Common Terminology Criteria for trexate (BTG International Inc., 2013). Glucarpidase Adverse Events (NCI-CTCAE) is used. converts methotrexate to its inactive metabolites, Other adverse effects that may be difficult to 4-deoxy-4-amino-N10-methylpteroic acid and gluta- grade are mucositis and cutaneous toxicity, even mate, and provides an alternate nonrenal pathway for when a patient is receiving 5-FU in the setting of methotrexate elimination in patients with renal dys- a clinical trial. Team members may need more de- function during high-dose methotrexate treatment. tailed education to describe clinical observations Glucarpidase has been available since 1993 regarding mucositis and skin concerns. Ms. Vogel through the FDA’s compassionate-use criteria emphasized, “Cutaneous toxicity may occur with (Rattu et al., 2013). The drug was formally ap- both methotrexate and 5-FU.” proved by the FDA in January 2012 for the treatment of toxic plasma methotrexate concentrations Osteosarcoma and High-Dose Methotrexate (> 1 μmol/L) in patients with delayed methotrex- Osteosarcoma is the most common primary ate clearance due to impaired renal function (BTG malignant bone tumor (Zhang et al., 2015). There International Inc., 2013). is a close relationship among methotrexate con- Patients may be candidates for glucarpidase centration, adverse reactions, and treatment ef- therapy if they have extremely high methotrexate fect, with large individual differences. levels, often accompanied by renal dysfunction. The incidence of toxicity has decreased as “You are trying to prevent the rare side effects a result of plasma methotrexate concentration such as neurotoxicity and seizures,” noted Dr. monitoring and appropriate leucovorin rescue, Campen. Other potential candidates for glucar- combined with adequate hydration and urine al- pidase therapy may include those with markedly kalinization. However, the higher the concentra- increased serum creatinine levels, CNS changes tion of methotrexate, the more side effects will (such as problems with speech, vision, or mental occur. In patients with osteosarcoma, the safe function), and extreme weakness/fatigue (BTG range for the AUC has been found to be between International Inc., 2013). 4,000 mM/h and 12,000 mM/h (Comandone Clinical studies have shown glucarpidase rapidly et al., 2005). reduces plasma methotrexate concentrations (Fig- “At our institution, we have a protocol for ure 2; Widemann et al., 2014; Widemann et al., 2010). osteosarcoma and high-dose methotrexate,” In a study by Widemann and colleagues (2014), 476 noted Dr. Vose “The protocol includes looking patients who developed renal toxicity and delayed for drug interactions, checking the patient’s methotrexate elimination from treatment for osteo- medication list, and making sure they are not sarcoma, non-Hodgkin lymphoma, or acute lympho- taking any over-the-counter medications you blastic leukemia were given IV glucarpidase. The don’t know about.” result was a 99% or greater sustained reduction in

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serum methotrexate levels within the first through the last measurements (15 minutes to 40 hours). The question of when to administer glucarpi- 100 dase was discussed by the panel and has been addressed in the medical literature. Widemann and 10 colleagues (2010) found that early intervention with a combination of glucarpidase and leucovo- 1 rin was highly effective in patients with high-dose methotrexate-induced renal dysfunction. How- 0.1 15 min ever, they noted that severe toxicity and mortal- [n=138] 00.1 ity occurred when glucarpidase was administered BL 1 h 2 h 1 d 2 d 3 d 4 d 5 d 6 d 7 d 8 d > 96 hours after the start of methotrexate infusion. [n=156] [n=149] [n=127] [n=102] [n=69] [n=53] [n=40] [n=36] [n=30] [n=25] [n=26] Still, even after 48 hours of elevated serum levels of methotrexate, glucarpidase may be a better option than dialysis or higher doses of leucovorin. Figure 2. Glucarpidase reduces plasma No major adverse effects have been reported methotrexate concentrations, but excellent with glucarpidase (Rattu et al., 2013). In nearly 300 supportive care is also necessary to reduce morbidity. BL = baseline; MTX = methotrexate. study patients, the most common side effects seen From Widemann et al. (2014). were paresthesia, flushing, and nausea/vomiting (all 2%; Green, 2012; BTG International Inc., 2013). ately. Glucarpidase reduces methotrexate levels in “Glucarpidase appears to be associated with the bloodstream but has no effect on intracellular little toxicity,” noted Ms. Vogel. “I would have a methotrexate levels. Therefore, leucovorin, which low threshold to use it, even if a patient was on the combats intracellular methotrexate, is a necessary borderline of a toxic dose.” Dr. Campen agreed: “If component of treatment (NCCN, 2014b). you have already maximized the dose of leucovo- The optimal timing of leucovorin rescue after rin and have not seen patient benefit, you need to high-dose methotrexate administration is a top- think of glucarpidase right away.” ic of debate. A recent study by Cohen and Wolff In fact, the NCCN Guidelines for both CNS lym- (2014) found that leucovorin rescue begun 30 to phomas and non-Hodgkin lymphoma include glu- 36 hours after the start of methotrexate was safe, carpidase (NCCN, 2014a; NCCN, 2014b). For patients whereas leucovorin rescue at 42 to 48 hours re- with CNS lymphomas who have delayed methotrex- sulted in toxicity. Thus, they concluded that leu- ate excretion and high plasma methotrexate con- covorin rescue should be started no later than 36 centrations, the NCCN Guideline notes that early hours after the start of methotrexate treatment. intervention with glucarpidase has demonstrated efficacy in rapidly reducing these high methotrexate plasma concentrations and preventing severe toxici- Table 4. Considerations for Patients Receiving Glucarpidase ty (Widemann et al., 2004) and should be considered over hemodialysis. Under the supportive care sec- General • Select appropriate patient population tion of the NCCN Non-Hodgkin Lymphoma Guide- • Become familiar with its mechanism of action lines (NCCN, 2014b), the NCCN panel recommends • Know its dosing and scheduling requirements considering the use of glucarpidase if a patient has • Promptly identify potential side effects significant renal dysfunction and methotrexate lev- Specific els > 10 mol beyond 42 to 48 hours. μ • Monitor patients for allergic reactions Advanced practitioners must be knowledgeable • Adjust administration schedule for leucovorin in glucarpidase administration along with leucovo- • Monitor methotrexate levels rin and precautions with its use (Table 4). Accord- • Monitor renal function laboratory results and urine ing to Dr. Campen, glucarpidase is typically given output in a single IV injection (50 U/kg; BTG Internation- • Provide standard-of-care treatment, including leucovorin therapy, hydration, and alkalization of urine al Inc., 2013) and begins working almost immedi-

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Collaborative Exchange: Use of administration of glucarpidase and should be contin- Glucarpidase in Clinical Practice ued until the patient’s methotrexate plasma concentration has been maintained below the leucovorin Wendy Vogel: Can you share your thoughts treatment threshold for at least 3 days (BTG Interna- and experiences regarding the use of glu- tional Inc., 2013). However, leucovorin should not be carpidase in actual practice? administered within 2 hours before or after glucarpidase (Widemann et al., 2010), as coadministration Julie Vose: The rare occasion when I have of these agents diminishes their effectiveness. seen this drug being utilized is for patients In addition, advanced practitioners should con- who have severe toxicity, and high-dose tinue with hydration and alkalization of urine, ac- leucovorin is not effective. Even though we cording to the physician’s recommendations (BTG have optimized hydration and have taken International Inc., 2013). Adequate hydration and measures to provide appropriate care, pa- alkalization greatly decrease the risk for nephro- tients may still exhibit acute renal dysfunc- toxicity,” noted Ms. Vogel. “Early renal dysfunction tion. In such patients, the methotrexate may not have clear clinical symptoms. Therefore, level remains dangerously high. This is it is vital that health-care professionals, often the when we would turn to glucarpidase. And advanced nurse practitioner or the physician assis- again, it is important to have a protocol in tant, closely monitor fluid intake and urinary out- place for this type of situation. There will put as well as serum and urine electrolyte concen- be patients who will need this drug, so you trations and plasma methotrexate concentrations.” should make sure the pharmacy has an emergency protocol in place to obtain it. Resumption of High-Dose Methotrexate Many cancer patients require multiple courses Christopher Campen: I think with glucarpi- of high-dose methotrexate, and the delay or omis- dase and specifically because of the rea- sion of these courses may adversely affect their sons Dr. Vose mentioned, it’s really impor- prognosis (Christensen et al., 2012; Scott, Ward, tant to address obtaining it with business Crews, Panetta, & Navid, 2014). The panel ques- management and formulary beforehand, so tioned whether it is safe to resume high-dose meth- you don’t run into a case where people are otrexate after acute kidney injury and glucarpidase panicking when the patient needs the drug. use. According to a small study by Christensen and You have to address it because it is a very colleagues (2012), an anecdotal report, and the view expensive medication, but it’s a potentially of the panel, the answer appears to be yes. lifesaving medication, which effectively de- “After the rescue, if the patient’s renal toxic- creases methotrexate levels in a patient ity resolves completely and the need is still there who has extremely high blood methotrex- (which it usually is), you can resume high-dose ate levels. Addressing these issues and hav- methotrexate cautiously,” stated Dr. Campen. “Most ing a plan in place can help to avoid poten- cases of renal dysfunction are short-lived.” Ms. Vo- tial dialysis or other possible problems. gel added: “A thorough discussion with the patient of retreatment risks, benefits, and interventions to When you discuss with patients and their prevent repeat renal dysfunction would ensue.” caregivers this option and compare the In the study by Christensen and colleagues costs and complexity of 1 or 2 days of dialy- (2012), 20 pediatric cancer patients received glu- sis vs. the cost of glucarpidase, I think they carpidase, and 13 of them received 39 courses of can kind of understand that. high-dose methotrexate afterward. The investiga- tors found that 11 of the 13 patients tolerated the rechallenge of high-dose methotrexate therapy According to the NCCN Guidelines for non- well. During treatment courses that necessitated Hodgkin lymphoma (NCCN, 2014b), leucovorin res- glucarpidase, the median time to complete metho- cue should be continued for at least 2 days after the trexate excretion was 355 hours during the first

18 METHOTREXATE AND FLUOROURACIL TOXICITIES REVIEW

course; 90 hours for the next course; and 72 hours individuals with a history of severe 5-FU toxicity. for subsequent courses. Although one patient ex- Early-onset toxicity should also be a red flag for perienced nephrotoxicity upon resumption of nurses. Ms. Vogel emphasized the need to edu- treatment, renal function returned to baseline cate nurses, particularly those handling the triage in all patients, and no patients died as a result of phone calls, that an early onset of severe side ef- methotrexate-induced nephrotoxicity. fects from a cancer treatment may indicate a life- threatening toxicity; for example, severe mouth Overexposure to 5-FU: Uridine Triacetate sores seen a few days after receiving 5-FU are not There is no FDA-approved antidote for 5-FU the same as the mouth sores that occur a week after overexposure. However, successful results have treatment with a combination cyclophosphamide been reported with the use of the investigational and doxorubicin. “Nurses need to know when to drug uridine triacetate (formerly known as viston- expect normal toxicities and when to bring that uridine; Bamat, Tremmel, O’Neil, von Borstel, & patient in for examination,” added Ms. Vogel. Fi- Wellstat Therapeutics Corporation, 2010; Bamat, nally, uridine triacetate could be considered for Tremmel, von Borstel, Helton, & Wellstat Thera- future courses of 5-FU, as noted by Dr. Campen. peutics Corporation, 2013; McEvilly, Popelas, & Uridine triacetate has demonstrated effec- Tremmel, 2011). This drug is an oral bioavailable tiveness for patients with emergency 5-FU over- prodrug of uridine, a direct biochemical antago- dose, as well as for those with known or suspected nist of 5-FU toxicity (Bamat, Tremmel, O’Neil, overexposure to 5-FU that occurs because of DPD von Borstel, & Wellstat Therapeutics Corporation, deficiency. In addition, there was an anecdotal re- 2010). After conversion of uridine triacetate to port of a patient with colon cancer experiencing uridine, it reduces incorporation of 5-FU metabo- 5-FU overdose who was successfully treated with lites, particularly into noncancerous cells (Busi- a 5-day course of oral uridine triacetate (McEvilly, ness Wire, 2012). Popelas, & Tremmel, 2011). Although not yet approved by the FDA in the An update on clinical experience with uridine United States, uridine triacetate is available under triacetate in 98 patients with 5-FU overexposure the expanded access protocol and in the European was presented at the 2013 Annual Meeting of the Union on a named patient supply basis (Business American Society of Clinical Oncology (ASCO; Wire, 2012; see the section on “Expanded Access Bamat et al., 2013). These patients received uri- Programs” beginning on page 20 and the sidebar dine triacetate, and 96 (98%) recovered fully. “Questions Answered About Uridine Triacetate” Patients also experienced reduced or absent GI, on page 32). Other potential applications of uri- hematologic, and other toxicities of overexpo- dine triacetate under study are for treatment of sure to 5-FU. Adverse events related to uridine neurodegenerative and mitochondrial disorders triacetate were reported as mild and infrequent (Business Wire, 2012) and combination use with (Bamat et al., 2013). high-dose 5-FU, which may enable repeated tumor exposure to unprecedented levels of intact Overexposure to Capecitabine: 5-FU that enhance antitumor efficacy. Uridine Triacetate Current candidates for treatment with uridine Oral capecitabine use has increased over the triacetate include those who have 5-FU overexpo- years, noted Dr. Campen. It is a prodrug that is sure due to a dosing error, pump malfunction, or enzymatically converted to 5-FU preferentially in error in programming an infusion pump. Patients tumor cells, which improves its therapeutic ratio, with partial or total DPD deficiency, for whom its Dr. Vose added. However, in the setting of severe accumulation may be potentially lethal, may also DPD deficiency, it is possible to experience life- be candidates for treatment with uridine triac- threatening toxicity from capecitabine (Saif, Syri- etate (Business Wire, 2012). gos, & Katirtzoglou, 2009; Genentech, 2014). According to Dr. Campen, other core patients If a patient develops capecitabine overdose, for whom uridine triacetate should be considered uridine triacetate is an appropriate option to pre- are those with very early onset 5-FU toxicity and vent severe morbidity or even death, Dr. Campen

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said. He noted that unlike 5-FU infusions, which methotrexate (Table 5) and 5-FU. All members of are given over 46 to 48 hours, capecitabine is of- the panel considered protocols essential for making ten given orally, twice daily, for 14 days of a 21-day prompt decisions regarding pharmacologic man- cycle in the treatment of colorectal cancer. If a pa- agement, such as treatment with glucarpidase and tient develops early toxicity such as grade 4 toxic- uridine triacetate. These agents are rarely used, so ity while still actively receiving capecitabine, uri- clear instructions should be posted on both inpa- dine triacetate may be an option after capecitabine tient and outpatient areas of clinical oncology sites. discontinuation and prompt supportive care. Protocols for glucarpidase use may vary, but most generally follow approved use from the full pre- Final Thoughts on Uridine Triacetate scribing information (BTG International Inc., 2013) The panel recommended steps to be taken by and note specific inclusion criteria, said Dr. Campen. the health-care team while awaiting the arrival of Protocols should be in place to guide the acquisition uridine triacetate. First, the patient should be admit- of uridine triacetate, which would include contact ted to the hospital, Dr. Campen said. Then each of information of the local investigational review board the patient’s symptoms should be treated, Dr. Vose and the pharmaceutical company. continued. For instance, diarrhea should be treated by institutional protocols, and good mouth and skin EXPANDED ACCESS PROGRAMS care is needed. “If the patient is neutropenic, pan- The FDA’s expanded access program is a means cultures should be done; in some cases, prophylactic by which manufacturers make investigational new antibiotics should be started,” added Ms. Vogel. drugs available, under certain circumstances, to treat Finally, the panel stressed the importance of patients with a serious disease or condition who can- developing and implementing triage plans and not participate in a controlled clinical trial. There is a protocols for monitoring patients on high-dose process to obtain and administer a drug through the

Table 5. Sample Protocol for Prevention of Methotrexate Toxicity in Patients Treated for Osteosarcoma Drug interaction check Pharmacist should review all medications for potential drug interactions with methotrexate. Assess for pleural effusions or ascites Consider methotrexate dose decrease of 25% to 50%. Assess renal function Creatinine clearance must be > 50 mL/min. If delayed methotrexate clearance occurred with previous cycles, consider a dose decrease of 25% to 50%. Mucositis If grade 3 or greater mucositis occurred with previous courses, consider dose of 25% to 50%. Assess hydration status Order intravenous fluids at a rate to exceed 200 mL/h to prevent renal dysfunction associated with methotrexate. Sodium bicarbonate, sodium acetate, Check urine pH every void and prior to the start of methotrexate. Urine pH or acetazolamide must be > 7. Continue to check every shift until methotrexate level < 0.05 μmol/L. Contact provider if urine pH is < 7. Methotrexate level 1–24 hr 24-hr goal < 5 μmol/L Methotrexate level 2–48 hr 48-hr goal < 0.5 μmol/L Methotrexate level 3–72 hr 72-hr goal < 0.05 μmol/L Leucovorin 25 mg po q6h Start 24 hr after initiation of methotrexate. If concentration level at any time point exceeds goal, increase leucovorin dose to 50 mg IV q6h and contact provider for further direction. Glucarpidase management if needed If plasma methotrexate level > 50 μmol/L at 24 hr, > 5 μmol/L at 48 hr, or greater than two standard deviations above the mean methotrexate elimination curve at least 12 hr following methotrexate administration, and serum creatinine increased greater than twofold above baseline (pretreatment with methotrexate) level, consider emergent use of glucarpidase.

20 METHOTREXATE AND FLUOROURACIL TOXICITIES REVIEW

expanded access program (see sidebar on Learning Concerns and Costs More About Expanded Access Programs). Use of the There are risks and concerns regarding ex- expanded access program has increased dramati- panded access programs (FDA, 2013). For in- cally in recent years. In 2010, 1,000 patients received stance, some serious safety issues may not become treatment via the expanded access program. A year apparent until post marketing. In addition, early later, that number had increased by 20% to 1,200 access to investigational therapies could make (FDA, 2010). phase II and III clinical trials more difficult to perform. Also, from the standpoint of the drug Requirements and Benefits manufacturer, the manufacturing capacity is often The basic requirements for a pharmaceuti- limited in early phases, and thus the supply of the cal agent to be accepted into the expanded access drug for expanded access could limit the supply program follow: needed for clinical trials. • There is no comparable or satisfactory alterna- From the patient perspective, health insurers tive therapy for a condition. may not reimburse substantial costs associated • The potential benefit justifies the potential with the drugs. From the physician perspective, risks of the treatment, and those risks are not the costs to provide access may not be fully com- unreasonable in the context of the disease or pensated; in addition, physicians may face liability condition being treated. issues, and their participation requires commit- • The use of the drug will not interfere with or ment (i.e., contacting the drug manufacturer and compromise its further development for clini- filing paperwork; FDA, 2014b). cal investigation (FDA, 2010). Investigational New Drug vs. Drug in the Ex- The benefits associated with expanded access panded Access Program programs include (FDA, 2010): Advanced practitioners should be cognizant • Providing access to drugs for patients with seri- of the difference between an investigational new ous or life-threatening diseases without alter- drug (IND) and a drug in the expanded access pro- native therapies (outside a clinical trial) and gram (FDA, 2014c). The main distinction is that who are to accept possible greater risks. expanded access users (patients and physicians) • May provide patients with a measure of auton- are not required to provide information about the omy in their health-care decisions. safety or effectiveness of the drug. In addition, to • This use of a new drug can help bridge the gap authorize the expanded access use, the FDA must between the latter stages of product develop- determine that the patient has a serious or life- ment and approval by making a drug widely threatening disease or condition and that no other available during that gap period. comparable or satisfactory therapeutic options • Expanded access use of an investigational agent are available. Moreover, the FDA cannot compel may help foster development of additional uses a drug manufacturer or marketer to provide ex- of a drug (e.g., from anecdotal evidence of ben- panded access to its drug, which is voluntary on efit in a disease other than that being studied). the part of a company (FDA, 2014c).

Clinicians must be careful not to provide a Steps to Obtaining a Drug via the Expanded sense of false hope that a particular patient may be Access Program able to receive further treatment via the expanded Clinicians must take certain steps to obtain a access program. The drug manufacturer and the drug via the expanded access program. First, he patient’s physician must make special arrange- or she should ensure that the manufacturer of the ments to obtain the drug for the patient. Clinicians unapproved drug is willing to provide the drug. If also need to make patients aware that drug com- the manufacturer agrees to provide the drug, the panies are not required to make their drug avail- clinician should submit an IND application to the able through the expanded access program or to appropriate review division. In an emergency sit- make more of a drug for that purpose (FDA, 2013). uation, the request to use the drug may be made

21 REVIEW METHOTREXATE AND FLUOROURACIL TOXICITIES

Collaborative Exchange: via telephone or other rapid means of communi- The Expanded Access Program cation, and authorization to ship and use the drug may be given by the FDA official over the tele- Wendy Vogel: Both health-care professionals phone. This process is referred to as an emergen- and patients should have a clear understand- cy IND application. In a nonemergency situation, ing of the expanded access program. Inter- a written request for individual patient use of an estingly, after our panel discussion at the first investigational drug must be received by the FDA JADPRO Live meeting in January 2014, I went before shipment of and treatment with the drug back to my practice and questioned what may begin (FDA, 2014c). protocols we had in place regarding drugs To obtain the drug, clinicians also must submit a that were only available through the expand- brief clinical history of the patient, including the died access program. And at this point, we agnosis, the disease status, prior therapy, response to have protocols in place to access the expand- prior therapy, and rationale for requesting the pro- ed access program. Dr. Campen, can you proposed treatment along with a list of available thera- vide more detail on what the expanded ac- peutic options that would ordinarily be tried before cess program entails? the investigational drug. In addition, clinicians must provide a proposed treatment plan describing the Christopher Campen: The program is guided dose, route, planned duration, monitoring proce- by the FDA with the cooperation of the vari- dures, and modifications for toxicity (e.g., dose re- ous drug manufacturers. The manufacturers duction or treatment delay; FDA, 2014c). have to agree to use their particular drug as part of the expanded access program and to THE BENEFITS AND BARRIERS OF supply the drug specifically to the patient. COLLABORATIVE PRACTICE Because prevention of and monitoring for How can patients access these drugs with methotrexate-based and 5-FU–based toxicities the assistance of health-care professionals? can be challenging, increasing numbers of health- care professionals are employing collaborative in- There are many groups we have to work terprofessional approaches to nurture improved through, and that’s why having contact num- patient outcomes. Aggressive monitoring and bers readily available is so critical. Remember, prompt intervention by clinicians can promote we are requesting this drug for emergency drug excretion, minimize many adverse effects, use, so time is key. It is important to have the and allow patients to receive subsequent treat- contact number for your IRB, a contact num- ment as appropriate. ber for working with the FDA, a contact num- Team-based care has been promoted as one ber for the drug company to get it all ap- essential component for meeting the supply and proved. There is also a reimbursement issue. demand work-force imbalance, as well as a crucial These drugs are not usually reimbursable by element to improving health-care delivery (Grein- insurance companies, so the drug manufacturer & Knebel, 2003). As most advanced practitio- ers may charge for the cost of manufacturing ners well know, team-based care in oncology takes the drug to cover their costs. many forms, such as inpatient care management teams or interprofessional disease-oriented care How quickly can a drug be obtained? programs (Hinkel et al., 2010). Both ASCO and the NCCN have embraced the benefits of interprofessional collaborative Since the drug has to be available and used practice. The ASCO Workforce Strategic Plan within 96 hours, there is basically a 24-hour recommends educating all oncologists about turnaround in these cases. It can be requested collaborative practice, including increasing for emergency use and available very quickly, awareness and acceptance of the role of ad- within 24 hours. vanced practitioners in oncology practice (Ba-

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CASE STUDIES: COLLABORATIVE els, and do frequent checks now of renal func- PRACTICE IN ACTION tion and methotrexate levels. The panel presented several case studies as Dr. Vose: At what point would this patient a platform for discussion of the considerations, be a candidate for glucarpidase? challenges, and interconnected roles of oncolo- Dr. Campen: At this point, based on the gists, nurse practitioners, physician assistants, and methotrexate levels, potentially yes, and she clinical pharmacists in safely managing patients likely would be a candidate for glucarpidase. through potentially life-threatening scenarios. Dr. Vose: I think if you’ve optimized every- thing we just talked about, and the patient is Case 1: High-Dose Methotrexate for a still not getting better, that would be the time Primary Central Nervous System Lymphoma you want to jump on that. The sooner you do A 44-year-old woman has been diagnosed that, the sooner the patient is going to get bet- with a primary CNS lymphoma. She is start- ter, and you can prevent the problems with renal ed on a course of high-dose methotrexate failure that can be going on for a longer time. (4 g/m2). Within 24 hours, she reports nau- Dr. Campen: Exactly. So the longer you sea and vomiting. Her serum creatinine level have high systemic levels of methotrexate, the has climbed from 0.7 mg/dL at baseline to higher the risk you have for other toxicities 4.6 mg/dL. She is also found to be hyperkale- such as neurotoxicity, severe myelosuppres- mic (serum potassium level, 5.5 mEq/L). sion, and severe systemic effects. With meth- Given the suspicion of hyperacute renal otrexate, it’s basically 90% renally eliminated, dysfunction, the panel considered that stop- so it is important that renal function always ping the infusion immediately would be the be taken into consideration. That is where the first step in the action plan. excretion and eventual elimination of the drug Ms. Vogel: I would stop the infusion as are. What would you do for follow-up and fu- soon as possible. ture treatment? Dr. Vose: Yes, stop the infusion. That would Dr. Vose: You would have to see what be good. Also the patient needs more hydra- happens with each individual patient. Some- tion. She is already getting lots of hydration, times, in a younger patient, additive therapy but obviously not enough. will completely reverse the problem, and the Ms. Vogel: What about adding leucovorin? patient will return to normal renal function. Dr. Vose: The patient should have already However, in older patients, they hardly ever been on leucovorin, but we want to make sure return to baseline, and you have to rethink we are seeing what the methotrexate level is, your treatment and possibly modify the dose so that will be the first thing we want to do: in the future. Obviously, if the patient has re- make sure the patient has alkaline urine and nal dysfunction that remains, you cannot use adequate hydration. What are some other high-dose methotrexate, so you will have to considerations that you can think of? closely monitor the patient with regard to flu- Ms. Vogel: You might consult a nephrologist. id status, renal function, and electrolyte levels. Dr. Vose: Absolutely. Anyone who has renal Thus, you may or may not be able to continue failure like that and this type of hypokalemia, methotrexate therapy in the future depending you are going to have to see the nephrologist on what happens. right away for possible emergency dialysis. Dr. Campen: I agree with Dr. Vose. It’s op- timizing leucovorin at that point, making sure Case 2: 5-FU for Rectal Carcinoma that you switch over to IV leucovorin from A 57-year-old man has been diagnosed oral, because with oral, you can only reach with rectal carcinoma. He is started on neoad- such high doses before you have decreased juvant chemotherapy, which includes continu- absorption of leucovorin. So it is important to ous 5-FU IV infusion (1,000 mg/m2 per day on optimize IV leucovorin, assess hydration lev- days 1–5) during the first and fifth weeks of

23 REVIEW METHOTREXATE AND FLUOROURACIL TOXICITIES

therapy. Although the patient is generally in before did not want to go back on 5-FU after good health (no history of cardiac disease), he experiencing such a toxic reaction to the drug. has some severe symptoms when he returns Ms. Vogel: We’ve had a few patients who on day 5 of his initial 5-FU therapy. He re- did go back on it, and we would rechallenge ports a sore mouth (oral mucositis), difficulty at 20%. That’s not a 20% dose reduction, but breathing, skin rash (erythematous), diarrhea, a 20% dose. and extreme fatigue. The patient is admitted to Dr. Campen: Yes, that’s a very good point, the hospital for hydration and supportive care. because you can monitor levels of the drug Routine laboratory tests reveal significant neu- with 5-FU. tropenia without fever (absolute neutrophil Dr. Vose: What if the patient had been count [ANC], 400 cells/µL); hemoglobin, 11.1 treated with capecitabine? g/dL; BUN, 56 mg/dL; and serum creatinine, Dr. Campen: Great question. There are no 2.4 mg/dL. criteria for approval included in the current The panel agreed that the first steps in this compassionate use protocol. So in the case of case would be to stop the 5-FU, hospitalize the a capecitabine overdose, the patient could be patient, and institute immediate supportive treated under a single patient IND. This would care measures. require medical monitor approval from the drug Ms. Vogel: So now what do you do? Should company under emergency compassionate use. uridine triacetate be a consideration? Dr. Campen: Yes, for this patient, uridine triacetate should be considered. This is very Case 3: 5-FU as Part of a Regimen for early toxicity associated with 5-FU to see by Metastatic Adenocarcinoma of the Colon the end of the infusion on day 5. JW is a 73-year-old man diagnosed with Ms. Vogel: As for his other concerns, we stage IV adenocarcinoma of the colon with me- are looking for mucositis and treating it cor- tastases to the lungs and liver. At diagnosis, his rectly. If this patient did have an infection, we medical history consisted of type 2 diabetes would certainly want to treat that. We also (controlled) and osteoarthritis. Tumor genetics want to manage the diarrhea and may need revealed mutant KRAS disease. Treatment was higher doses of loperamide. initiated with mFOLFOX6 (5-FU, leucovorin, Dr. Campen: Those are great points. As for and oxaliplatin) + bevacizumab (oxaliplatin, the initial management, you definitely want to 85 mg/m2; 5-FU, 400 mg/m2; leucovorin, 400 get the patient stabilized. For many years, uri- mg/m2; and bevacizumab, 5 mg/kg followed dine triacetate wasn’t available, so we would by a continuous infusion of 5-FU 1,200 mg/ basically stabilize and deal with the dehydra- m2/day for 2 days) to be administered every tion that is present with significant diarrhea. 14 days. The patient reported no adverse ef- Ms. Vogel: So, step one is stop the infu- fects during treatment in the infusion center sion, and step two is to initiate your protocol and was discharged from the clinic. for getting this drug. On day 2, after the first infusion, the pa- Ms. Vogel: Perfect. And this actually is a tient attempted to shovel snow from the drive- patient who we could consider doing DPD de- way after a brief snowstorm. While shoveling ficiency testing on because of this early onset snow, he experienced pressure in his chest and of severe symptoms. What do you think about subsequently called 911. Upon admission to the rechallenging this patient with 5-FU after hospital, the 5-FU pump was disconnected, and some sort of toxicity like this? an electrocardiogram (ECG) identified ischemia Dr. Campen: In many patients, it depends with ST elevation. Cardiac evaluation was nega- on whether there is a DPD deficiency. Likely, we tive for myocardial infarction. The symptoms re- would try to avoid rechallenge because of the solved approximately 4 hours after discontinua- early onset of toxicity. Many patients I’ve seen tion of 5-FU.

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The patient was discharged with follow-up Dr. Vose: What steps should we take upon for a stress test 1 week later, which was normal. resumption of 5-FU in a patient such as JW? The patient was counseled on the risks of effort Dr. Campen: In many cases, ischemia oc- myocardial ischemia related to 5-FU treatment curs with reintroduction of 5-FU, which ne- and was continued on treatment with mFOL- cessitates the discontinuation or modification FOX6 with bevacizumab. Follow-up ECG was of treatment. performed with the next treatment of 5-FU Ms. Vogel: It is a challenge for us regarding and was normal for any changes. Throughout reintroduction or discontinuation of 5-FU. We subsequent courses, there was no indication could have to remove patients from receiving of cardiac symptoms during treatment. 5-FU, even in potentially curative settings, be- Dr. Campen: We know cardiotoxicity asso- cause of the cardiotoxic effects. ciated with 5-FU treatment is a relatively in- Dr. Campen: Unfortunately, complete che- frequent but serious adverse effect that may motherapy plan changes may be required with be life-threatening. The clinical presentation the removal of 5-FU. In many cases, this re- is variable, ranging from myocardial ischemia sults in suboptimal treatment efficacy, given both at rest and with effort, to cardiac arrhyth- the high therapeutic benefit of 5-FU in these mia, left ventricular dysfunction, and myocar- solid tumors. dial infarction (Lestuzzi et al., 2014; Polk, Vis- Dr. Vose: We know the method of delivery tisen, Vaage-Nilsen, & Nielsen, 2014). should be taken into consideration as a pos- Ms. Vogel: In such a case, it would be wise sible cause of cardiotoxicity and as a guide to to have knowledge of the patient’s cardiovas- moving forward with treatment. cular history. Dr. Campen: Good point. It has been de- Dr. Campen: Yes, that would be an impor- scribed that continuous infusion of 5-FU is more tant step, especially with a patient such as JW. likely to be associated with a higher cardiotoxic- It has been reported that the presence of cor- ity risk than bolus injection. So this is a point for onary artery disease may worsen the clinical consideration in how best to move forward. presentation of disease (Lestuzzi et al., 2014). Dr. Vose: But we should keep in mind that Ms. Vogel: What about the presence of the level of toxicity associated with a bolus noncardiovascular risk factors? dose of drug can also be quite significant. Dr. Campen: As far as we know, no patient- Dr. Campen: That's definitely another im- associated risk factor has been proven to in- portant consideration. In some cases, bolus crease the risk of 5-FU–induced cardiotoxicity. 5-FU can be administered instead of contin- Ms. Vogel: So, what do you think was the uous infusion. But that may not be optimal, reason for cardiotoxicity in this patient? due to decreased general efficacy and wors- Dr. Campen: On initial response, that ened tolerability. would be difficult to determine. It appears Dr. Vose: What about the use of that there are multiple mechanisms responsi- capecitabine or other management options? ble for 5-FU cardiotoxicity. The incidence var- Dr. Campen: Capecitabine is not a likely ies widely across reports but is generally ac- alternative to infusional 5-FU due to the con- cepted as approximately 10% (Polk, Vistisen, tinuous 5-FU exposure. The addition of cal- Vaage-Nilsen, & Nielsen, 2014). Variability in cium channel blockers and nitrates has been reported incidence is likely due to subclinical reported to be beneficial, but I don’t believe it ECG changes or arrhythmia, in addition to the has been well studied (Ambrosy, Kunz, Fisher, infusion duration. & Witteles, 2012).

25 REVIEW METHOTREXATE AND FLUOROURACIL TOXICITIES

jorin & Hanley, 2011; Towle et al., 2011). To this end, ASCO offers multidisciplinary cancer man- PREVENTING AND MANAGING agement courses in academic and community TOXICITIES RELATED TO settings for physicians, nurses, and pathologists METHOTREXATE AND 5-FU and has worked with both the Oncology Nurs- ing Society (ONS) and the American Academy of • Despite the common use of methotrex- Physician Assistants (AAPA) to address the edu- ate and 5-FU, many patients receiving cational needs of the oncology care community these drugs may develop severe and po- in the value of collaboration. tentially life-threatening side effects. As for the NCCN, its alliance of leading cancer centers pioneered the concept of the interpro- • These serious adverse drug effects re- fessional team approach to patient care (NCCN, quire proper prevention, early recogni- 2015), and those familiar with its tumor-specific tion of the signs and symptoms of drug guidelines are aware of the repeated mention of toxicity, and prompt treatment through the role of collaborative practice in cancer care. the collaborative efforts of oncologists, Furthermore, a 2003 Institute of Medicine report nurse practitioners, and clinical pharma- recommended that all health-care professionals cists to ensure optimal outcomes with be educated to deliver care in collaborative mod- minimal morbidity. els (Greiner & Knebel, 2003). Although there are numerous benefits to pro- • Protocols should be in place for all staff moting and implementing collaborative oncol- to use with high-dose methotrexate to ogy practice initiatives, there are remaining issues help prevent and manage toxicities. and barriers to implementation. The education of oncology nurses, physician assistants (PAs), and • Calculation double-checks with 5-FU pharmacists varies greatly, and overlapping and continuous pumps should be performed complementary roles have not been addressed. In 100% of the time. addition, most programs for oncology advanced practice nurses (APNs), including nurse practitio- • High-dose methotrexate toxicity can be ners (NPs) and clinical nurse specialists, as well effectively treated with glucarpidase, an as PA programs have little oncology content. Ad- enzyme that rapidly and thoroughly re- ditionally, licensing and regulation of APN and PA duces toxic methotrexate plasma levels. practice vary from state to state. Administrators, managers, and clinicians must • An antidote to acute severe 5-FU tox- work to differentiate and delineate roles designed icity exists through expanded access to maximize productivity in patient-care services availability of uridine triacetate, and suc- and in the development of effective communica- cessful intervention requires prompt at- tion strategies among team members to reduce tention by the care delivery team to ob- duplication and establish effective collaborative tain and administer the drug. practice models (Coniglio, 2013). It is vital that all oncology collaborative practice team members engage in ongoing self-examination and deter- the counter, and supplements, to identify potential mine how all team members may best contribute drug interactions with chemotherapy agents. In ad- to deliver high-quality and cost-efficient patient dition, oncology pharmacists may collaborate with care (Mitchell et al., 2012). physicians regarding dosing changes and contrib- Clinical pharmacists have key roles as well, ute important clinical details to therapy protocols. such as ensuring the accuracy of all drug calcula- For instance, oncology pharmacists have collabo- tions and assuring the safety of inpatient and ambu- rated with oncologists to decrease the potential for latory infusion pumps. The pharmacist can review drug-drug reactions in patients with lymphoma re- all patient medications, including prescription, over ceiving methotrexate (Ranchon et al., 2011).

26 METHOTREXATE AND FLUOROURACIL TOXICITIES REVIEW

Advanced practice nurses—NPs and clinical with physicians to monitor and manage patients nurse specialists—and PAs are instrumental in with methotrexate-induced toxicities (Nowicki educating patients, families, and other care pro- et al., 2008). viders involved with particular patients about In today’s oncology practice, the roles of PAs, treatment regimens, potential adverse effects APNs, and oncology pharmacists are expanding to and manifestations, and management strate- settings such as wellness clinics, survivorship and gies. For instance, advanced practitioners should long-term follow-up clinics, breast health clinics, teach and reinforce the importance of patient pain and palliative care services, and other sub- monitoring to staff, clinic, and infusion nurses. specialty areas within cancer care (Hinkel et al., For a patient receiving high-dose methotrex- 2010). In one instance, a regional Canadian cancer ate, this would include serum drug levels, uri- network successfully implemented a program that nary output and urine pH, and serum creatinine. promotes increased interprofessional collabora- Nurses must promptly recognize symptoms sug- tion among nurses, physicians, pharmacists, and gestive of toxicity, understand the importance of other health-care providers such as nutritionists adequate hydration, and administer medications and social workers on cancer teams (Tremblay as directed. There are published reports of how et al., 2010). oncology clinic nurses successfully collaborate CONCLUSION Collaborative Exchange: The Benefits of There is often a delicate balance between the Collaborative Practice benefits and side effects of treatments—one that requires keen attention and clinical knowledge by Wendy Vogel: I think teamwork entails us- all members of the health-care team, particularly ing absolutely every member of the team the advanced practitioner. Clearly, patients cannot and every member of the board. We are all obtain the short- or long-term benefits of treat- working together from the standpoint of ment if they experience dose-limiting, unmanage- the physician, the advanced practitioner, able, or intolerable adverse effects of therapies. and the nurse at the bedside. It’s all part of The roundtable discussion on preventing and the team process. treating methotrexate and 5-FU toxicities held at the JADPRO Live at APSHO 2014 educational Jule Vose: Yes, I agree that we all have to symposium not only offered clinical strategies but work as a team. For example, one member collaborative practice ones as well. Featuring an of the team might notice some small issue oncologist, an advanced practitioner, and a clini- such as mucositis, perhaps, whereas for an- cal oncology pharmacist, the roundtable discus- other member of the team, it may not be sion provided a clear example of how collabora- so obvious. This is how collaborative prac- tion actually works, particularly with regard to tice begins. What is vital is passing it on preventing and managing toxicities associated and sharing this information with other with the administration of high-dose methotrex- members of the team. ate or 5-FU. In addition, the panel demonstrated the continued importance of increasing and en- Christopher Campen: Another important hancing interprofessional collaborative practice example is communication among the to maximize the quality of care given to patients team for future cycles, for potential dose with cancer, whether the goal of therapy is cura- adjustment, especially with methotrexate. tive or palliative.

What you have said, Chris, is very impor- References tant, especially as we now use electronic Agha, R., Kinahan, K., Bennett, C. L., & Lacouture, M. E. (2007). medical records. Sometimes necessary in- Dermatologic challenges in cancer patients and survivors. Oncology (Williston Park), 21, 1462–1472. formation doesn’t get passed along. Ahmed, Y. A. A. R., & Hasan, Y. (2012). Prevention and management of high-dose methotrexate toxicity. Journal of Cancer

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Access to investiga- Retrieved from http://www.nccn.org/professionals/phys tional drugs outside of a clinical trial. Retrieved from www. ician_gls/pdf/nhl.pdf. fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ Newton, H. B. (2012). Neurological complications of chemo- AccesstoInvestigationalDrugs/ucm176098.htm. therapy to the central nervous system. Handbook of Clinical US Food and Drug Administration. (2014c). Physician request Neurology, 105, 903–916. http://dx.doi.org/10.1016/B978-0- for an individual patient IND under expanded access for 444-53502-3.00031-8 non-emergency or emergency use. Retrieved from www. Nowicki, T. S., Bjornard, K., Kudlowitz, D., Sandoval, C., & Jaya- fda.gov/ Drugs/DevelopmentApprovalProcess/HowDrug- bose, S. (2008). Early recognition of renal toxicity of high- sareDevelopedandApproved/ApprovalApplications/Inves dose methotrexate therapy: A case report. 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dose methotrexate. Clinical Journal of Oncology Nursing, Widemann, B. C., Schwartz, S., Jayaprakash, N., Christensen, 13, 177–180. http://dx.doi.org/10.1188/09.CJON.177-180 R., Pui, C. H., Chauhan, N.,…Howard, S. C. (2014). Efficacy Widemann, B. C., & Adamson, P. C. (2006). Understanding of glucarpidase (carboxypeptidase g2) in patients with and managing methotrexate nephrotoxicity. Oncologist, acute kidney injury after high-dose methotrexate therapy. 11, 694–703. Pharmacotherapy, 34, 427–439. http://dx.doi.org/10.1002/ Widemann, B. C., Balis, F. M., Kempf-Bielack, B., Pratt, C. B., phar.1360 Ferrari, S., Bacci, G.,... Adamson, P. C. (2004). High-dose Yarris, J. P., & Hunter, A. J. (2003). Roy Hertz, M. D. (1909-2002): methotrexate-induced nephrotoxicity in patients with The cure of choriocarcinoma and its impact on the develop- osteosarcoma. Cancer, 100, 2222–2232. ment of chemotherapy for cancer. Gynecologic Oncology, 89, Widemann, B. C., Balis, F. M., Kim, A., Boron, M., Jayaprakash, 193–198. N., Shalabi, A.,…Adamson, P. C. (2010). Glucarpidase, Zhang, W., Zhang, Q., Tian, X., Zhao, H., Lu, W., Zhen, J., & Niu, leucovorin, and thymidine for high-dose methotrexate- X. (2015). Population pharmacokinetics of high-dose meth- induced renal dysfunction: Clinical and pharmacologic otrexate after IV administration in Chinese osteosarcoma factors affecting outcome. Journal of Clinical Oncology, 28, patients from a single institution. Chinese Medical Journal, 3979–3986. http://dx.doi.org/10.1200/JCO.2009.25.4540 128, 111–118. http://dx.doi.org/10.4103/0366-6999.147829

This supplement provides 1 1 CREDIT/CONTACT HOUR

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QUESTIONS ANSWERED ABOUT GLUCARPIDASE

QQ.What is glucarpidase (Voraxaze)? AA. It is a carboxypeptidase enzyme indicated for the treatment of toxic plasma methotrexate concentrations (> 1 µmol/L) in patients with delayed methotrexate clearance due to impaired renal function. It is administered as a single IV injection of 50 U/kg.

QQ.Who might benefit from glucarpidase? AA. Patients who are experiencing delayed methotrexate clearance may benefit from glucarpidase therapy. QQ.Should leucovorin rescue be continued with the administration of glucarpidase? AA. Leucovorin therapy should continue after glucarpidase is administered. However, leucovorin should be given 2 hours before or 2 hours after administration of glucarpidase. QQ.For how long should leucovorin therapy be continued after the administration of glucarpidase? AA. Therapy with leucovorin should be continued until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. Hydration and alkalinization of the urine should be continued as indicated.

QQ.What are the side effects associated with glucarpidase therapy? AA. Serious allergic reactions, including anaphylactic reactions, may occur with glucarpidase. The most common adverse reactions (incidence > 1%) are paresthesias, flushing, nausea and/ or vomiting, hypotension, and headache.

QQ.How is glucarpidase supplied? AA. It is supplied as a sterile, preservative-free, white lyophilized powder in single-use vials. Each vial contains 1,000 U of glucarpidase, lactose monohydrate (10 mg), Tris-HCl (0.6 mg), and zinc acetate dihydrate (0.002 mg).

QQ.How quickly does glucarpidase start to work? AA. Clinical trials have shown the effectiveness of glucarpidase to begin as early as 15 minutes after administration (BTG International Inc., 2013).

QQ.How long is glucarpidase effective? AA. One clinical trial showed that patients achieved more than a 95% reduction in methotrexate concentrations for up to 8 days following the initial injection of glucarpidase (BTG Interna- tional Inc., 2013).

QQ.What should patients know about glucarpidase therapy? AA. Patients should be informed that allergic reactions, including potentially serious reactions, may occur during treatment with glucarpidase. In addition, they should immediately report any signs and symptoms of infusion reactions (such as fever, chills, flushing, rash, hives, itching, throat tightness or breathing problems, tingling, numbness, or headache). Patients should be aware that after completion of glucarpidase therapy and discharge from the hospital, they may continue to be monitored for methotrexate blood concentrations and renal status.

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QUESTIONS ANSWERED ABOUT URIDINE TRIACETATE

QQ.What is uridine triacetate? AA. It is an investigational, orally active prodrug of uridine currently under development as an antidote to overexposure of 5-FU. Although not yet approved by the FDA, it has been shown to be effective in treating patients in emergency 5-FU overdose settings (Bamat et al., 2010; Bamatet al., 2013; McEvilly, Popelas, & Tremmel, 2011) and is available in the United States under the expanded access program.

QQ.Who might benefit from uridine triacetate? AA. The primary group of patients that benefit from uridine triacetate are those who have excess toxicity due to an overdose of 5-FU. This could be related to the dose or an incorrect infusion administration rate. Patients who have experienced early-onset toxicity from high doses of 5-FU (within 2 to 3 days of infusion) or impaired elimination may be candidates for immediate treatment with uridine triacetate. Patients with known or suspected overexposure to 5-FU as a result of DPD deficiency also may be candidates for treatment with uridine triacetate.

QQ.When should uridine triacetate be given? AA. It seems that the earlier uridine triacetate is given after 5-FU overexposure the better. However, it appears to be of benefit in patients who experience early-onset toxicities (e.g., severe mucositis, fever, diarrhea, and rash) 2 or 3 days after their 5-FU infusion.

QQ.What is the expanded access program? AA. The expanded access program is a means by which manufacturers make investigational new drugs available, under certain circumstances, to treat patients with a serious disease or condition for which there is no comparable or satisfactory alternative therapy outside of a clinical trial. In such cases, the potential benefit justifies the potential risks of treatment.

QQ.How is uridine triacetate obtained via the expanded access program? AA. A patient’s physician and the drug manufacturer make special arrangements to obtain the drug for the patient. In an emergency situation, the physician can request the drug via telephone or other rapid means of communication, and authorization to ship and use the drug may be given by an FDA official over the telephone. In addition, the physician must submit a brief clinical history of the patient, including the diagnosis, the disease status, prior therapy, response to prior therapy, and the rationale for requesting the proposed treatment. Signed informed consent by the patient is also necessary.

QQ.How long does it take to get uridine triacetate once requested? AA. In emergency situations, the drug is delivered rapidly, generally the day requested or within the next 24 hours.

QQ.Are there cost considerations associated with obtaining and using uridine triacetate? AA. Costs may include the manufacturer’s cost of preparing the drug and the institution’s cost of administering the drug. The cost associated with the use of uridine triacetate may be re- imbursed by some health insurers but not all. As for physicians, the cost to provide access to this drug may not be fully compensated, there may be liability issues, and participation requires commitment (contacting the drug manufacturer and filing paperwork).